The Selfish Brain: Competition For Energy Resources

Neuroscience and Biobehavioral Reviews 28 (2004) 143–180
www.elsevier.com/locate/neubiorev
Review
The selfish brain: competition for energy resources

A. Petersa,*, U. Schweigerb, L. Pellerine, C. Hubolda, K.M. Oltmannsb,
M. Conradc, B. Schultesa, J. Bornd, H.L. Fehma
a
Department of Internal Medicine, University of Luebeck, Ratzeburger Allee 160, D-23538 Germany
b
Psychiatry and Psychotherapy, University of Luebeck, Ratzeburger Allee 160, D-23538 Germany
c
Institute of Mathematics, University of Luebeck, Ratzeburger Allee 160, D-23538 Germany
d
Institute of Neuroendocrinology, University of Luebeck, Ratzeburger Allee 160, D-23538 Germany
e
Institut de Physiologie, Universite de Lausanne, 7 Rue du Bugnon, 1005 Lausanne, Switzerland
Received 1 December 2003; revised 12 March 2004; accepted 17 March 2004
Abstract
The brain occupies a special hierarchical position in the organism. It is separated from the general circulation by the blood-brain barrier,
has high energy consumption and a low energy storage capacity, uses only specific substrates, and it can record information from the
peripheral organs and control them. Here we present a new paradigm for the regulation of energy supply within the organism. The brain gives
priority to regulating its own adenosine triphosphate (ATP) concentration. In that postulate, the peripheral energy supply is only of secondary
importance. The brain has two possibilities to ensure its energy supply: allocation or intake of nutrients. The term ‘allocation’ refers to the
allocation of energy resources between the brain and the periphery. Neocortex and the limbic-hypothalamus-pituitary – adrenal (LHPA)
system control the allocation and intake. In order to keep the energy concentrations constant, the following mechanisms are available to the
brain: (1) high and low-affinity ATP-sensitive potassium channels measure the ATP concentration in neurons of the neocortex and generate a
‘glutamate command’ signal. This signal affects the brain ATP concentration by locally (via astrocytes) stimulating glucose uptake across the
blood-brain barrier and by systemically (via the LHPA system) inhibiting glucose uptake into the muscular and adipose tissue. (2) High-
affinity mineralocorticoid and low-affinity glucocorticoid receptors determine the state of balance, i.e. the setpoint, of the LHPA system. This
setpoint can permanently and pathologically be displaced by extreme stress situations (chronic metabolic and psychological stress,
traumatization, etc.), by starvation, exercise, infectious diseases, hormones, drugs, substances of abuse, or chemicals disrupting the endocrine
system. Disorders in the ‘energy on demand’ process or the LHPA-system can influence the allocation of energy and in so doing alter the
body mass of the organism. In summary, the presented model includes a newly discovered ‘principle of balance’ of how pairs of high and
low-affinity receptors can originate setpoints in biological systems. In this ‘Selfish Brain Theory’, the neocortex and limbic system play a
central role in the pathogenesis of diseases such as anorexia nervosa and obesity.
q 2004 Elsevier Ltd. All rights reserved.
Keywords: ATP, adenosine triphosphate; KATP, ATP-sensitive potassium channels; Naþ/Kþ-ATPase, sodium potassium dependent adenosine triphosphatase;
BBB, blood–brain barrier; LHPA, limbic-hypothalamus-pituitary –adrenal; SNS, sympathetic nervous system; MR, mineralocorticoid receptors; GR,
glucocorticoid receptors; VMH, ventromedial hypothalamus; PVN, paraventricular nucleus; LH, lateral hypothalamus; ARC, arcuate nucleus; CRH,
corticotropin-releasing hormone; ACTH, adrenocorticotropin; POMC, pro-opiomelanocortin; a-MSH, a-melanocyte-stimulating hormone; MC,
melanocortin; NPY, neuropeptide Y; GABA, g-amino-butyric acid; BDNF, brain-derived neurotrophic factor; NMDA, N-methyl-D -aspartate; AMPA,
amino-3-hydroxy-5-methyl-4-isoxazol propionate; LTP, long-term potentiation; LTD, long-term depression; CREB, cAMP responsive element binding
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
2. Physiological glucose regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
2.1. Setpoints in the brain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
2.1.1. Setpoint of brain ATP regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
2.1.2. Setpoint of limbic-hypothalamic-pituitary – adrenal system regulation . . . . . . . . . . . . . . . . . . . . . . . . . 152
2.1.3. Homeostasis: brain ATP and the LHPA system in balance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
* Corresponding author. Tel.: þ 49-451-500-3546; fax: þ49-451-500-4807.

E-mail address: achim.peters@uni-luebeck.de (A. Peters).
0149-7634/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.neubiorev.2004.03.002
144 A. Peters et al. / Neuroscience and Biobehavioral Reviews 28 (2004) 143–180
2.2. Load of the brain-supplying regulatory system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155

2.2.1. Malnutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
2.2.2. Psychological stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
2.3. Sleep and the consolidation of setpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
2.3.1. Stressors and the limbic system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
2.3.2. Stress reactions and the limbic system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
2.3.3. Memory formation during sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
3. Pathological glucose regulation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
3.1. Hypoglycemia unawareness (type 1 diabetes mellitus). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
3.2. Anorexia nervosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
3.3. Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
3.4. Type 2 diabetes mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172
4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
1. Introduction transportation mechanisms across the blood – brain barrier

[2,3]. Thus, the transfer of substrates and hormones into the
How does the human organism control its energy supply? brain is very strictly controlled. The capacity of the brain to
The answer to this question is the key to treating many store energy is extremely limited, but maintenance of the
diseases: obesity and the so-called metabolic syndrome with energy supply to the brain is of prime importance to the
diabetes mellitus, hyperlipoproteinemia, hypertension and survival of the whole organism. It is not therefore
cardiovascular diseases belonging to these disorders. surprising that the energy content immediately available
Gynecological diseases including polycystic ovaries or to the brain, i.e. in the form of adenosine triphosphate
psychiatric disorders such as depression or eating disorders (ATP), is strictly regulated within extremely narrow
are also associated with disrupted regulation of energy boundaries. The brain is almost exclusively dependent on
supplies. Two different processes can be distinguished that the metabolization of glucose. As such, selection of
regulate energy metabolism: energy supply (appetite, intake substrates by the brain is highly specific, while peripheral
of foods) and allocation (assignment). The various organs of organs (muscle) can metabolize glucose, fat or proteins.
the body must compete for the allocation of a limited Fatty acids can not traverse the blood –brain barrier. Only
number of energy resources. in special situations, such as with hypo or hypernutrition,
The brain occupies a special position amongst all the does the organism produce significant amounts of alterna-
organs concerning energy metabolism. It is the central tive substrates such as ketones or lactate that can traverse
organ for regulating energy supply, and it is able to receive the blood – brain barrier and assume a role in supplying
information about the peripheral organs via peripheral energy to the brain. Finally, the brain is able to memorize
(e.g. hepatic) sensors and their afferent neuronal pathways. information about its control actions and their subsequent
Conversely, it can also control the functions of many effects, and to learn from the outcomes. It can use its
peripheral organs, e.g. the skeletal musculature, the heart, plasticity to optimize its control behavior.
the gastrointestinal tract or the sexual organs, via its Overall, therefore, the unique position of the brain is
efferent nerve pathways. It is probable that this control is characterized by
not just restricted to physical movements and the function
of many inner organs, but that it also includes the 1. its physical barrier properties,
regulation of energy metabolism. The neuronal discharge 2. its high energy consumption,
and release of neurotransmitters and neuropeptides requires 3. its low energy storage capacity,
exceptionally large amounts of energy [1]. The energy 4. its substrate specificity,
consumption of the brain, related to its small proportion of 5. its plasticity, and
the entire body mass, is much larger than the energy 6. its ability to record information from and to control
consumption of all other organs (e.g. muscle). The peripheral organs.
proportion of energy consumed by the human brain
exceeds the proportion found in all other known species. In order to account for the idiosyncrasies of the brain’s
This fact may be relevant for the origin of characteristics energy supply and to establish the meaning of these for the
and disorders of metabolism found primarily in humans, entire organism, we propose here a new paradigm for the
e.g. obesity. The brain is separated from the general regulation of energy supply in the organism:
circulation by the blood –brain barrier. Specific substrates
(such as glucose and lactate) or hormonal signals (such as † The brain prioritizes adjustment of its own ATP
insulin or leptin) are transported exclusively by specific concentration. For this reason it activates its stress
A. Peters et al. / Neuroscience and Biobehavioral Reviews 28 (2004) 143–180 145
system and in so doing competes for energy resources ‘leptin resistance’. Such a leptin resistance is found both as
with the rest of the organism (allocation). an inherited phenomenon with monogenetic defects [9,10]
† The brain then alters the appetite (food intake) so that it can and as an acquired phenomenon after overfeeding [11].
alleviate the stress system and return it to a state of rest. A large number of neurotransmitters, neuropeptides and
their receptors that mediate the leptin effect in the brain, e.g.
With these two postulates, the brain simultaneously anorexigens such as ‘Melanocyte Stimulating Hormone’
represents the highest regulatory authority and the consumer (a-MSH), have been studied in detail over the last few years
with the highest priority. The brain looks after itself first. [12]. The phenomenon of leptin resistance has as such been
Such selfishness is reminiscent of an earlier concept in which well described, but its origin has so far escaped explanation.
the brain’s selfishness was addressed with respect to The glucostatic and the lipostatic theories have explicitly
addiction [4]. We chose our title by analogy but applied it or implicitly provided the basis for a large number of
in a different context, i.e. the competition for energy research strategies and therapeutic interventions for diabetes
resources. During stress and times of shortage it safeguards mellitus, obesity and other diseases. Against this, however,
its own supply even at the expense of all the other organs. The a range of observations have accumulated that can not be
brain’s obligation to alleviate its stress system in a second satisfactorily explained by these views and research
step and allow it to return to a state of rest is not trivial. From a approaches:
regulatory-theoretic standpoint we presume that the stress
system is adjusted around a so-called setpoint at which it is at † If healthy people are advised in a study to overeat
a state of rest. In the second step the brain therefore pursues considerably over a period of months, they do increase
the objective of satisfying its own energetic needs and those substantially in weight during this time, but within a few
of the entire organism on a long-term basis in the most months they can return again to their initial body weight
economic way possible. The regulation of the mass of the [13]. Clinical experience on the other hand shows that
various body compartments such as the adipose tissue is then although many people show good body mass regulation at
considered to be a secondary objective with this paradigm. the start of their life, in later life (e.g. in the third decade),
According to traditional paradigms the brain regulates their body mass increases. If these people then attempt to
body mass by changing the intake of foods. Maintenance of reduce their body weight by dieting, the ‘yo-yo’ effect
blood glucose within narrow limits is also of key importance then sets in, and one gets the impression that body weight
for maintaining health. The ‘lipostatic’ theory was orig- is regulated at a new, raised virtual setpoint [14].
inally formulated by Kennedy 1953 [5]. Jeffrey Friedman Phenomena such as the yo-yo effect show that the system
and coworkers of the New York Rockefeller University of body mass regulation is more complex than previously
supported this view in 1994 with their ground-breaking assumed. If only a simple defect within the regulatory
finding of the hormone leptin [6]. With leptin, a hormone system for weight regulation exists, such persons should
was discovered in fat and muscle tissue that sends a be able to return to and maintain their initial body weight
feedback signal to the brain so that the brain is informed with their normal nutrition after a diet. However, the body
about the status quo of peripherally stored energy. Most mass often exceeds the previous maximum. The fact that
researchers considered this to be a closed regulatory system only few people succeed in reaching and maintaining their
in which the absorption of nutrients is the regulator, body initial body weight means that the traditional view that
mass is the controlled parameter, and leptin is the feedback changes can be found within the assumed closed loop of
signal. Notably, before leptin was discovered, the research the body mass regulatory system (e.g. single or multiple
team of Stephen Woods and Daniel Porte at the University gene mutations) is too simple.
of Washington, Seattle, presented compelling evidence for † The study of metabolic, endocrine and behavioral
insulin being an adiposity signal [7,8]. With the ‘gluco- phenomena in repeated hypoglycemia has shown that
static’ theory, blood glucose is considered to be the the brain has mechanisms for protecting its functionality
regulated parameter in the center of the regulatory system actively within certain limits despite the existence of
and it is assumed that endocrine changes (for example very variable blood glucose concentrations. The energy
insulin, glucagon, growth hormone, and cortisol) and supply of the brain therefore represents more than just a
behavioral changes are mainly responsible for maintaining by-product of the energy supply of the whole organism.
the concentration of blood glucose within narrow limits. † If the energy supply of the brain is threatened, lipostatic
The implicit assumption that an adequate energy supply to signals do not play any significant role in behavioral
the brain automatically results from the constant behavior of regulation: ravenous hunger with hypoglycemia occurs
the fat reserves and the blood glucose is common to both the independently of the adipose tissue mass of the organism.
glucostatic and the lipostatic theory. Another common † Traditional treatment concepts of type 2 diabetes mellitus
feature is the assumption that with obesity a defect can be are derived from the glucostatic theory and aim at
traced to the closed feedback loop. It can indeed be shown normalization of blood glucose concentrations. The
that with most overweight people leptin is not able to restrict United Kingdom Prospective Diabetes Study showed
the intake of foods. This phenomenon has been termed that ‘tight’ blood glucose control results in a reduction in
the risk of microvascular but not of macrovascular diseases the fundamental mechanisms of lipostasis or glucostasis
[15]. No effects on the overall mortality were observed. As have not yet been observed until now. These observations
side effects of such concepts using hypoglycemic agents or cast doubt on the priority of lipostatic signals in particular.
insulin, undersupply of the brain (recurrent neurogluco- † Despite intense research and the outstanding methodology
penic comas) or oversupply of fat stores (body mass gain) that is now available, genetic defects have been able to
occurred [15]. Peter G. Kopelman from the Bartholo- explain only a small proportion of obesity and diabetes
mew’s and the Royal London School of Medicine cases up until now. The observed obesity epidemic
commented in the editorial that the ‘inevitable rise in throughout the entire industrialized world illustrates this
glycosylated HBA1c witnessed throughout the study [17,18]. The fact that people of a similar genetic
period, despite strict glycemic control, emphasizes the background under defined environmental conditions
need for a better understanding of the pathogenesis of type remain of normal weight or develop excessive overweight
2 diabetes in susceptible individuals’ [16]. early on, however (e.g. Nauruans or Pima Indians) [19],
† Traumatization and psychiatric conditions such as supports a significant role of genetic factors. The
depressive or eating disorders lead to modifications in traditional view fails to consider that a disorder might
the stress hormone system and various central transmitter also lie outside the feedback system for weight regulation,
systems. They can also lead to considerable increases e.g. in a higher-ranking regulatory system providing it with
and also reductions in body fat, even where defects in commands.
Fig. 1. The ‘Fishbone Model’ of glucose metabolism. The cerebral cortex sends a ‘glutamate cinnabd’ signal to the subordinate regulatory subsystems: 1. the
allocation sybsystem assigns glucose via the glucose transporter 1 (GLUT1) to the brain, and via GLUT4 to the muscle and adipose tissue (yellow arrow).
2. The appetite regulatory subsystem controls the total amount of glucose available for allocation (red arrow). The energy content of the brain and peripheral
tissues is measured with multiple sensors. The limbic-hypothalamic-pituitary-adrenal (LHPA) system, which includes the sympathetic nervous system, plays a
decisive role in allocating glucose. The activity of the LHPA-system is indicated by the serum cortisol concentration. Feedback signals on the energy status in
the brain (glucose), the peripheral organs (leptin), and on the activity of the LHPA system (cortisol) act on the various hierarchical levels of the system, i.e. the
cerebral cortex, the limbic system and the hypothalamic sites for allocation (ventromedial hypothalamus) and intake (lateral hypothalamus) of foods.
† Cortical balance. If the brain-ATP is too low, the glutamate command signal is stimulated in the cerebral cortex via high-affinity ATP-sensitive potassium
channels; if the brain-ATP is too high, it is suppressed via low-affinity ATP-sensitive potassium (KATP) channels. In this way the system strives for a balance
whereby the opposing effects of high-affinity and low-affinity KATP channels are of the same magnitude.
† Limbic balance. If the serum cortisol is too low, the LHPA system is stimulated via high-affinity brain mineralocorticoid receptors (MR); if the serum
cortisol is too high, it is suppressed via low-affinity brain glucocorticoid receptors (GR). Here, the LHPA system strives to achieve a balance whereby the
stimulating and suppressing feedback signals are of the same magnitude.
† Allocation. If the energy content is too great in the muscle and adipose tissue, leptin activates the ventromedial hypothalamus (VMH) that allocates glucose
to the brain; if the energy content of the brain is too large, the brain ATP suppresses the VMH, so that glucose is allocated more to the musculature and adipose
tissue. Thus, the allocation-subsystem strives for a balance whereby the feedback signals from the brain and the periphery are of the same magnitude.
† Appetite. If the energy content is too low in peripheral tissues, the appetite stimulating lateral hypothalamus (LH) is activated via NPY; if the
energy content is too large in the periphery, the LH is inhibited via a-MSH. The NPY- and a-MSH-signals are filtered in the arcuate nucleus (ARC)
and conveyed only under certain circumstances to the LH. The key feedback-signal for regulating the intake of foods is brain glucose.
If the stimulatory and inhibitory feedback-signals in the cerebral cortex, in the LHPA system, and in the hypothalamus are balanced, the organism
achieves a state of energetic homeostasis. Coordinates indicate positions in the model that are referred to in the text.
While most research continues to focus on crucial distinguished differences in the timing of their feedback
hypothalamic circuits, a small group of scientists have signals, however, in principle they transmit redundant
already broken new ground, since recent work has clearly messages. The stimulatory insulin feedback pathway can be
shown that ingestive behavior is influenced by a widely integrated into the fishbone model without changing its
distributed neural network, which includes the caudal fundamental structure. Only the degree of redundancy, and not
brainstem, limbic and cortical structures [20 –22]. the relevancy of the model, is changed through such additions.
The paradigm proposed by us places the regulation of Is the model too complex or explicit?
ATP-concentration in the brain at the focal point. The brain We have in fact refrained from including a large number
initially adjusts its own ATP-concentration by burdening its of biological mechanisms that might also fulfill functions in
own stress system and competing for energy resources the model. A list of various possible redundant signals was
within the body. The brain changes eating behavior so that it presented in an earlier manuscript [23]. However, we decided
can then alleviate the stress system and return it to a state of to assign only a single functional mechanism and a single
balance. The regulatory principles of this paradigm have anatomical structure to a single signal pathway in the model.
been formulated mathematically as a dynamic system and Leptin acts for example as a ‘substitute’ for a class of signals
graphically illustrated in the form of a so-called ‘fishbone that contains insulin amongst other elements, and which can
model’ [23] (an overview is given in Fig. 1, more details are fulfill all the functions described in the model. We are aware
explained in chapter 2). that there might be a better selection for such a substitute, and
Readers and authors are faced with a dilemma regarding that in the future hormones might be discovered that fulfill
the needs of simplicity and complexity, i.e. between merely a this function better and so have a greater biological relevance
suggestive and an explicit representation of specific than the ones mentioned here. This may likewise account for
mechanisms. The fishbone model has a simple but not a the selection of brain structures referred to in this paper. The
trivial structure: it represents a hierarchically organized limbic system and the hippocampus for example are
system with a forward pathway (similar to the spine of a fish) extremely complex structures per se, supporting many
and multiple paired stimulatory and inhibitory feedback other specific functions not relevant here, and of course,
pathways (the fishbones). Flow charts of complicated control those relevant here may in part be fulfilled by other redundant
systems can be simplified by mathematical transformations structures. We are also aware that the assignments proposed
[24]. The most simple model for allocating energy resources here might be the subject of some debate, but we feel that the
to 2 organs, e.g. to the brain and muscle, has a ‘fishbone’ like specificities of the model presented are less important than
structure. Such a special model structure is suitable for the general basic principle proposed here for energy
dealing with different levels of complexity. metabolism. We followed the advice that ‘everything should
Is the model oversimplified or too abstract? be made as simple as possible, but not simpler’ [27].
One point of view might be that important hormones The newly presented theory regarding the regulation of
(e.g. resistin, ghrelin) escape mention here so that the true energy supply is only valid within a certain scope. For
complexity of energy metabolism is not delved into. We example, many experiments that are cited here in support of the
reviewed the literature and indeed often found two or more model have only been carried out under special experimental
biological mechanisms for each individual component in the conditions in in-vitro or in animal studies, but have not yet been
mathematical model. As such there appears to be much confirmed in humans. Also, many studies in humans cited here
redundancy in glucose regulation. Redundant signal pathways have only been performed in men but not in women. Several
can be added to the fishbone model (new fishbones) without hypotheses can be derived from the presented model. In the
changing the basic model structure. The activation of the future, testing of such hypotheses shall allow a redefinition of
sympathetic nervous system is mediated by leptin and insulin the scope within which the theory is valid, whether it be
as well. In the model, the hormone leptin conveys a signal to broadened or narrowed. In this review article we would like to
the brain that energy has been stored in peripheral organs, apply the ‘selfish brain theory’ to offer new explanations for
particularly in the adipose tissue, and is not therefore available phenomena which until now have escaped clarification.
at that time as a substrate for the brain. Correspondingly, leptin
conveys a signal to certain hypothalamic neurons [25] and in
this way invokes an increase in sympathetic nervous system 2. Physiological glucose regulation
activity and thereby an increased allocation of glucose to the
brain. Insulin sends a similar signal analogous to this. Insulin 2.1. Setpoints in the brain
in the same way informs the brain that glucose is stored and
unavailable for supplying the brain. Correspondingly, insulin 2.1.1. Setpoint of brain ATP regulation
can influence the same hypothalamic neurons in the same
manner [26], so that the sympathetic nervous system is 2.1.1.1. Measurement with two receptors. How does the
stimulated and the appropriation of glucose by the brain is brain maintain ATP constant at a specific concentration?
ensured. This example shows that leptin and insulin transmit To answer this we propose a principle whereby the brain
related or similar signals to the brain. There may be controls this concentration using high-affinity and low-affinity
ATP-sensitive potassium channels. ATP-sensitive potassium occupied. There are KATP channels in the entire cortex
channels (KATP) belong to a special class of ion channels that [33,43 – 47], where they are localized both presynaptically
couple bioenergetic metabolism to membrane-excitability and postsynaptically [48]. In some brain areas presynaptic
[28]. KATP is present not only at neurons and neuroendocrine KATP channels reduce the liberation of g-amino-butyric acid
cells, but also on many other cell types, such as those of (GABA): e.g. in the hippocampus [49] and in the substantia
skeletal and smooth muscle [29,30]. These KATP channels are nigra [50 – 53]. It is worthy of note that both low-affinity and
closed by intracellular ATP. While the energy-rich ATP high-affinity ATP-sensitive potassium channels have been
closes these potassium channels, the low-energy adenosine found in human neocortex [54]. Although it has not been
diphosphate (ADP) can open the ATP-sensitive potassium confirmed in any single experiment, we do presume from
channels. For this reason the intracellular ratio of ATP to ADP current data that in human neocortex there are also
is a key regulator for the functional state of the ATP-sensitive presynaptic, low-affinity ATP-sensitive potassium channels
potassium channel. ATP and ADP bind to specific parts of the that reduce the GABAergic tone. This assumption is also
KATP channel: at the ‘nucleotide binding domain’ of the so- supported by the clinical observation that with progressive
called sulfonylurea receptor (SUR), that together with the energy deficiency in the brain there is initially an excitatory
actual channel pores forms a single morphological unit [31]. stage with a raised seizure tendency, followed by a calming
The SUR protein belongs to the ‘ATP binding cassette (ABC) of the cortex. These findings are consistent with a
family’ [32]. The KATP channel therefore represents a presynaptically mediated GABAergic tone, which with a
membranous, molecular structure that fulfills the regulat- slight energy deficit can be reversed via low-affinity
ory-theoretic criteria of an ‘energy sensor’ (or more simply an ATP-sensitive potassium channels [53].
‘ATP sensor’). If one assumes that the high-affinity ATP-sensitive
If one provides an excitatory neuron with sufficient energy potassium channels are located on excitatory neurons, while
reserves, i.e. a high intracellular ATP to ADP ratio, these the low-affinity ATP-sensitive potassium channels are
membranous KATP channels are closed. With closed KATP localized on inhibitory neurons, this distribution pattern
channels a potassium efflux from the cell is prevented via this leads to the following dynamic behavior: with critically
ion channel, which enables depolarization. Calcium flows reduced ATP both the excitatory and inhibitory neuron
into the cell interior. The neuron releases neurotransmitter populations are functionally inactive. This phenomenon has
(such as the excitatory amino acid glutamate) or neuropep- been described as a ‘global silencing’ of the cerebral cortex
tides (such as the neurotrophin ‘brain-derived neurotrophic [55]; its clinical correlate is the ‘hypoglycemic’, or better said
factor’; BDNF) from its nerve endings. If the energy content the ‘neuroglucopenic’ coma. With low, but non-critical ATP-
of the neuron is high enough, the KATP channels allow a content in both neuronal populations, ATP binds almost
neuronal excitation. If on the other hand a fall in intracellular exclusively to the high-affinity ATP-sensitive potassium
ATP content occurs, the KATP channels are opened, the channels, i.e. to those on the excitatory neurons that release
neuron is hyperpolarized (and thereby electrically stabilized), glutamate. Contrastingly, with high cerebral ATP concen-
and its function is deactivated. The KATP channels therefore trations the inhibitory neurons also become active, i.e. those
also have a cytoprotective function: with energy deficiency that exert an inhibitory effect on the excitatory population. All
the function of the cell is turned off and the residual energy is in all, a biphasic activity pattern results for the excitatory
saved for structural maintenance of the cell [33–35]. neuronal population that depends on intracellular ATP
Interestingly enough, there are two different types of KATP content (Fig. 3a). Of decisive importance is the fact that the
channels: those with high-affinity and low-affinity ATP- balance between excitatory and inhibitory neuronal popu-
binding sites. These ATP-binding properties allow them to be lations changes depending on brain ATP concentration. At
assigned to two subtypes, i.e. SUR1 and SUR2 [36–39]. With low brain ATP concentrations the glutamatergic population is
low intracellular ATP content the high-affinity ATP-sensitive dominantly active, while at high ATP concentrations the
potassium channels are mainly occupied, and are closed as a activity of the GABA ergic population predominates.
result. These high-affinity ATP-sensitive potassium channels An effective regulatory system for brain ATP can be
are found in the cortex and in many other brain areas on described with the following overall principle:
excitatory neurons [40,41]. Such neurons are able to be
electrically active with a low ATP content. However, if the
ATP-concentration declines to a very low and thereby critical 1. ATP binds to high- and low-affinity ATP-sensitive
concentration for survival of the neuron, these high-affinity potassium channels.
ATP-sensitive potassium channels no longer bind adequately. 2. Bound high affinity ATP-sensitive potassium
The corresponding KATP channels are then opened and the channels permit glutamatergic neuronal activity,
cell function is deactivated. The high-affinity ATP-sensitive while bound low-affinity ATP-sensitive potassium
potassium channels in the neocortex play an essential role in channels permit GABA-ergic activity.
protecting against seizures and neuronal damage [42]. 3. Glutamatergic neurons raise brain ATP, while
In contrast, with high intracellular ATP content the low- GABA-ergic neurons lower it.
affinity ATP-sensitive potassium channels are also
Up to now we have demonstrated the first and the second (Naþ/Kþ-ATPase) [59]. Glutamate is converted into
rule. In the next chapter we shall explain the third rule and glutamine which is released by astrocytes and taken up by
how the glutamate command signal promotes an increase in the neuronal terminal. There it is enzymatically converted
the brain’s energy content. These three simple rules again into glutamate so that the neuronal glutamate pool is
regarding the interplay between ATP, the two different refilled again. There is no ATP exchange between astrocytes
affinity ATP-sensitive potassium channels and the glutama- and neurons, so that each cell type must secure its own
tergic and GABAergic neuronal populations describe energy supply.
a secure regulatory system that balances the brain ATP The end-feet of the astrocytes are equipped with specific
around a certain concentration. This concentration can be transporter molecules, i.e. glucose transporter 1 (GLUT1),
described as a ‘balance setpoint’ for brain ATP. and enclose practically all the capillary walls within the
brain. A close morphological and cytological relationship
2.1.1.2. Astrocytic ‘energy on demand’. The brain can exists between astrocytes and cerebral capillaries. In this
supply itself by requesting energy firstly from the body way the preconditions for a functional coupling between
periphery and secondly from the environment. For this synaptic activity and glucose uptake are fulfilled: glutamate
purpose the brain must invest considerable expense, e.g. activates its glutamate transporter and stimulates glucose
activate its stress systems or acquire new food resources in uptake into astrocytes [60,61]. Glucose is broken down in
order to actually procure the requested amount of energy. If this process to lactate, which is then released and
there is not an adequate food supply (such as during times of made available as an energy source for neighboring neurons
starvation), the brain has no other possibility but to compete [62,63]. The energy that arises during the glycolytic
for energy resources within the organism. breakdown of glucose to lactate is used in the astrocytes
How does the brain compete with the body for energy to support the activity of the Naþ/Kþ-ATPase and to
resources? convert glutamate into glutamine [59], while in the neuron
The brain controls the allocation of glucose between the lactate utilization will be employed for closing the
brain on the one hand and the musculature and adipose postsynaptic KATP channels and for excitation [64]. This
tissue on the other. In order to allocate glucose to itself, the cascade of molecular events represents a direct mechanism
brain must open the blood – brain barrier for glucose and cut for the coupling between synaptic glutamate release and
off the supply to peripheral tissues. glucose allocation to the neuron via the blood –brain barrier
As mentioned above, it is the glutamatergic neuronal and the astrocytes.
population that activates the allocation of glucose to the
brain. Although all neurons independently of the type of 2.1.1.3. Systemic ‘energy resource request’. How can the
neurotransmitter released (glutamate or GABA) use energy, brain prevent glucose uptake into muscle and adipose
it has only been verified for the glutamatergic population tissue?
that they also serve for energy replenishment [56]. Peripheral glucose uptake can be restricted through
GABAergic neurons on the other hand do not mediate any activation of the limbic-hypothalamic-pituitary – adrenal
such allocation of glucose to the brain [57], but instead (LHPA) system. The LHPA system is a neuroendocrine
inhibit the glutamatergic neurons with the help of their system closely associated with stress in mammals [65]. This
transmitters and only consume energy. system allows a rapid reaction to stressful stimuli and
Which molecular mechanisms can glutamate utilize to ultimately guarantees a return to homeostasis via complex
enhance energy substrate availability for parenchymal feedback mechanisms. Hierarchically, the limbic system
cells? therefore represents the highest authority in the control of
The astrocyte, a specific type of glial cell, plays a key stress reactions. In the limbic system there are two core
role in allocating glucose across the blood – brain barrier. regions that carry out this control: the hippocampus and the
The principle ‘energy on demand’ has been used to describe amygdala. These limbic neurons project with axons directly
the (local) response of astrocytes to glutamatergic activity in or via the VMH into the paraventricular nucleus (PVN).
order to provide lactate to active neurons as an energy Here, the sympathetic nervous system is activated and
substrate [56]. Glutamate that is freed at the synapse upon neuropeptides are formed and released such as cortico-
excitation is rapidly removed again to allow subsequent tropin-releasing-hormone (CRH) and vasopressin. These
transmission events. Astrocytes enclose most glutamatergic releasing hormones stimulate adrenocorticotropin (ACTH)
synapses and collect released glutamate with a highly release into the general blood circulation within the
efficient and specific transporter system. Transporters are pituitary. ACTH ultimately stimulates the release of cortisol
driven by the electrochemical sodium gradient, a fact that from the adrenal cortex. The sympathetic nervous system
leads to a tight coupling between glutamate and sodium projects with its efferent nerve pathways to the adrenal
uptake [58]. The astrocyte is now confronted with two tasks: medulla where it stimulates the liberation of adrenaline. The
the recovery of glutamate and the restoration of the sodium sympathetic system also innervates the pancreatic b cells
gradient. The gradient is restored by the activation of the [66] where it suppresses insulin release [67 – 69], as well as
sodium- and potassium-dependent adenosine triphosphatase the musculature and adipose tissue where it suppresses
the uptake of glucose [70 –72]. In this way, the LHPA anatomical site to the functional component ‘appetite’ in
system can increase the glucose concentration in the blood. the model.
In the limbic system, energy needs, in addition to Glutamate is a potent stimulus that stimulates neurons in
activating the ‘energy on demand’ signal (local), also trigger the LH to increase appetite and initiate food intake [78,79].
a systemically effective ‘energy resource request’ signal The LH, however, is under the direct influence of the limbic
(for the whole brain), with glutamate being the mediator in system. Upon cortical excitation, multiple locally effective
both cases. In addition to that direct limbic mechanism ‘glutamate command’ signals from cortical neurons are
requesting energy (internal sensing or detector area), other integrated within the limbic system. The limbic system
parts of the cortex will also signal their needs to the limbic functions as a transducer between this integrated glutamate
system. Thus, the limbic system might act both as a detector command signal and setpoints of subordinate hypothalamic
and transducer of global brain energy needs. systems: one setpoint signal is conveyed via neuronal
What effects do cortical glutamatergic neurons have on pathways to the VMH (allocation), and another is conveyed
limbic neurons? to the LH (appetite). The limbic system transduces the
Patricia Molina and coworkers of the Louisiana State signals to the VMH and the LH differently. While the signal
University in New Orleans were able to show recently that to the VMH is adapted under certain conditions, i.e.
primarily glutamate receptors of the NMDA subtype amplified or suppressed [80,81], the signal to the LH is
mediate the activation of the LHPA system with brain rather robust and less altered. As an example, recurrent
glucose deficiency [73]. The NMDA receptor plays a key hypoglycemia leads to attenuation of VMH-mediated
role for the pyramidal cells of the limbic system and has a counter-regulation (e.g. adrenaline, glucagon)[82], but not
function not only for setting the tone of the LHPA system, to an attenuation of hunger (LH) [83]. The limbic system
but also in memory formation (see the chapter ‘memory also coordinates the order in which the VMH or LH are
formation during sleep’). The stimulation of other subtypes activated. The VMH mobilizes glucose for the brain within
of glutamate receptors also brings about a strong activation seconds, but an activation of the LH only leads after a delay
of the LHPA system [74,75]. The above-mentioned team (and only with sufficient food intake) to an increase in
also succeeded in establishing a link between cortical glucose supply to the brain. The limbic system therefore
glutamatergic activity and the activation of stress systems. conveys the ‘energy resource request’ signal first to
It is well known that stress systems can restrict the the VMH, whereas the LH is inhibited by this signal [84].
allocation of glucose to muscle and adipose tissue. In If the output to the VMH is weak, the appetite controlling
summary, cortical glutamatergic neuronal populations are LH is disinhibited. The allocation controlling VMH is
apparently able to adjust the allocation of glucose to the therefore ranked higher than the appetite controlling LH,
brain by favoring glucose utilization in brain while whereby these two components have reciprocal functions
impeding it in muscle and adipose tissue. [85 –87].
The cerebral cortex sends the ‘glutamate command’ The activated neurons of the LH also provide ‘orexi-
signal to both of its regulatory subsystems that control genic’ (i.e. appetite increasing) neuropeptides via
glucose allocation and appetite. Energy supply for the brain projections to different parts of the brain [88]. These
results from the activity of the two regulatory subsystems. orexigen-secreting neurons increase the drive for feeding
Brain ATP binds to low- and high-affinity ATP-sensitive and ultimately also have an influence on complex
potassium channels as a feedback signal. High-affinity behavioral patterns (e.g. purchasing behavior for foodstuffs)
ATP-sensitive potassium channels increase the cortical related to feeding.
glutamatergic tone and in so doing the glutamate command Fig. 2a summarizes the command principle once again:
signal. Low-affinity ATP-sensitive potassium channels cortical glutamatergic neuronal populations release gluta-
increase the cortical GABAergic tone and in so doing mate upon excitation. On the one hand the glutamate
suppress the glutamate command signal. In this way the command signal triggers an astrocytic ‘energy on demand’
primary regulatory system strives for a cortical balance process. On the other hand the glutamate command signals
between glutamatergic and GABAergic neuronal activity at input into the limbic system, where they are transduced into
which the ATP concentrations are optimal. ‘energy resource request’ signals. These setpoint signals are
How does the brain request energy resources from the conveyed to the subordinated hypothalamus. Here the VMH
environment? (allocation) and the LH (appetite) are stimulated. The VMH
The LH is a key region of the brain that controls appetite increases the proportion of circulating glucose to be
and eating behavior [76]. Feeding and fasting is not simply assigned to the brain, while the LH strives to increase the
controlled by a hypothalamic center, but rather by quite a total amount of circulating glucose. Allocation and food
large network of neurons located at many different sites supply therefore determine the proportion of glucose that is
(thalamus, subcortical nuclei, hypothalamus, brainstem, and assigned to the brain. The amount of glucose available to the
medulla). Signals originating in the LH appear to reach brain influences the amount of ATP available to it. With low
other brain sites by first descending to the parabrachial ATP in the brain the high-affinity ATP-sensitive potassium
nucleus [77]. Here, we assign the LH as one representative channels are closed for the most part (i.e. those channels
enabling the stimulation of glutamatergic neuronal popu- in ensuring that the LHPA system returns to homeostasis. In
lations), and these demand further energy. If the brain ATP fact, three years later the group showed in vivo that
on the other hand is high, the low-affinity ATP-sensitive peripheral injection of a larger dose of a glucocorticoid
potassium channels are also closed, and the GABAergic reduced hippocampal firing activity [90].
neuronal population decreases the brain’s energy demand. Pyramidal cells in the hippocampus and the amygdala
In this way a regulatory system results that resembles the express both MR as well as GR receptors [91]. One known
principle of supply and demand in a free market economy, function of these limbic MR and GR receptors is to modify
and which is able to regulate brain ATP around a specific memory storage and retrieval [92,93]. Both receptors are
balance setpoint. formed in the cell nucleus and are then released into the
cytosol of the neuron. Cortisol traverses the external cell
2.1.2. Setpoint of limbic-hypothalamic-pituitary –adrenal membrane of the neuron without a specific transporter and
system regulation binds in the cytosol with high affinity to MR and with low
How does the brain regulate the activity of its LHPA- affinity to GR. The cortisol concentration as well as the
system? number of MR and GR present in the cytosol determine how
We propose that it regulates this with the aid of high- many cortisol molecules bind to GR and MR. Only cortisol
affinity and low-affinity brain corticosteroid receptors. Two bound MR and GR complexes can traverse the nuclear
types of corticosteroid receptors are known in the brain. membrane and reach the cell nucleus where the cortisol-
Starting in the year 1968 with the milestone paper of Bruce bound receptors form dimers with one another [94 – 96]:
McEwen at the Rockefeller University in New York [89], a MR – MR homodimers, MR – GR heterodimers and GR – GR
large number of researchers have since managed to homodimers. The homodimer MR –MR binds to a ‘gluco-
characterize the two brain receptor subtypes both biochemi- corticoid responsive element’ (GRE) in the genome. The
cally and functionally. The type I or MR in the brain other dimer-types compete with the MR –MR homodimer for
resembles the MR in the kidney and has a high specificity these GRE binding sites in the genome and inhibit its effect.
for selectively binding cortisol, the primarily active What influences do MR and GR have on the activity of
glucocorticoid in humans [65]. In the brain, the MR is the LHPA system and with that the secretion of cortisol?
localized most densely in the limbic system, i.e. in the We assume that cortisol-bound MR stimulates the LHPA
hippocampus and in the amygdala, where it binds cortisol system while cortisol-bound GR prevents this stimulation.
with high affinity. Contrastingly, the type II or GR binds This assumption is supported by a unique study in which
cortisol with a low affinity. The presence of GR receptors cortisol effects over a very broad range of cortisol
has been confirmed in many brain regions, including the concentrations were illustrated [97]. In this study patients
limbic system, the hypothalamus, and the pituitary. MR with Cushing’s disease, who had had both adrenal glands
binds cortisol with a 10-fold higher affinity than does removed completely, were infused with cortisol. During
the GR. These receptor properties allow MR and GR to infusion, serum cortisol climbed from very low concen-
regulate LHPA system activity. MR is bound with low trations continuously to very high concentrations. With low
cortisol concentrations and develops its effects mainly cortisol concentrations there was a marked increase in
during the evening nadir of the cortisol circadian profile. At ACTH secretion, while with high cortisol concentrations
high cortisol concentrations, e.g. after morning awakening there was a marked decline. This finding is consistent with an
or during a stressful incident, MR also bind cortisol, but the MR-mediated stimulation and a GR-mediated suppression
bound GR dominates in its effect and is decisively involved of the LHPA-system. In this investigation a bell-shaped
R
Fig. 2. (A) The primary regulatory system for brain ATP regulation. The cerebral cortex sends the ‘glutamate command’ signal to both of its regulatory
subsystems that control glucose allocation and appetite. Energy supply for the brain results from the activity of the two regulatory subsystems. Brain ATP binds
to low- and high-affinity ATP-sensitive potassium channels as feedback signal. High-affinity ATP-sensitive potassium channels increase the cortical
glutamatergic tone and in so doing the glutamate command signal. Low-affinity ATP-sensitive potassium channels increase the cortical GABAergic tone and in
so doing suppress the glutamate command signal. In this way the primary regulatory system strives for a cortical balance between glutamatergic and
GABAergic neuronal activity at which the ATP concentrations are optimal. (B) The LHPA system as a regulatory subsystem of brain ATP regulation. The
LHPA-system restricts the GLUT4-mediated glucose uptake into muscle and adipose tissue and with this increases the GLUT1-mediated glucose uptake into
the brain. Cortisol is the feedback-signal for the LHPA-system. Cortisol binds in the limbic system to high-affinity mineralocorticoid (MR) and low-affinity
glucocorticoid (GR) receptors. With low cortisol concentrations MR stimulate the LHPA-system, and with high cortisol concentrations GR suppress its
activity. In the hierarchically subordinate hypothalamus (PVN) only GR-receptors act inhibitorily at high cortisol concentrations. The activity of the LHPA-
system determines the allocation of glucose to the brain and the periphery. In this way the LHPA-system defines the setpoint for regulation of body mass.
(C) Leptin and its amplifier. Leptin conveys the feedback-signal regarding energy status in the adipose and muscle tissues to the hypothalamic VMH where
leptin stimulates the allocation of glucose to the brain. An amplification mechanism for leptin activity is localized in the arcuate nucleus (ARC). Here, at low
leptin concentrations, the appetite stimulating NPY is primarily produced, while at high leptin concentrations the appetite suppressing a-MSH is mainly
produced. a-MSH stimulates the allocation centre (VMH) and thereby amplifies the direct effect of leptin, while NPY on the other hand suppresses the effect of
leptin on the VMH.
dose-response relationship was shown for cortisol in humans, the circulation according to its half-life: after 2, 4, and 6 h it is
analogous with a similar relationship found by other reduced to 1/2, 1/4 and 1/8. This means that without adrenal
investigators in numerous experiments investigating the production and secretion of cortisol more than 85% of the
effects of cortisol on the excitability of neurons in the cortisol is already eliminated from the circulation after 6 h. In
hippocampus [98,99]. the cortisol circadian profile it falls continuously to a
There is a debate as to whether limbic MR act in a minimum in the evening from a morning maximum after
stimulatory or inhibitory way on the LHPA-system. awakening. However, this drop-off rate is much slower than
Pharmacological interventions with MR-inhibitors result that of the hepatic cortisol clearance. The slow reduction in
in elevated basal glucocorticoid concentrations, possibly cortisol over the day therefore requires a continuous release
suggesting an inhibitory effect of MR [100]. However, of cortisol from the adrenal gland which slows the fall in
it must be considered that with such interventions cortisol. One can see that the limbic system has to stimulate
the underlying process is not a simple ligand – receptor the hypothalamic center continuously in order to prevent a
interaction, and that ‘heterodimerization’ (see above) or the rapid reduction in serum cortisol. The stimulatory effect of
‘autoregulation’ (see below) of MR and GR can cause the limbic system must be even greater if one considers that at
paradoxical effects (as have clearly been demonstrated in hierarchically lower levels CRH, ACTH and cortisol are still
literature [101,102]). Thus, conclusions based on pharma- subject to a GR-mediated feedback-inhibition (Fig. 3b).
cological inhibition may be erroneous. Processes like We propose the following general principle to illustrate
heterodimerization and autoregulation are so-called ‘non- how the activity of the LHPA system is regulated:
linear’ [24], and it is this very nonlinear property that makes
an experimental analysis difficult, but at the same time
makes the LHPA-system particularly stable. 1. Cortisol binds with high affinity to MR and lower
Neurons of the limbic system are the starting point for the affinity to GR.
stimulation of the LHPA system. Here, MR and GR regulate 2. Cortisol bound MR and GR assemble into three
the expression and transcription of a large number of genes. forms of dimers: MR –MR, MR – GR or GR – GR.
One group of genes controls the behavior of ion channels 3. MR –MR homodimers stimulate the LHPA system
(e.g. calcium channels), a second gene group regulates and thereby cortisol secretion, while GR interferes
ligand-bound ion channels (e.g. glutamate receptor coupled with this effect.
channels) and a third group influences G protein-coupled
receptors. Ronald de Kloet and Marian Joëls at the
University of Amsterdam/Leiden, Netherlands, discovered These three simple rules regarding the interplay between
many such corticosteroid effects and described them in a cortisol, the two differing affinity receptors MR and GR and
number of comprehensive reviews [98,99]. Thus, MR has the various MR and GR homo- and heterodimers describe a
the ability to influence the excitability of limbic neurons via control system that regulates cortisol secretion around
the expression and transcription of a variety of gene a setpoint. This concentration can be designated as a
products. MR and GR modulate amongst other things balance-setpoint for the activity of the LHPA system, which
glutamate-mediated signal input [103]. in humans is usually achieved during the evening. The
Here we focus on the effects of MR and GR on reader will surely notice at this point that the regulation
limbic neurons that stimulate the hypothalamic neurons. principle underlying brain ATP regulation and LHPA
The neurons stimulate via direct or indirect neuronal system regulation is the same. It would not be surprising
pathways the hypothalamic release of CRH and vasopressin. if during evolution a reliable and simple regulatory principle
The latter release-hormones activate the formation of pro- that has proven its worth with one aspect of metabolism
opiomelanocortin (POMC) peptide in the pituitary, from should also be encountered in other areas.
which ACTH is cleaved. Pituitary ACTH is secreted and
stimulates the adrenal release of cortisol. Therefore, in this 2.1.3. Homeostasis: brain ATP and the LHPA
model MR promotes and GR inhibits the release of cortisol system in balance
via a range of intermediate steps. The hierarchical positions of brain ATP regulation and
Circulating cortisol is metabolized in the liver and LHPA regulation are different. The brain ATP regulation
eliminated with a half-life of about 120 min. The clearance has the highest biological priority. It therefore represents a
function for cortisol corresponds to an elimination of the first primary regulatory system. This primary regulatory system
order, i.e. the clearance rate of cortisol is proportional to its for brain ATP regulation operates with the glutamate
concentration. The higher the cortisol is in the serum, the command signal. This signal is conveyed to its two
higher is its hepatic elimination. ACTH has a half-life of regulatory subsystems, i.e.: (1) to the LHPA system, and
about 20 min and CRH a half-life of about 9 min. (2) to the appetite-regulating LH. The LHPA system
Individuals who no longer have adrenal glands, e.g. patients determines the allocation of glucose to the brain and the
with Addison’s disease, can no longer produce any cortisol body periphery while the LH is essential for eating behavior.
themselves; in such individuals cortisol is removed from Thus, the brain has two ways of fulfilling its demand
Fig. 3. (A) Setpoint for brain ATP regulation. The rate of change in brain ATP over time [dATP/dt] (ordinate) depends on the brain ATP itself (abscissa). High
affinity ATP-sensitive potassium channels on glutamatergic neurons are closed at low brain ATP concentrations so that the neurons can become functionally
active (green function). Low affinity ATP-sensitive potassium channels on GABAergic neurons permit functional activity only at higher brain ATP
concentrations (red function). Since the GABAergic neurons are inhibitory towards glutamatergic neurons, a reduction of glutamatergic neuron activity occurs
at higher brain ATP-concentrations (green function). Inset on the upper right: Dependency of the energy balance of glutamatergic neurons on brain ATP is
shown here: glutamatergic neurons stimulate glucose transport across the blood–brain barrier using the ‘energy on demand’ signal. These neurons require
for energy. On the one hand it can alter glucose allocation, channels are balanced. Depending on the magnitude of
i.e. the percentage of glucose transported across the blood – allocation, a food quantity arises from this relationship that
brain barrier, and on the other it can alter food intake, i.e. the the brain requires to fulfill its demand for energy.
total amount of glucose available for distribution. If There is a substantial difference between the two
sufficient energy resources are available to the organism, regulatory subsystems for allocation and food intake. The
the brain can request energy via both regulatory subsystems LHPA system that determines allocation can be burdened in
(i.e. allocation and appetite). This means that the greater the unusual crisis situations, e.g. in times of starvation, but it
allocation to the brain the less food intake is necessary or always strives to return to its resting balance. This resting
vice versa, the greater the amount of food consumed by the balance is designated as the so-called MR – GR brain
organism the less allocation to the brain is necessary. The corticosteroid balance. In Fig. 5a all the points are
reciprocal relationship between allocation and food intake represented in a second function, in which MR and GR
required to satisfy the energy needs of the brain is are balanced for the LHPA subsystem.
represented graphically in Fig. 5a. A special situation therefore occurs in which both high-
This reciprocal relationship between allocation and and low-affinity ATP-sensitive potassium channels are in
required food intake can be mathematically derived as a state of balance, i.e. whereby both the brain ATP is
follows. Glucose uptake into the brain is b [g min21 kg21] constant and the MR and GR are in a state of balance,
while m represents glucose uptake into muscle and fat meaning that the LHPA system is at a resting state.
[g min21 kg21]. The ratio between the two glucose uptake At exactly this intersection point the energy metabolism
rates is defined as allocation: is in a state of homeostasis, graphically depicted in Fig. 5a.
b If brain ATP regulation and the LHPA system are in
Allocation ¼ ð1Þ a state of balance, a certain required food intake
m
results from that. If this food intake can be realized,
If B is designated as the mass of the brain [kg] and M that of the organism can remain stable in this metabolic
the muscle/fat [kg], the required intake of foods is: equilibrium state. The body mass is, however, already
adequately set by this balance. The idea of an independent
Necessary nutrient uptake ¼ bB þ mM ð2Þ
system that regulates body mass therefore becomes
If one inserts m from Eq. (1) into Eq. (2), the following superfluous.
relationship between food intake and allocation results: Basically, this balance-setpoint represents an ideal
equilibrium state which in fact is rarely achieved. The
M organism is instead continuously exposed to stresses and the
Necessary nutrient uptake ¼ b B þ ð3Þ
Allocation nutrient supply is variable so that it must continually strive
If one assumes that the brain keeps its ATP content constant, to achieve this ideal balance state.
the variable b in Eq. (3) is regulated within very narrow
limits and kept almost constant. The mass of the brain B is a 2.2. Load of the brain-supplying regulatory system
constant parameter. Eq. (3) is represented in Fig. 5a. All
values of this function are characterized by the fact that the Loads can put stress on the brain-supplying regulatory
brain ATP concentration is held at a constant concentration, system. Does the newly proposed paradigm comply with our
whereby the high- and low-affinity ATP-sensitive potassium knowledge on how the organism reacts to these situations?
R
energy themselves for their excitation. The green function (D energy) shows how glutamatergic neurons provide energy for themselves and for GABAergic
neurons depending on the brain ATP. GABAergic neurons on the other hand are not able to promote glucose transport across the blood–brain barrier in this
way; instead they only consume energy. At low brain ATP concentrations it is the glutamatergic neurons that mobilize glucose and increase brain ATP content
that are mostly active; at high brain ATP-concentrations GABAergic neurons that only consume energy and thereby lead to a lowering of brain ATP-content
are mostly active. The setpoint for brain ATP regulation is found at the intersection point of the green and red functions (upper panel); here, the rate of change
in brain ATP is equal to zero and the regulating system is at a state of balance (lower panel). (B) Setpoint of the LHPA-system. The rate of change in cortisol
over time ½dCortisol=dt (ordinate) depends on the cortisol concentration itself (abscissa). High-affinity mineralocorticoid receptors (MR) are active at low
cortisol concentrations and stimulate the LHPA system and with that adrenal cortisol production and release. Low-affinity glucocorticoid receptors (GR) are
active only at high cortisol concentrations and inhibit the LHPA system so that adrenal cortisol production and secretion are decreased (green function). The
hepatic clearance rate of cortisol depends on the cortisol concentration itself (red function). The setpoint of the LHPA-system is found at the intersection point
between the green and red functions (upper panel); here, the rate of change of cortisol is equal to zero and the LHPA system is at a state of balance (lower
panel). (C) The leptin amplifier in the arcuate nucleus. The neuronal activity of NPY and POMC neurons in the ARC (ordinate) depends on the leptin
concentration (abscissa). Leptin inhibits the activity of NPY neurons so that at low leptin concentrations the NPY neurons are spontaneously active. Leptin
stimulates the POMC neurons so that at moderate leptin concentrations they are activated. NPY and POMC neurons are glucose responsive and feature ATP-
sensitive potassium channels that are opened at high leptin concentrations; for such reasons these neurons become deactivated at high leptin concentrations.
The ARC neurons project into the VMH. POMC neurons act inhibitorily while NPY neurons act in a stimulatory manner in the VMH. The combined output of
both neuronal populations to the VMH is illustrated in the lower panel. With low leptin concentrations the inhibitory NPY neurons predominate, at moderate
leptin concentrations the stimulatory a-MSH predominate, and at high leptin concentrations both neuronal populations are inactivated. It is worth noting that
leptin at high concentrations can no longer activate the ARC neurons, and these neurons therefore appear to be ‘leptin resistant’.
From the aspect of competition for energy resources, two part of a ranger training exercise. On the 5th day he loses
types of stress are possible: a pending energy deficiency in all his provisions through an accident. He manages to
the brain and an excessive glucose-utilizing body mass. survive the remaining 5 day journey without practically
According to the ‘selfish brain paradigm’, the brain must be any intake of foods, although during this time he loses
informed continuously about the magnitude of these two 4 kg in body mass, and arrives exhausted in the training
stressors in the form of feedback-signals. Its integrating camp before indulging in a heavy meal. In the subsequent
centers receive feedback signals for this purpose from all 2 weeks his food intake is also increased until his original
brain areas as well as from the glucose-utilizing muscle and body mass returns.
adipose tissues. The feedback signal from the brain itself is
ATP, while the feedback signal from muscle and adipose In healthy individuals the brain ATP concentration is
tissue is leptin [12]. Leptin is formed and secreted in fat strictly regulated so that a marked reduction in ATP is not to
tissue and musculature in a manner closely coupled with be expected during a 5 day fasting period [111]. Never-
the glucose uptake of these tissues [104,105]. Leptin theless, the brain is able to measure even only a tiny
conveys a signal describing the quantity of peripherally reduction in brain ATP. As already mentioned in the chapter
stored energy; it is closely correlated with body mass. From ‘balance-setpoints’, cortical high- and low-affinity
the standpoint of the new paradigm, leptin can be under- ATP-sensitive potassium channels play a decisive role.
stood as a ‘load signal’ that informs the brain of the size of With a tiny reduction in brain ATP, only the low-affinity
the metabolic stressors, i.e. the muscle and fat mass ATP-sensitive potassium channels react while the high-
competing for glucose. If this load signal is interrupted, as affinity ATP-sensitive potassium channels remain closed.
is the case with leptin receptor defects, a key stimulus is A minor activation of the low-affinity ATP-sensitive
missing for the allocation of glucose to the brain. The potassium channels reduces the GABAergic tone in the
development of db=db mice expressing a leptin receptor entire cerebral cortex. The balance between active gluta-
defect has confirmed that the brain mass in the first postnatal matergic and GABAergic neurons is displaced with a slight
weeks develops only slowly and inadequately, while the ATP deficit to the benefit of glutamatergic excitation (see
body mass increases disproportionately [106]. Leptin can Fig. 4a).
therefore be assigned as a class of cytokine due to its Glutamate is taken up by the astrocytes where it
functional and biochemical properties and can be under- stimulates glucose uptake, and this in turn is closely coupled
stood as a load signal targeted towards the brain. with the transport of glucose via the blood – brain barrier
Why is the regulatory system burdened by increasing (Fig. 4e) (model a2 – e2). GLUT1 transports glucose both
body mass? through the luminal and abluminal cell membranes of the
The more food an organism consumes, the larger cerebral endothelial cells. Activation of the glutamate
becomes the peripheral mass that must compete with the receptors has not only this rapid effect on GLUT1, but it
brain for glucose. With increasing body mass, leptin also exerts a prolonged stimulatory effect on the expression
increases as an indicator of this ‘metabolic load’. Leptin of GLUT1 mRNA [112]. Glutamate therefore facilitates the
stimulates the sympathetic nervous system in the hypo- passage of glucose across the blood – brain barrier in a
thalamus and in so doing the allocation of glucose to the number of cortical regions and can in this way correct a
brain [107 – 109]. This functional feedback between intake reduction in brain ATP partly or even completely.
of foods and glucose allocation is mediated via the feedback In parallel a glutamatergic tone in the cerebral cortex
effect of leptin (see Fig. 5b). ensures via a series of intermediary steps that the
musculature utilizes fatty acids instead of glucose. Gluta-
2.2.1. Malnutrition mate stimulates the glutamate receptor on limbic neurons
via projections that innervate the limbic system from
2.2.1.1. Metabolic stressors. In this chapter we basically various cortical regions (see Fig. 4b) [73] (model a2 –b2).
repeat the principles of the model while focusing on its According to Larry Swanson’s topographical model of
dynamic behavior. We also provide more insight into cerebral hemisphere organization, both hippocampus and
biological details by assigning one representative specific amygdala pyramidal cells contribute to triple descending
metabolic or neuroendocrine mechanism as well as one projections—with excitatory, inhibitory, and disinhibitory
specific anatomical site to each component of the fishbone components—extending to specific parts of the hypothala-
model. There are 14 components (flow-chart arrows) in Fig. 1 mus (VMH and PVN) [113]. Excitatory components include
which are referred to, e.g. as model a1 –a2 in the following the amygdala basolateral complex and the hippocampal
text. Mechanisms and neuroanatomical structures involved CA1 – 3 fields; inhibitory components include the amygdala
are explained with the help of a case study on malnutrition central nuclei and the lateral septum; and disinhibitory
oriented towards the studies of Per Opstad [110]: components include the bed nuclei stria terminalis and the
medial septal/diagonal band complex [113]. Signals from
Case 1: The 25-year old Olaf goes on a 10-day hippocampus and amygdala, which are transmitted via these
wilderness expedition to the mountains of Norway as multiple descending pathways, have been shown to affect
Fig. 4. (A) Cerebral cortex. Excitatory neurons produce the neurotransmitter glutamate and the neuropeptide brain-derived neurotrophic factor (BDNF). These
neurons project into the limbic system where they release glutamate and BNDF. They are permanently under feedback control: (1) Postsynaptic high-affinity
ATP-sensitive potassium channels are localized on these neurons. These channels are themselves closed at low glucose concentrations and ensure the functional
activity of the excitatory neurons. (2) Low affinity ATP-sensitive potassium channels are localized presynaptically on GABAergic neurons. These channels are
closed at high glucose concentrations so that the nerve endings release the inhibitory neurotransmitter GABA that inhibits the excitatory neurons. Low glucose
concentrations act permissively, and high glucose concentrations inhibitorily on the activity of cortical excitatory neurons. (B) The limbic system. Excitatory
neurons are localized in the core regions of the limbic system. These neurons project with their neuronal pathways into the ventromedial hypothalamus or into the
paraventricular nucleus. They are stimulated by cortical glutamate that binds to the membranous glutamate receptors (Glu-R). These excitatory limbic neurons
are subject to the influence of presynaptic GABAergic glucoresponsive neurons. The excitatory limbic pyramidal cells produce two important types of proteins in
their cell nucleus: Under the influence of cortisol and its two receptors MR and GR they form proteins that define the excitability of these neurons. Under the
influence of BDNF and its two receptors trkB and p75 they form so-called CREB-proteins which determine the number of membranous glutamate receptors
during the process of long-term potentiation (LTP). At low cortisol concentrations MR are primarily active and these downregulate their own synthesis. MR also
promote the synthesis of BDNF receptors (trkB). At high cortisol concentrations GR are mainly active, and these also downregulate their own production. Under
the influence of GR, BDNF-receptors (p75) are produced. BDNF stimulates via its high-affinity trkB receptors the CREB gene, while it inhibits the CREB gene via
its low-affinity BDNF receptors (p75). CREB-proteins lead to LTP and a durable alteration in the number of membranous glutamate AMPA receptors. In this way
glutamatergic transmission is subject to modulation by cortisol and BDNF, and this can be stabilized over the long-term by LTP. (C) Ventromedial hypothalamus.
Ventromedial hypothalamus-(VMH)-neurons stimulate the CRH-neurons in the paraventricular nucleus (PVN) and with that both the sympathetic nervous
system and ACTH-release from the pituitary. These excitatory VMH neurons also mediate GABAergic output to the lateral hypothalamus. Limbic neurons
stimulate VMH neurons. These excitatory VMH neurons are also subject to a dual feedback-control: At high brain-glucose concentrations, ATP-sensitive
potassium channels on presynaptic GABAergic neurons are closed, which as a result release GABA and act inhibitorily on the excitatory VMH neurons. At high
leptin concentrations the same ATP-sensitive potassium channels on the presynaptic GABAergic neurons are opened so that the neurons release less GABA and a
stimulatory effect on the excitatory VMH neurons results. a-MSH from the ARC amplifies the stimulatory effect of leptin on the excitatory VMH neurons, while
NPY from the ARC decreases the leptin effect. The neurons of the VMH measure the difference between the peripheral (leptin) and central (brain-glucose)
feedback signals and generate the VMH output from this result. (D) Lateral hypothalamus. The glucose-sensitive neurons of the lateral hypothalamus release
orexigenic peptides and in so doing stimulate food intake. The orexigenic neurons are stimulated by glutamatergic neurons and inhibited by GABAergic VMH
neurons. They are subject to feedback-inhibition by brain glucose. With high brain glucose concentrations their sodium/potassium ATPase is activated so that
these neurons become hyperpolarized and stop releasing orexigens. In addition, neuropeptides from the ARC also exert a modulatory influence. In energetic
homeostasis, however, the stimulatory influence of NPY and the inhibitory influence of a-MSH are at a state of balance. (E) The blood–brain barrier and the cell
membranes of muscle/adipose tissue. Glucose is transported by glucose transporter 1 (GLUT1) across the blood–brain barrier. Neuronal glutamate is taken up by
the astrocytes and stimulates glucose uptake across the blood– brain barrier. Glucose is transported by the insulin-sensitive GLUT4 across the membranes of
muscle and fat cells. The sympathetic nervous system regulates glucose uptake into muscle and adipose tissue by inhibiting pancreatic b-cells, thereby limiting
the insulin-receptor (IR) mediated glucose uptake into peripheral tissues. Both neuronal glutamate release and activation of the sympathetic nervous system lead
to an allocation of glucose to the brain, whereby both processes restrict peripheral glucose uptake. (F) Arcuate nucleus. The glucose-responsive neurons of the
arcuate nucleus produce POMC and NPY. Both neuronal populations project into the VMH and the LH. In these two core regions the POMC neurons release
a-MSH and the NPY neurons NPY. In the ARC, leptin binds to the leptin receptor (LR), thereby stimulating the POMC-neurons, and inhibiting the NPY-neurons.
In addition, leptin directly accesses the VMH. At very high leptin concentrations the ATP-sensitive potassium channels which are localized on both ARC-neuron
types are opened so that these neurons become hyperpolarized and deactivated.
Fig. 4 (continued )
Fig. 4 (continued )
the hypothalamus-pituitary – adrenal system [114 – 116] During the first day of fasting, serum leptin concentration
(model b2 – c2). Hippocampal stimulation or microinjec- lowers drastically due to the reduced allocation of glucose to
tions have been shown to activate both VMH neurons [117] adipose and muscular tissue [140]. During this phase the liver
and PVN neurons [118 – 121] (see Fig. 4c). A subsequent forms ketone bodies from free fatty acids. Since the brain can
rise was observed in the hormones ACTH, corticosterone, metabolize these ketone bodies as an alternative substrate,
epinephrine, norepinephrine [121 – 123] and in the substrates the loading of the regulatory system for glucose allocation is
blood glucose and lactate [122,124]. We want to emphasize alleviated (Fig. 5b). The decrease in body mass on the other
that although these structures and functions are understood hand occurs far more slowly than does the leptin reduction.
as potential candidates they do not represent the absolute and At the end of the fasting period Olaf had lost approx. 4 kg in
final mechanisms. In summary, glutamatergic cortical mass. His brain at the end of the fasting period therefore had
signals can activate limbic structures that enhance to compete with a reduced glucose-utilizing organ mass. This
hypothalamic neuronal activity, and in so doing request entails a certain disburdening for the regulatory system
and mobilize circulating fuels. which is already burdened by a threatening state of ATP
A minor reduction in ATP opens the KATP channels in deficiency in the brain. In Fig. 5b the characteristics for low
the presynaptic VMH-neurons so that the VMH neurons are body mass and additional ketone formation are graphically
not just stimulated by the limbic system, but they are also illustrated, and they lie below the normal characteristic. The
locally disinhibited. These hypothalamic KATP channels body mass M is included into the calculation of this
belong to the network of hierarchically organized ATP characteristic according to Eq. (3). This means that with a
sensors that maintain glucose homeostasis [125 – 128]. small body mass M; less glucose allocation suffices in order
The VMH governs glucose allocation by limiting to supply the brain with adequate energy for the same intake
peripheral glucose uptake (model c2 – e2). Local or systemic of foods. On the 5th day of fasting the brain’s energy supply
glucoprivation increases signal output from the VMH [129, remains critical, but the competition between brain and
130]. VMH neurons project towards the PVN, where they periphery has shifted somewhat to the benefit of the brain.
can stimulate CRH and vasopressin release [131,132]. At
the same time, GABA- and BDNF-containing neurons are 2.2.1.2. Replenishment. During fasting, the glutamate
activated in the VMH [133,134] which project to the LH and command signal acts on the appetite controlling LH (Fig.
inhibit appetite. Both a release of ACTH from the pituitary 4d) (model a2 – d2). It is beyond question that on the 5th day
and cortisol from the adrenal gland as well as a stimulation of fasting Olaf in case 1 suffered an extreme feeling of
of the sympathetic nervous system coincide with the hunger. Upon intake of food a large amount of glucose is
stimulation of PVN neurons. The sympathetic nervous then available for allocation to the brain and the periphery.
system innervates the pancreatic b cells [66,135] where the After a few minutes the raised substrate supply results in
stimulation of a2-adrenergic receptors suppresses the more glucose reaching the brain across the blood – brain
secretion of insulin [68,69], and antagonizes insulin effects barrier. The brain ATP increases further during food intake
on muscle and adipose tissue [70]. As a result, less glucose until the setpoint is achieved for ATP (model a3 – a2). The
transporter 4 (GLUT4) is translocated onto the cell KATP channels on the GABAergic cortical neurons are
membranes of muscle and adipose tissue (Fig. 4e). The closed and the GABA-ergic tone increases. Glutamatergic
sympathetic nervous system also innervates the musculature and GABA-ergic activity return to a state of equilibrium,
where it can open KATP channels, and this also decreases the and the ‘glutamate command’ signal normalizes. The
insulin-mediated glucose uptake [136,137]. Since GLUT4 is energy supply to the brain returns to an optimal state.
the main glucose transporter for these peripheral tissues, a Only in the next step is the allocation of glucose to the
decreased peripheral glucose uptake is seen during fasting. periphery regulated. The KATP channels in the VMH and the
Glucose is therefore guided past the peripheral tissues and is pancreatic b cells play key roles during the replenishment
instead available for uptake by the brain [138,139]. Again, phase for the periphery (model c3 – c2). Immediately after the
each particular mechanism identified here can fulfil its role start of food intake, the brain is already optimally supplied
in the model, although the whole theory is not necessarily again while the peripheral energy depots are still depleted.
bound to any specific one. The brain ATP is normal, while the leptin concentration and
In conclusion, a raised glutamatergic tone in the cerebral the body mass are still noticeably reduced.
cortex activates allocation of glucose to the brain by How does this pattern of events influence the functional
promoting GLUT1-mediated glucose transport across the state of the KATP channels in the VMH?
blood – brain barrier and restricting GLUT4-mediated Leptin can open KATP channels directly and within
glucose transport into muscle and adipose tissue. During minutes (model c1 – c2). However, circulating Leptin is
a 5-day fasting period, a latent brain ATP deficit therefore subject to only slow changes over time. It is transported via
activates glucose allocation to the brain. a specific transport mechanism across the blood – brain
How does ketone body formation on the one hand and a barrier. Leptin binds to its leptin receptor in the VMH [141,
reduction in body mass on the other alter the burdening of 142] which is localized on presynaptic GABAergic neurons
the regulatory system? [143] (Fig. 4c). Mike Ashford’s research group from
Fig. 5. (A) Balance and Setpoint. The food intake required for brain nourishment (ordinate) depends on glucose allocation to the brain (abscissa). The reciprocal
relationship describes how much food intake is necessary in order to achieve an adequate energy supply to the brain with a given glucose allocation to the brain.
If there is adequate energy supply of the brain, the effects of high- and low-affinity ATP-sensitive potassium channels are in equilibrium. Glucose allocation is
described as the ratio between the glucose uptake rate of the brain and the glucose uptake rate of the muscle and adipose tissue. The higher the allocation,
the University of Aberdeen, United Kingdom, succeeded in Immediately after starting food intake the inhibitory
determining the key facts surrounding this process. The signal of brain ATP dominates over the stimulatory leptin
leptin receptor activated in the VMH opens the cells own signal and the KATP channels are closed. Closed KATP
KATP channel via an intracellular signal cascade (via channels in the VMH lead to a decrease in noradrenergic
phosphoinositide-3-kinase) [25]. The KATP channel in the tone (that stimulates the sympatho-adrenal system) and via
VMH has a dual input: an inhibitory input for ATP and a vagal stimulation lead to a secretion of insulin from the beta
stimulatory input for leptin. This KATP-sensor with a dual cells [135,144]. In parallel to that the LH is disinhibited, and
input measures the difference between a signal representing these neurons stimulate insulin secretion via direct efferents
brain ATP and one representing the peripherally stored to the beta cells [145]. Insulin enables glucose allocation to
energy. From a regulatory-theoretical viewpoint, one can the muscle and adipose tissue.
expect such a dual input for a sensor controlling allocation During the replenishment phase, leptin increases in the
to two organs. The principle of allocation control can be blood and increasingly opens the KATP channels in
described briefly as follows: if the signal for brain energy the VMH. If the KATP channels are opened, the tone of
status dominates (i.e. ATP is sufficiently available), the the sympatho-adrenal system increases and allocation of
hypothalamic KATP channels are closed and glucose is glucose to the periphery is curbed (Fig. 4c).
assigned to the periphery; if the signal for peripheral energy The energy needs of the brain and the entire organism
status (leptin) dominates, the hypothalamic KATP channels can be balanced over the long-term with the aid of the
are opened and glucose is assigned to the brain. brain’s hypothalamic allocation regulator. The extent to
R
the more glucose is assigned to the brain. With very high glucose allocation the glucose is assigned almost exclusively to the brain so that food intake almost
exclusively covers the energy needs of the brain (dashed line). With very low glucose allocation the greater proportion of the glucose is assigned to the
musculature and adipose tissue so that a larger food intake is necessary in order to ensure that the brain is supplied. The LHPA system determines glucose
allocation to the brain and strives to achieve a balance state (setpoint) under the influence of the corticosteroid feedback loop. The setpoint of the LHPA system
(vertical straight line) is determined by the MR-GR balance. The intersection point of the reciprocal function and the vertical straight line characterizes the
setpoint for homeostasis: here, the brain ATP concentration is sufficient and the LHPA system is at a state of balance. (B) Loading of the regulatory system. The
reciprocal function describes the forward signal path of the regulatory system. With a given glucose-allocation to the brain the required food intake is controlled
according to the reciprocal function. The feedback signal-path (diagonal straight line) describes the reverse effect of the food intake on glucose allocation. The
more food that is consumed, the more glucose enters into the musculature and adipose tissue so that the leptin concentration increases. Leptin stimulates the
allocation centre (VMH) in the hypothalamus. The feedback signal path therefore describes the association whereby an increased food intake leads to increased
glucose allocation to the brain.The lower reciprocal function describes the forward signal path when load on the regulatory system is alleviated. With a
reduction in body mass (M), the food intake required for brain energy supply is smaller (compare equation 3). Correspondingly, alternative substrates that
provide a portion of the brains energy supply, such as ketones, lead to a disburdening of the regulatory system. The numbering describes the chronological
sequence of events provided in the first case study (ranger training):
1. Increased glucose allocation to the brain due to stress from fasting.

2. Disburdening of the regulatory system through ketogenesis and body mass reduction.
3. Replenishment of the stores due to glucose allocation to the muscle and adipose tissue.
4. Normalization of body mass.
5. Return of the LHPA system to a state of balance (setpoint).
(C) Feedback amplification. The leptin signal can be modulated by neuropeptides from the ARC, i.e. a-MSH and NPY. In this way the feedback function is
complemented by the feedback signal l(leptin). The way in which the feedback signal l (leptin) is generated in the ARC is illustrated in Fig. 3c. The modulated
feedback signal [Leptin þ l(Leptin)] at high leptin concentrations produces an amplified stimulation of the sympatho-adrenal system and as such an increased
glucose allocation to the brain. At low leptin concentrations it attenuates the sympatho-adrenal system and with that the glucose allocation to the brain. At
extremely high leptin concentrations the amplifier mechanism is ineffective ½lðleptinÞ ¼ 0 and leptin only exerts its own, unmodulated effect on glucose
allocation. (D) Setpoint-change. Glucose allocation to the brain is determined by the LHPA system. The LHPA-system is influenced by the MR–GR balance
which determines the system’s balance state (setpoint). Extreme loading of the LHPA system can lead to a pathological change in the MR-GR balance. If the
setpoint of the LHPA-system is chronically too low, glucose allocation to the brain also decreases. Food intake, necessary for an adequate brain supply,
becomes greater as a result. With a lowered setpoint the brain supply is therefore maintained more by intake than by allocation of nutrients. (E) Development of
obesity. Obesity can develop in three stages: (1) A setpoint-reduction of the LHPA-system leads to an inadequate glucose allocation to the brain (with increased
allocation to muscle and adipose tissue) and makes it necessary to increase the uptake of nutrients. (2) Consequently, a loading of the brain-supplying
regulatory system is due to the continuous increase in body mass. (3) Under the feedback influence of leptin the LHPA system is stimulated in the burdened
regulatory system and glucose allocation to the brain is increased. Therefore the LHPA-system, whose setpoint is reduced but whose load is increased, shows
an apparently ‘normal’ activity. The ‘normal’ activity of the LHPA-system does not suffice, however, to supply the brain with energy so well that a reduction in
food intake can be enabled. [The deep red areas describe situations in which body mass has a tendency to increase, while the yellow areas describe situations
where it tends to decrease.] (f) Development of a type 2 diabetes mellitus. The development of type 2 diabetes mellitus can occur in 3 stages: (1) A setpoint-
reduction of the LHPA system. (2) A loading of the regulatory system due to increase in body mass. (3) An amplified feedback-effect of leptin from
melanocortins. Leptin and melanocortins both stimulate the LHPA system. Individuals of a certain genetic background with an especially strong melanocortin
system can amplify the leptin-effect on the sympatho-adrenal system in such a way that the burdened LHPA system is hyperactive. Such an overactivity of the
LHPA-system leads to an increased glucose allocation to the brain, a rise in blood glucose, and in extreme cases to glucosuria. The loss of glucose via the
kidneys represents an additional load on the regulatory system. An amplified glucose allocation to the brain may lead not only to a type 2 diabetes mellitus, but
also during the further course of disease to a loss in body mass (yellow area).
which the limbic system also represents a center that The central adipose tissue is an energy depot for the brain,
integrates the feedback-signals brain ATP and leptin is not while the peripheral adipose tissue is an energy depot for
yet clear. There are KATP channels [146] and leptin the musculature. The brain can optimize its energy supply
receptors [142,147] in the limbic system that also play a by maintaining lactate and ketones during phases of food
role in memory formation and long-term potentiation supply and deficit. In order to safeguard its energy needs
[148 – 150]. These findings indicate that the limbic system during critical nutritional states over particularly long
plays a supraordinate role over the hypothalamus in periods it can utilize central adipose tissue stores (Fig. 6).
balancing the energy needs of the brain and the entire
organism (compare chapter ‘sleep and the consolidation of Case 2: The natives of the pacific island of Nauru often
setpoints’). In case 1 a homeostasis gradually appeared over undertook long canoe journeys from one island to the
the ensuing three weeks during which both the brain/ next before the era of European colonization. Numerous
periphery energy balance and the LHPA system returned to reports have suggested that such canoe rides sometimes
a state of calm. lasted several weeks and, contrary to expectations, were
Fig. 5b summarizes the five different constellations that frequently survived [19].
appeared in case 1 during fasting and replenishment of
nutritional stores: How can an organism maintain its brain supply over
extremely long periods of undernutrition?
1. At the beginning of fasting, glucose allocation to the There is a neuronal network in the hypothalamus that
brain was activated because of a threatening state of reinforces the effect of leptin during nutritional surplus and
cerebral energy deficiency. curbs its effects during undernutrition [12]. This reinforce-
2. After 2 days the brain is supplied in part by ketone ment of the leptin effect works as a kind of servo-
bodies. During the further course of fasting the body mechanism. With food surplus it leads to an increase in
mass decreased. Both ketones and the reduced body mass sympatho-adrenal activity which is associated with an
led to a disburdening of the regulatory system. With increased release of lactate from the musculature. During
falling leptin concentrations the allocation of glucose to this phase, when peripheral stores are replenished, the brain
the brain was somewhat reduced. employs glucose and lactate. In this process it leaves the
3. Immediately after the start of the replenishment phase the glucose, spared by the lactate, for retention in central
brain supply returned to an optimal state so that adipose tissue. With prolonged fasting, free fatty acids are
allocation of glucose to the musculature was restored. released from central adipose tissue and converted to
4. During the replenishment phase the body mass renorma- ketones in the liver; during this phase of fasting the brain
lized. The increasing leptin concentrations activated utilizes glucose and ketones. The metabolization of ketones
glucose allocation to the brain more and more. in the brain allows a reduction of sympatho-adrenal tone
5. The LHPA system returned to its resting state with an
equilibrated MR-GR balance. Thus, the allocation of
glucose to the brain and the muscle/adipose tissue had
returned to a state of equilibrium.
2.2.1.3. Economics of the alternative brain-specific sub-

strates. The brain’s ‘strategy’ of efficiently using lactate or
ketones for its energy needs may shed new light on the
pathogenesis of type 2 diabetes (see Chapter 3.3.4. diabetes
mellitus). Lactate and ketones pass the blood –brain barrier
with the help of specific monocarboxylate transporters, can
be directly metabolized by neurons as energy substrates
[151,152], and can protect the brain against hypoglycemia
[153 – 157]. Lactate arises in the muscle tissue from the
glycolytic, anaerobic breakdown of glucose. Ketones are Fig. 6. Economics of alternative brain-specific substrates. An amplification
mechanism of the leptin-feedback effect allows at times of nutrient intake a
formed in the liver. The liver utilizes free fatty acids for particularly strong activation of the sympatho-adrenal system that promotes
ketogenesis that are lipolytically released from visceral lactate release from the muscle. As a result, lactate instead of glucose can
central adipose tissue and reach the liver via the portal vein. cover a portion of the brain’s energy. The glucose spared in this way can be
Contrastingly, only a small proportion of the free fatty acids stored instead under the influence of insulin and cortisol in central adipose
circulating in the general circulation (arising from periph- tissue stores. With long-term fasting, free fatty acids from central adipose
tissue can be employed for ketogenesis in the liver. As a result, ketones
eral adipose tissue) gain access to the liver, and to all intents instead of glucose can cover a portion of the brain’s energy needs.
and purposes these are not available for ketogenesis. The Therefore less glucose-allocation to the brain is required, and load on the
free fatty acids arising from peripheral adipose tissue are sympatho-adrenal system is alleviated, i.e. it can operate in ‘save mode’ and
used as substrates for cardiac and skeletal musculature. can maintain brain supplies economically over a long period of time.
and consequently a reduction in glucose allocation to the While the body energy stores are being replenished the
brain. Thus, the utilization of ketones as an alternative melanocortin system is able to amplify the sympatho-
substrate for the brain allows a ‘saving mode’ to be entered. adrenal activity [161,162]. Catecholamines and cortisol
Leptin amplification is provided by the melanocortin favor the increased build up of lactate in the musculature
system in the hypothalamic ARC (Fig. 4f). Under [163 –165]. The brain can employ lactate directly as an
the stimulating influence of leptin a neuronal population of alternative substrate [151 –157]. A certain proportion of the
the ARC synthesizes the precursor molecule pro-opiomela- glucose is therefore available for other tasks: to be stored in
nocortin (POMC), from which the melanocortin a-MSH is visceral central adipose tissue. Cortisol also favors the
cleaved [12]. The axons of these POMC neurons innervate storage of glucose in exactly this fat compartment. One such
the VMH, where a-MSH is released and stimulates cortisol effect with central fat accumulation is known to
noradrenergic neurons via its melanocortin (MC4) receptor clinicians in the form of Cushing’s disease.
(Fig. 4c). This signal pathway runs parallel to the above- The melanocortin system can also increase allocation to
described primary leptin signal which directly acts on the the brain. Under the influence of melanocortin, the brain not
KATP channels in the VMH (Fig. 4c) (model d1– c2). One can only receives an additional energy supply from lactate—as
distinguish a primary leptin signal that sends information described above—but also an additional share of glucose.
directly from the periphery to the VMH (allocation), from an The increased allocation under these conditions enables the
amplifying secondary leptin signal, which only acts on the organism to take in less food. In the same way an appetite
VMH with the aid of a-MSH after conversion in the POMC suppressing effect of a-MSH is possible without the brain
neuron. In this way, a-MSH amplifies the leptin effect on supply being endangered. The melanocortin system
CRH (which promotes glucose allocation to the brain) and increases the role of allocation and decreases that of food
thereby attenuates food intake [158]. The POMC neuron also intake (Fig. 2c). Under the influence of the melanocortin
projects with its axons directly into the appetite-controlling system a somewhat reduced intake of foods occurs while
LH (model d1– d2). Here a-MSH acts inhibitorily via its store replenishment is taking place, so that less energy is
MC4 receptor on the appetite-inducing orexigenic neurons.
stored in peripheral adipose tissue. In conclusion,
POMC neurons are glucose-responsive, i.e. they possess
the melanocortin system amplifies the leptin effect; it
KATP channels that are closed by ATP and opened by leptin or
mobilizes lactate and glucose for the brain and in this way
insulin [26,159]. With cerebral ATP deficiency or peripheral
promotes central adipose tissue growth while maintaining
leptin surplus the KATP channels are opened and the POMC
adequate supply to the brain.
neurons are inactivated. This means that the leptin-amplify-
In times of prolonged fasting these accumulated central
ing melanocortin system is only fully functional with a
fat depots can ensure a long-lasting supply of ketone bodies
balanced cerebral ATP content and a normal body mass.
to the brain. From a biomechanical standpoint the storage of
Leptin amplification can also be accomplished through a
energy in certain strongholds, i.e. in the core of the body, is
second signal pathway emanating from the ARC. Here,
leptin inhibits a neuronal population that synthesizes particularly favorable. Peripherally stored masses can
neuropeptide Y (NPY), a powerful appetite stimulator considerably restrict physical mobility (larger inertial
(Fig. 4f) [160]. The NPY neurons project with their axons momentum), whereby a mass at the body’s center of gravity
also into the VMH, where unlike a-MSH they act (smallest inertial momentum) [166] permits an almost
inhibitorily, and they project to the LH, where unlike a- unrestricted mobility. The central (visceral) adipose tissue
MSH they act in a stimulatory manner [12]. produces less leptin than peripheral fat [167], and therefore
Fig. 3c provides an overview of the activity of POMC allows more energy uptake.
and NPY neurons depending on leptin concentration. At low Currently it is not known whether the natives of Oceania
leptin concentrations, e.g. after long-term fasting, the NPY described in case 2 have a supranormally effective
neurons are activated, with moderate leptin concentrations melanocortin system. James Neel in his ‘thrifty gene
the POMC neurons are active, while with high leptin hypothesis’ [168] postulated that a combination of genes
concentrations both the POMC and NPY neurons are might exist that allows an especially efficient utilization of
inactivated. From Fig. 3c it should also be noted that with nutrients and improves the survival chance of their carriers
moderate leptin concentrations mainly melanocortin in situations of long-term starvation. Our above-described
(a-MSH) is released by the ARC while with low leptin views on how an effective melanocortin system can allow a
concentrations NPY is mostly secreted. In conclusion, the long-lasting brain supply allows us to assume that the
melanocortin system is activated with nutrient surplus (with natives of Oceania do indeed carry genes that allow
moderate leptin concentrations); as such the leptin effect on particularly effective hypothalamic leptin amplification.
glucose allocation in the VMH is amplified. In contrast, Fig. 5c summarizes the behavior of a brain equipped with
glucose allocation in the VMH is reduced during fasting a leptin amplification system in the ARC: It responds to an
(with low leptin concentrations). Fig. 2c shows that the increased intake of foods with an especially effective
melanocortin system is able to amplify glucose allocation loading of its stress system that coincides with an increased
and decrease the intake of foods. glucose allocation to the brain. It responds to undernutrition
with a highly effective restriction of its stress systems, the brain. It has indeed been shown that hyperphagia during
enabled by an economically effective utilization of ketones. hypoglycemia is not mediated via signals from the ARC
[176]. The leptin resistance of the melanocortin system is
2.2.1.4. The ‘primacy of the brain’. What mechanisms therefore a necessary condition to maintain the ‘primacy of
underlie the primacy of the brain regarding energy supply? the brain’ regarding energy supply.
Two independent mechanisms are available to the brain
for measuring cerebral ATP content: the KATP channels and
the Naþ/Kþ-ATPase. As described above, the KATP channels 2.2.2. Psychological stress
act as sensors for the regulation of glucose allocation. The Case 3: Sascha, a 22-year-old architectural student,
Naþ/Kþ-ATPase is a molecular structure that is ATP- undertakes his first parachute jump. In the parachute-
sensitive and which can activate the appetite-stimulating school beginners are strapped for a so-called ‘tandem
orexigenic neurons in the LH [169,170]. The neurons in the jump’ to the front of an experienced trainer. At 10 a.m.
VMH (KATP channels) and the LH (Naþ/Kþ ATPase) differ the plane ascends to a height of 3500 m. During the
fundamentally. With ATP deficiency the VMH neurons 15 min ascent and particularly during the seconds before
hyperpolarize, while the LH neurons depolarize. Correspond- the jump Sascha appears somewhat excited. He senses
ingly, the VMH neurons are also known as ‘glucose- severe palpitations, shaking, and inner unrest. The
responsive’, while those in the LH are designated as tandem jumpers experience 45 s of freefall before the
‘glucose-sensitive’ [171,172]. With cerebral ATP deficiency parachute opens and 5 min coasting under the opened
the hyperpolarization of presynaptic GABAergic neurons in parachute. A safe landing follows. The psychological
the VMH allows glucose allocation to the brain. Contrast- stress is resolved immediately. At 1.00 p.m. during the
ingly, depolarization of glucose-deprived LH neurons leads to subsequent communal lunch with the other beginners,
the release of orexigenic neuropeptides (e.g. orexins; Fig. 4d) Sascha expresses euphorically that he wants to learn to
[173–175] (model d3–d2). In the life-threatening situation of parachute at any cost. During the evening he falls
a cerebral energy deficit, also known as neuroglucopenia, exhausted but satisfied into a deep, restful sleep.
both the allocation mechanisms as well as hunger are
activated independently of one another. One such situation What effects does psychological stress have on glucose
occurs for example with insulin-induced hypoglycemia metabolism?
which is frequently seen in individuals with type-1 diabetes. Sascha was exposed to a strong psychological stressor
The brain has yet another mechanism to guarantee its and put into a state of great tension, excitement, and
primacy regarding its energy supply. If a cerebral energy attentiveness. Many new experiences had to be dealt with,
deficit or a peripheral energy surplus occurs (both of which selected, and judged. In this state, cortical excitatory
are critical constellations regarding the competition for activities, especially of glutamatergic neuronal populations
energy resources), signals from the periphery are only were dominant. The GABAergic neuronal activity in this
conveyed in a restricted way to the regulatory centers of the situation took the back seat. As described above, the
brain. There is a signal-filter in the ARC that controls glutamatergic neuron population provides the glutamate
whether the leptin signal should be relayed. Although the command signal. The cortical balance between glutamater-
leptin-signal can reach the VMH at any time unhindered, the gic and GABAergic activity prevailing during exposure to
melanocortin signal from the ARC is transmitted only under psychological stress resembles that observed during meta-
certain conditions: i.e. with sufficient brain ATP and at bolic stress such as neuroglucopenia. Glucose transport
physiological leptin concentrations. With cerebral ATP across the blood – brain barrier is increased. Cortical
deficiency or leptin excess the postsynaptic KATP channels glutamate via receptors in the limbic system stimulates
of the ARC neurons are opened [25,26,159] so that these projections activating the LHPA system [73]. Activation of
neurons are hyperpolarized and stop releasing melanocortin the LHPA system coincides with stimulation of the
(a-MSH) at their synapses. In obese individuals, who have sympathetic nervous system (leading to symptoms such as
high leptin concentrations, the stimulatory effect of leptin on ‘palpitation’) and with the release of hormones from the
the melanocortin system has been lost as a rule. This hypothalamus-pituitary system [177,178]. As already
phenomenon is often described as ‘leptin resistance’. shown in the chapter ‘malnutrition’, activation of the stress
The melanocortin system suppresses appetite and food systems promotes glucose allocation to the brain and
intake and can therefore theoretically induce a serious reduces the uptake of glucose into muscle and adipose
conflict in a life threatening neuroglucopenia. Since in tissue. In conditions of psychological stress the brain is
neuroglucopenia the brain is dependent on all possibilities for adequately supplied with energy in this way.
obtaining energy, i.e. allocation and food intake, it The degree of activation of the LHPA system is indicated
deactivates the melanocortin system in such crisis situations. by blood cortisol concentrations. With a parachute jump, as
This neuroprotective mechanism permits a ravenous hunger in the above described example, serum cortisol climbs from
sensation during hypoglycemia, even in situations where an 15 to 25 mg/dl [179]. Catecholamine, cortisol and insulin
excessive peripheral body mass provides a ‘satiety’ signal to play a role in allocating glucose. Cortisol and insulin also
feedback to the brain [98,180]. The rise in cortisol indicates fall off according to their half-life. VMH neurons that inhibit
how strongly the organism reacts to stressor exposure. the LH [84,134] decline in activity. The LH in turn releases
Cortisol easily crosses the blood – brain barrier as a appetite-stimulating orexigens. In addition, cortisol sup-
lipophilic hormone. Sites of cortisol feedback appear to presses CRH in the PVN which also has an appetite
include the limbic system, the hypothalamus, the pituitary, suppressing effect aside from its function as a releasing
and the adrenals. There is a debate as to whether the locus of hormone [192]. Because of this Sascha is able to eat food
limbic feedback action can be traced by lesion studies to the again after his successful landing. Interestingly, the ingestion
hippocampal formation [181 – 183]. Such controversial of glucose may additionally suppress the LHPA system
findings suggest that other brain regions, e.g. the amygdala, activity [193,194]. The stores are replenished, as described in
are also essentially involved. The limbic neurons belong to a detail in the chapter ‘malnutrition’.
complex information processing system, and they can act in In the evening, serum cortisol concentrations reduced
concert via triple (excitatory, inhibitory, and disinhibitory) continuously. The lower the cortisol is, the less binding there
descending pathways to exert corticosteroid feedback. is to GR in the limbic system, and MR– MR homodimers
In our opinion, it is the information stored within these predominate. MR – MR homodimers increase excitability of
limbic neuron populations, in terms of emotional or the limbic neurons that control the LHPA system (model
declarative memories, that optimises the energy request b1– b2). Under the influence of CRH and ACTH, cortisol is
signal. The energy request is only a crude—but necess- released from the adrenals sufficiently to prevent further
arily—anticipatory estimate of the energy need, i.e. the decline. Before sleeping the cortisol concentrations reach a
amount of energy that will actually be utilized. An nadir of about 3 mg/dl. At this time-point the adrenal cortisol
inadequate energy request might be harmful to the brain. production is approximately as large as the hepatic cortisol
An excessive energy request mediated by the LHPA system elimination so that cortisol concentrations stabilize. During
may be harmful to the body (catabolism). It is therefore slow wave sleep in the first half of the night the MR-MR
adaptive to match the energy request closely with the energy homodimers are mainly active at the low cortisol concen-
need. The limbic system modulates the glutamate command trations that then prevail. As we shall explain in the following
signal on the basis of previous experiences. Learning chapter, a consolidation of memory and metabolic setpoints
modifies limbic signal transduction in three ways: fear can occur under the influence of MR – MR homodimers
conditioning enhances, contextual learning of familiar during the slow wave sleep phase.
content attenuates, and contextual learning of aversive
content potentiates [184]. The triple descending projections 2.3. Sleep and the consolidation of setpoints
described by Swanson which consist of excitatory, inhibi-
tory, and disinhibitory components precisely reflect this In addition to its general restorative function, sleep also
functionality [113]. Accordingly, the limbic system can use serves to consolidate memory. The definition of memory
memories to make the most economic energy request. refers in this case to a fundamental function of controlled
Cortisol binds to MR and GR in the limbic system and to biological systems whereby a memory is formed for the
GR in the hypothalamus. At high cortisol concentrations it is purpose of consolidating and stabilizing setpoints. During
primarily GR –GR homodimers and MR – GR that form in the wake phase setpoints are newly acquired (learned) as part
the pyramidal cells of the limbic system. These GR-dimers of an adaptive interaction between the organism and its
with their feedback effects control the excitability of the environment; existing (inborn as well as learned) setpoints
limbic neurons that determine activity of the LHPA system are subject to destabilizing influences (stressors). Unlike the
(model b3– b2). With long-lasting stressors, cortisol inhibits wake phase, sleep represents a phase during which the
the mRNA of those peptides and receptors that convey or consolidation of memory is optimized. During a period of
amplify the glutamate command signal from the limbic minimum reactivity towards environmental stimuli, sleep
system to the body periphery: in the PVN CRH [185] and allows the reorientation of an inner homeostasis through the
vasopressin [186], in the ARC POMC [187], in the pituitary stabilization of setpoints and with that a lasting ‘strategic’
CRH receptors [188] and POMC [189], in the adrenal gland adaptation to stressors.
melanocortin (MC2) receptors [190], and on glucose- Glutamate receptors are necessary for conveying the
responsive cells high-affinity ATP-sensitive potassium glutamate command signal to the body periphery [73]. The
channels [191]. However, as long as the psychological cerebral cortex communicates with the limbic system via a
stress persists, the LHPA system continues to be stimulated glutamate-mediated synaptic transmission. There are two
by widespread cortical glutamatergic input. main types of ionotrophic glutamate receptors: the AMPA
After a safe parachute landing the psychological stressors receptor involved in basal synaptic transmission, and the
are no longer present. Cortical excitation normalizes, as does NMDA receptor that specifically modulates a form of
the stimulatory input to the LHPA system. Now the LHPA synaptic plasticity, i.e. so-called long-term potentiation
system is subject to the dominant inhibitory feedback (LTP) [195]. LTP is thought of as the basic neuronal process
influence of the GR-dimers in particular. Under the inhibitory underlying the formation of memory. Activation of
feedback influence, Sascha’s serum cortisol concentrations the NMDA receptors increases the calcium concentration
in the postsynaptic neuron and thereby activates a range of gene activation and protein synthesis, with this effect fading
intracellular biochemical signal pathways. These intracellu- within a few hours. Alcino Silva and Eric Kandel of Columbia
lar signals modify both the number and the activity of the University in New York showed that the ‘cAMP responsive
postsynaptic AMPA receptors with lasting effect. In LTP, element binding’ (CREB) gene produces exactly the proteins
AMPA receptors are recruited in greater numbers to the cell that appear to be essential for neuronal plasticity and long-
membrane so that synaptic signal transmission is increased term memory [207,208]. CREB is a so-called ‘early’ gene, and
[196,197]. In the counteracting process, i.e. long-term the CREB protein a transcription factor [209]. With LTP the
depression (LTD), AMPA receptors are endocytosed so CREB protein controls production of effector proteins that
that synaptic transmission is reduced [196] (see Fig. 4b). stabilize synaptic modification and help to form new synapses:
amongst these include structural proteins for new synapses,
2.3.1. Stressors and the limbic system receptors for the cell membrane, as well as kinases and
How do limbic neurons find the optimal conditions for proteins that maintain vital functions of the neuron. Genes like
LTP? CREB activate a genetic chain reaction by activating diverse
As an answer we propose: ‘later’ genes. After a few hours the synthesis of glutamatergic
AMPA receptors intensifies. The number of AMPA receptors
1. With the assistance of high-affinity and low-affinity at the cell membrane stabilizes over the long-term.
BDNF receptors and In summary, BDNF mediates its effect on LTP as
2. with the assistance of high-affinity and low-affinity follows:
brain corticosteroid receptors.
A major breakthrough was the identification of the 1. BDNF binds with high affinity to the trkB receptor
neurotrophin BDNF by Yves Barde and Hans Thoenen at and low affinity to the p75 receptor.
the Max-Planck-Institute in Martinsried/Munich [198]. 2. BDNF-bound trkB and p75 receptors form three
BDNF and other neurotrophins, such as the formerly known types of dimers: trkB-trkB, trkB-p75, and p75-p75.
nerve growth factor, are trophic proteins necessary for the 3. The trkB-trkB homodimers mediate the BDNF
differentiation and survival of neurons. In addition they effects on LTP while the p75 containing dimers
modulate synaptic transmission and plasticity [199]. Unlike prevent these.
their slow effects on neuronal survival or differentiation (h or
days), modulation of synaptic transmission is much faster (s to
min). It has now become apparent that BDNF exerts its effects This interaction of a ligand with two receptors also
on LTP and LTD via two different membrane receptors: the reminds us of a general principle which we have already
high-affinity trkB receptor and the low-affinity p75 receptor illustrated with the brain corticosteroid receptors (MR and
[200,201]. Like most growth factor receptors the trkB GR) and the high- and low-affinity ATP-sensitive potassium
receptor displays a cytoplasmic domain with a tyrosine channels. A bell-shaped dose-effect-relationship for BDNF
kinase. After binding BDNF, tyrosine kinase mediates on the production of CREB-protein results from the
autophosphorylation of the trkB receptor as the first step of behavior of BDNF and its two receptors (Fig. 7).
intracellular signal transduction. The p75-receptor on the
other hand lacks the intracellular tyrosine kinase domain. That
means that the p75-receptor competes with the trkB-receptor
to prevent trkB-induced activation of cellular processes.
The neurotrophin receptors form three kinds of dimers:
trkB – trkB homodimers, trkB – p75 heterodimers and
p75 – p75 homodimers [202 – 204]. The receptor dimers
bind in each case one BDNF molecule. Consequently
trkB – trkB homodimers are predominantly active at low
BDNF concentration, while at high BDNF concentrations
p75-containing dimers are. The complete effect of BDNF is
mediated in this case via the homodimer trkB –trkB, through Fig. 7. Optimal conditions for long-term potentiation. Induction and
maintenance of long-term potentiation (LTP) involves induction of CREB
mutual phosphorylation of the two cytoplasmic tyrosine proteins. CREB protein expression depends on BDNF concentration, with a
kinase residues. The p75-containing dimers do not transmit bell-shaped dose-effect relationship. BDNF-(trkB) receptors must be
the signal because of their lacking cytoplasmic domains. present in sufficient numbers for the complete BDNF effect. BDNF-
Opposing (e.g. antiapoptotic and proapoptotic) effects of (trkB) receptor synthesis depends on cortisol, again with a bell-shaped
trkB and p75 receptors have indeed been demonstrated [203]. dose-effect relationship. After a stressful event, LTP induced during
wakefulness is maintained during slow wave sleep only if both cortisol and
BDNF mediates the induction of LTP [199,205] and atte- BDNF lie within optimal ranges. In this way the effects of BDNF (as an
nuates LTD [206] via its trkB receptor. Autophosphorylation indicator for the scale of the stressor effect) and cortisol (as an indicator for
of the trkB receptor activates a cascade of kinases leading to the scale of the stress reactions) are integrated.
2.3.2. Stress reactions and the limbic system the storage of which relies essentially on the functions of the
Cortisol also modulates synaptic transmission and plas- hippocampal formation. It is assumed that the memory
ticity. The effects of cortisol in the limbic system are enhancing effect of sleep is generated by a ‘replay’ of the
influenced by the interaction between MR and GR. memory representation newly acquired in a learning phase
Originally, various groups found that cortisol-bound MR during prior wakefulness [226]. Thus, a certain spatio-
[210–213] and GR [214–218] were subject to ‘autoregula- temporal pattern of excitation within limbic neuron net-
tion’, i.e. they both suppressed their own production. Bruce works associated with a particular behavior solution to a
McEwen and colleagues showed that MR activates LTP while problem (i.e. a stressor) during wakefulness becomes
GR attenuates it [219–221]. Extending these findings, Ronald reactivated during slow wave sleep. This eventually results
de Kloet and coworkers showed how cortisol modulated LTP in strengthened synaptic efficacy and enduring memory for
when they confirmed that corticosteroids influence the this behavior, induced by the process of LTP and the
production of BDNF receptors [222]. Expression of trkB– expression of immediate early genes discussed above.
mRNA was highest with low corticosteroid concentrations, A success of this replay for enhancing memory can be
while at high corticosteroid concentrations it was barely predicted from the balanced cortisol concentration achieved
evident and not different from the vehicle injected controls. during this period. If cortisol is too high during the early
This dose-effect relationship supported the idea that pre- period of sleep replay activation would fail to enhance
dominant MR activation is critical for the production of trkB present memory [227], and the respective behavior would
receptors. Recently it was shown that GR activation enhances not be associated with a return to homeostasis.
the production of p75 receptors [223]. Together, these If specific behavioral programs are activated during the
findings lead us to conclude a bell-shaped dose-effect curve stress of the wake phase day and the organism returns to
for corticosteroids on trkB receptor production (Fig. 7). homeostasis (MR – GR balance) during the evening, these
BDNF and cortisol jointly regulate LTP. Fig. 7 shows programs are consolidated during slow wave sleep. This
that both BDNF and cortisol have bell-shaped dose-effect strategy appears beneficial towards the organism’s survival.
curves regarding corresponding gene products: cortisol on It would be just as beneficial if programs whose activation is
the BDNF-(trkB) receptor, BDNF on the CREB protein. not associated with a return to homeostasis were to be
The effect on CREB gene transcription is maximal if BDNF deleted. Both excessively high and low cortisol during the
and cortisol are ‘balanced’, i.e. within an optimal concen- evening hours have unfavorable effects on slow wave sleep
tration range. Cortisol concentrations are optimal during the and potentially disrupt the consolidation of memories
nadir of the circadian cortisol profile, allowing for [227 – 229]. Low but balanced cortisol concentrations,
maximum numbers of trkB receptors to be formed. The such as those established during slow wave sleep periods
number of trkB receptors is the limiting factor for the effect of the early night provide conditions optimal for the
of BDNF on the CREB gene. Thus, LTP and associated consolidation of memories.
induction of immediate early genes as the basis of memory Here we present the view that BDNF and cortisol
formation, occur only if both BDNF and cortisol are within furthermore regulate the consolidation of metabolic
their optimal concentration range. setpoints. If the LHPA system returns to its setpoint at the
BDNF is released upon cortical excitation together with beginning of the night with balanced cortisol concentrations,
glutamate. For this reason BDNF can be considered as a MR and GR are in equilibrium. In this constellation, MR–
general indicator of metabolic or psychological stress. MR homodimers are present in sufficient numbers to allow an
Complementarily, cortisol is an indicator for the magnitude adequate number of trkB receptors to be produced. There are
of an organism’s stress response. In healthy individuals, hints that BDNF concentrations in limbic regions such as
BDNF and cortisol responses with stress coincide, while hippocampus, are maintained during sleep and thus remain in
pathological states may selectively impair the cortisol an optimal range [230]. Under these conditions BDNF binds
response. Because of the tight association between BDNF to a sufficient number of trkB receptors and allows for
and cortisol in their effect on LTP, it might be speculated in optimal expression of LTP and CREB, required for the
this context that the magnitude of a ‘stressor’ might be presumed stabilization of glucose setpoints in limbic-
balanced by the ‘stress reaction’. This means that storage of hypothalamic networks. In this way a stable and effective
information in memory would be favored especially if a communication between the brain cortex and the body
state of balanced cortical activity and balanced stress periphery is present which ensures the conveyance of the
reaction would prevail after stressor exposure. glutamate command signal.
2.3.3. Memory formation during sleep

Slow wave sleep, which is dominant during the early part 3. Pathological glucose regulation
of nocturnal sleep, has been proposed to enhance the
formation of declarative types of memory [224,225]. These The limbic system plays a decisive role in the communi-
are memories for facts and episodes (including the survival cation between the cerebral cortex and the body periphery.
strategies taken by experimental rats to find food in a maze) Limbic neurons modulate and mediate the cortical glutamate
command signal to the muscle and adipose tissue. They do unconscious. He is brought immediately to the hospital
not just control the activity of the LHPA system, but in fact by ambulance. Upon arrival his plasma-glucose value is
they also have the capacity to store information on a long- 25 mg/dl. He had already suffered a hypoglycemic coma
term basis with the help of the molecular mechanisms a year previously.
involved in long-term potentiation (LTP). With these
properties, limbic neurons are in principle able to ‘memorize’ Asymptomatic hypoglycemia represents a major pro-
experiences and using these to persistently change the blem in the modern treatment of diabetes mellitus.
setpoint of the LHPA system. One such LHPA system Approximately a third of people with type-1 diabetes
setpoint alteration entails considerable long-term conse- mellitus suffer severe hypoglycemia with comas, without
quences for glucose allocation to the brain and the body noting any earlier warning symptoms such as shaking,
periphery. sweating or palpitations. The inability to sense such warning
The MR–GR balance can be seen as an indicator for the symptoms or the absence of such symptoms before the
setpoint of the LHPA system. This MR-GR balance is development of a severe neuroglucopenia is known as
genetically programmed, but can be altered by experiences in hypoglycemia unawareness [178].
the postnatal period [231–233] as well as in later life [65]. So-called ‘glucose counterregulation’ is the physiologi-
A unique traumatic experience can lead for example to cal mechanism that normally prevents hypoglycemia very
persistent modifications in the LHPA system. Israel Liberzon effectively and corrects it wherever necessary [235]. This
and coworkers of the Mental Health Research institute in Ann counter-regulation is based mostly on the activation of the
Arbor were able to show that an amplified negative cortisol LHPA system. This activation includes the stimulation of
feedback effect, as observed with post-traumatic stress the sympatho-adrenal system with the associated increase in
disorder, can be induced by application of a single prolonged serum catecholamines and cortisol. In addition, insulin
stress paradigm [234]. The research group employed different concentrations fall in line with the counterregulation [236].
stressors in animal experiments during a single extended Individuals with type-1 diabetes mellitus, who must inject
session, and then allowed a stress-free period to pass before insulin, can not lower their serum insulin concentrations at
the MR–GR balance was examined post mortem one week short notice through suppression of b cells. Catecholamines
later. A week after stressor exposure, a reduction in the MR- must compensate for this lacking insulin reaction. There is
GR ratio was revealed in the hippocampus; these changes also broad agreement that severe hypoglycemia arises from an
persisted for 14 days after the stressor exposure. It is certainly interaction between absolute and relative insulin excess on
remarkable that a single stress-intensive episode is able to the one hand and an impaired counter-regulation on the
lead to such long lasting, possibly even permanent modifi- other. Patients at risk to severe hypoglycemia have more
cations in the MR–GR balance. likely type-1 than type-2 diabetes mellitus, a longer diabetes
Fig. 5d shows the consequences that result from an duration, a low concentration of glycosylated hemoglobin,
alteration in the MR – GR balance: the pathologic balance an autonomous neuropathy, or have already suffered
setpoint, at which both the energy supply of the brain and episodes of hypoglycemic coma [237,238].
the LHPA system are balanced, results in a lower glucose Recurrent hypoglycemia plays a key role in the origin of
allocation and a higher food intake. In such a constellation disrupted hypoglycemia awareness. During a hypoglycemic
the brain increases the intake of foods and in so doing episode the counter-regulatory hormones increase strongly,
safeguards its energy supply. Thus, a change in the MR – GR while during recurrences these reactions are quite clearly
balance leads in the long-term to a change in body mass. reduced [239]. With mild, short hypoglycemia, such an
What diseases arise when the setpoint of the LHPA attenuation is barely evident [240]. With moderate hypo-
system is altered and glucose allocation to the brain changes glycemia, the attenuation lasts for up to 5 days [241],
as a consequence? whereas amongst patients with recurring hypoglycemic
Considering this question we shall now discuss the origin coma the counter-regulation is decreased on a long-term
of hypoglycemia unawareness, anorexia nervosa, obesity basis [242]. Two research groups have studied whether the
and type-2 diabetes mellitus. infusion of a high cortisol dose results in a reduced increase
in the counter-regulatory hormones with hypoglycemia on
3.1. Hypoglycemia unawareness (type 1 diabetes mellitus) the following day [243,244]. Only Stephen Davis’s group
could confirm this presumed effect [243]. They supported
Case 4: Walter, a 50 year-old plumber, has suffered from their first results by verifying in animal experiments that
type 1 diabetes for 25 years. He attends a company intra-cerebroventricular infusion of cortisol also decreases
function where the best-working employees are being the hormonal hypoglycemia response on the following day
honored. Before he leaves home he injects his usual dose [245]. These findings support the notion that episodic
of insulin. The dinner is served about one hour too late. cortisol excess plays a key role in the pathogenesis of
Walter notices that he has difficulties going to the hypoglycemia unawareness.
podium and conducting his thanksgiving speech. He goes The role of the limbic MR– GR balance in the origin of
back to his table, wobbles on his feet, and falls to the floor disrupted hypoglycemia awareness has not yet been
examined. An initial study on the MR–GR balance suggested neuroprotective mechanisms appear to be mobilized at
that the ratio of MR and GR in the hippocampus is reduced in critical brain ATP concentrations leading to a hypoglycemic
acute hypoglycemia [246]. Both a BDNF and a glucocorticoid coma, i.e. one involving cortical, and the other involving
excess occur with severe hypoglycemia [247,248]. Our model nigral, KATP channels. From this viewpoint it would appear
of brain ATP regulation predicts that the coincidence of that the syndrome of hypoglycemia unawareness is based on
BDNF and glucocorticoid excess in the limbic system induces a ‘learned’ setpoint reduction of the LHPA system and an
an LTD. Furthermore, it also predicts that the number of inadequate glucose allocation to the brain. As a result of
AMPA receptors on the limbic neurons that control the LHPA episodic, metabolic insults, the brain then competes
system is also reduced. A hypocortisolism then results on the inadequately with the body periphery for energy resources
day after the hypoglycemic episode which can be demon- and does not care for itself sufficiently.
strated by the reduced morning cortisol concentrations [239].
Because of the autoregulation of the brain corticosteroid 3.2. Anorexia nervosa
receptors, the ratio of MR to GR decreases and the circadian
cortisol profile stabilizes to a lower concentration. Although A long-term, regular loading with mid-level stressors can
the essential steps of this sequence of events have been lead to a completely different reaction pattern of the
demonstrated by various individual experiments elsewhere organism compared to a single short-term overwhelming
(see chapter 2), it still remains to be checked whether a single stressor load. While in the previous chapter we showed that
episode of a hypoglycemic coma can lead to a lasting setpoint hypoglycemic comas can lead to a hyporesponsiveness of
reduction of the LHPA system in humans. With our current the LHPA system, we shall show in the current chapter that
state of knowledge it can be hypothesized that hypoglycemic a chronic stress can instead lead to a hyperresponsiveness of
comas, similar to the ‘single prolonged stress paradigm’ the LHPA system.
employed by Liberzon, can lead to persistent alterations in the
limbic MR–GR balance. Case 5: The 15 year-old Anna lives in permanent stress.
If one assumes a setpoint reduction of the LHPA system Both parents are alcohol-dependent and get very violent
after one or several hypoglycemic comas, glucose allocation when they are drunk. Anna and her younger brother have
to the brain can be considered to be inadequate with type 1 already been hit very frequently. Despite this burden-
diabetes and as a result the sympatho-adrenally mediated some situation she is very ambitious and has set goals for
alarm symptoms are less marked. In such individuals, the her life. She has good grades at school, and every
brain with its falling ATP content is dependent on an afternoon she goes to the sport’s club where she trains for
immediate intake of foods. Unlike the sympatho-adrenally 2 h. During a summer camp Anna intensifies her training
mediated alarm symptoms, hunger is not attenuated with and diets. Her weight falls from 54 kg at 1.65 m (BMI of
recurrent hypoglycemia [83]. With rapidly progressing 16.5 kg/m2) to 45 kg. When she comes back to school her
neuroglucopenia there is often insufficient time to allow friends are shocked by her appearance, but Anna feels
the correction of an energy deficiency in the brain through lively and active, sleeps well, does more sport and
food intake. continues her fasting.
With mild neuroglucopenia, presynaptic low-affinity
ATP-sensitive potassium channels on inhibitory cortical Chronic exposure to various psychological stressors, as
neurons are opened, which causes an increase in food intake described with Anna, leads to a loading of the LHPA system
and glucose allocation to the brain. With type-1 diabetes [249,250]. Even a relatively short-lasting stimulation of the
with disrupted detection only an inadequate time period is LHPA system has effects on glucose allocation: the
available for food intake. Because of this a stronger allocation of glucose to the brain is increased while that to
neuroglucopenia can develop. With critically low ATP- the body periphery is decreased. The activated allocation-
concentrations in the brain the high-affinity ATP-sensitive controlling VMH is hierarchically superior to the appetite
potassium channels are also opened (model a1 –a2). The adjusting LH and inhibits it (forward signal pathway). In
result of this is that neurons over the entire neocortex addition, both VMH and LH are subject to inhibition by
become hyperpolarized and deactivate [55]. This resting brain ATP (feedback signal pathway) independently of one
state of the neocortex can be understood as a neuroprotec- another. Since the VMH is subject to a lasting stimulatory
tive mechanism, whereby neurons employ their last influence of the limbic system, food intake is curbed so far
remaining energy merely for structural maintenance. that the brain ATP concentration is balanced (high- and low-
Susumu Seino and Nabuya Inagaki at the Akita and Chiba affinity ATP-sensitive potassium channels in balance). As a
Universities in Japan showed recently that KATP channels result, a smaller amount of glucose is available for glucose
localized in the substantia nigra can also support neuropro- allocation, and glucose uptake is reduced in the muscular
tection at critical brain ATP concentrations [35]. The and adipose tissue. Thus, body mass decreases over the long
research groups showed that KATP channels activate a nigral term. Overall, there is a decrease in body mass brought
protection mechanism against generalized seizures at about by a centrally defined ratio between brain-glucose
critical brain ATP-concentrations. In conclusion, two uptake and peripheral glucose uptake.
The model of brain ATP regulation predicts that under We shall now explain how secondary metabolic conse-
chronic stressor exposure there is not just a loading of the quences can burden the LHPA system.
LHPA system, but there is in fact also a limbic amplification
of the glutamate command signal. A chronic stimulation of Case 6: The now 23 year-old Clara grew up in prosperous
the LHPA system typically leads to hypercortisolism. In and well-protected circumstances. After her school-
animal experiments it has been shown that corticosterone leaving examinations she traveled with her boyfriend
delivery to the amygdala increases CRH mRNA in who was an enthusiastic surfer to the Atlantic coast. After a
the central amygdaloid nucleus, anxiety-like behaviour, wind accident her boyfriend became a quadriplegic and
and hypothalamo-pituitary-adrenal responses to behavioral died after a 3 month treatment in hospital. Clara never left
stress [251,252]. In hypercortisolism, the number of GR his side during this time. After the death of her boyfriend
decreases due to autoregulation of the brain corticosteroid she refused to speak. She starts her law studies, but
receptors. Conversely, the number of MR increases. If the withdraws socially, avoiding friendships, sporting activi-
hypercortisolism is only mild, sleep patterns remain ties and travel. After a year she becomes increasingly and
unchanged for the most part. During slow wave sleep continuously depressed, and is very sensitive and feels
there is an increased influence of MR leading to LTP. The easily offended. She sleeps regularly for 12 h, eats a lot and
number of AMPA receptors on the limbic neurons that has already gained 20 kg in weight (current weight 74 kg at
control the LHPA system increases. This prediction is 1.65 m, BMI of 27.2 kg/m2). Her fasting plasma glucose
consistent with the observation that an early postnatal stress (102 mg/dl) and cholesterol (180 mg/dl) are normal.
exposure due to maternal deprivation leads to a persisting
hyper-responsiveness of the LHPA system [233]. If the After the traumatic loss of her partner, Clara developed
LHPA system is stimulated chronically, this can lead to an an atypical depression. Patients with atypical depression are
increase in the system setpoint. lethargic, tired, hyperphagic, hypersomnolent, and avoid
If one assumes a setpoint increase of the LHPA system social contact. Unlike the endocrine modifications with
with chronic psychological stress, glucose allocation to the typical depression, patients with atypical depression show a
brain was increased while that to the body periphery was less active LHPA system, characterized by CRH deficiency
decreased in Anna’s case. As such the strength of the and hypocortisolism [255]. Dissociative behavior is also
glutamate command signal determines the low body mass. associated with low cortisol [257]. In its clinical presen-
If the glutamate command signal of the brain is very large or tation and neuroendocrine status atypical depression shows
is amplified by the limbic system, a loss in body mass many common features with ‘posttraumatic stress disorder’
critical to survival results. With chronic fasting, ketone body [258]. The neuroendocrine modifications resemble those
formation occurs in the liver. These ketone bodies can be caused by Liberzon in the ‘single prolonged stress’
metabolized by the brain in place of glucose. If ketone body paradigm (see above) [234]. The findings with atypical
formation in progressive anorexia nervosa is activated, a depression are consistent with a decreased MR to GR ratio
ketone-induced inhibition of the sympatho-adrenal system and can therefore be considered to represent a setpoint
in the hypothalamus occurs during this late stage of disease reduction of the LHPA system.
[153]. As a result, glucose allocation to the brain decreases. If one assumes a setpoint reduction of the LHPA system
Up until now no effect of ketone bodies on hunger has been after a single traumatic experience, it can be understood that
confirmed [253,254]. Ketones allow that at least a glucose allocation to the brain is inadequate amongst such
proportion of the available glucose is assigned to the traumatized individuals. Unlike the situation with progres-
musculature and adipose tissue. In the progression of sing hypoglycemia whereby only a few minutes are
anorexia nervosa, ketones therefore assume an important available for taking food, patients with a setpoint alteration
function for supplying energy to the brain and in so doing after a traumatic experience have sufficient time to ensure
enable the body mass to be maintained and stabilized. supply to the brain by increasing their food intake (see
Fig. 5d). The combination of increased glucose allocation to
From this new way of looking at limbic, long-term
muscle and adipose tissue results over the long term in a
changes, anorexia nervosa is based on a ‘learned’ setpoint
marked increase in peripheral body mass. In the Canadian
increase of the LHPA system with inadequate glucose
Twin Study it could indeed be shown that low plasma
allocation to the muscle and adipose tissue. As a result of
cortisol is a predictor for a substantial increase in body
this chronic stress, the brain competes excessively with the
weight [259]. A setpoint elevation of the LHPA-system, in
body periphery for energy resources.
contrast, results in opposite effects on body mass.
Experiments in mice with inactivated GR in the nervous
3.3. Obesity system (i.e. increased MR/GR-ratio and elevated setpoint)
showed increased activity of the LHPA-system and
A short-term load with a traumatizing stressor can cause a decreased peripheral fat accumulation [260].
setpoint reduction of the LHPA system [255,256]. Such a A setpoint-reduction of the LHPA system may result
setpoint change entails considerable metabolic consequences. from a wide spectrum of conditions and disorders that
disrupt or alter the ‘glutamate command’ signal and the various fractures, recovered only sluggishly, and resumed
MR – GR balance. These conditions may include extreme work only a year later. Before the accident Pedro was
stress situations (neuroglucopenia, traumatization, etc.), healthily and athletically built. In the time after his
starvation, exercise, or infectious diseases. Also ‘endocrine hospitalization, however, he puts on 15 kg in weight,
disrupting chemicals’ [261], i.e. environmental agents that mainly around the abdomen. For the last four weeks Pedro
alter the endocrine system, may displace the limbic is feeling weak, has resorted to drinking large amounts of
MR – GR balance and in so doing influence the mass of water, and loses 2 kg. After he finally seeks hospital
the body. Disturbances of the LHPA may also be located at treatment for angina pectoris the doctors diagnose
the hypothalamic level. As predicted by the model, VMH diabetes mellitus (blood glucose 350 mg/dl) as well as
and PVN lesions induce obesity [87,262]. Obesity also arterial hypertension (200/100 mmHg). Diabetes mellitus
arises from an attenuation of the stimulatory input from the occurred frequently in Pedro’s family.
periphery (e.g. fat-derived leptin or muscle-derived inter-
leukin-6) into these hypothalamic nuclei [6,263 – 266]. Pedro suffered a physical trauma. Similar to the
Similarly, the stimulatory input into these hypothalamic psychological trauma suffered by Clara, a serious physical
regions is reduced in melanocortin (MC4) condition can lead to a setpoint alteration in the LHPA
receptor deficiency. In our model, a-MSH and NPY act as system. Common to both situations is the coincidence of an
leptin-amplifying and leptin-attenuating signals, respect- insult and cortisol excess, which can lead to a decreased
ively. Selective disruption of the a-MSH pathway at the tone of the LHPA system. Similar to Clara, Pedro in the
MC4-receptor level would produce a predominance of NPY subsequent period developed obesity. However, the further
neurons and their attenuating action on the leptin signal. course of disease differed fundamentally.
Hypothalamic stimulatory input would be attenuated and, as The genetic background of people with a Mexican-
expected, obesity does indeed develop in MC4 deficient American origin differs from those of a European origin
mice [267]. Such disruptions may be localized in the [19]. The prevalence of type 2 diabetes mellitus and the
neocortex, the limbic system, or the hypothalamus. Higher metabolic syndrome (hyperglycemia, hyperlipoproteine-
brain structures and functions have therefore found a new mia, hypertension and abdominal obesity) is increased
role in the pathogenesis of obesity. amongst individuals of a Mexican-American origin
With increasing body weight ðMÞ; the brain ATP [269 –271]. In the chapter ‘economics of the alternative
regulatory system is burdened secondarily (Fig. 5b and e). brain-specific substrates’ we discussed that some groups
A larger peripheral adipose tissue mass is then able to with genetic peculiarities (Nauruans, Pima Indians) can
absorb more glucose, representing a larger competitor to the survive particularly long periods of starvation. We presume
brain for energy resources. The organism can respond to this that this adaptation is made possible by a leptin amplifier
metabolic load by increasing either food intake or mechanism. The melanocortin system fulfills the criteria for
allocation. The feedback effect of leptin mediates an one such leptin amplifier mechanism. If obesity develops
activation of glucose allocation to the brain (see the amongst people with specific genetic background allowing
feedback characteristic in Fig. 5b and e). The organism leptin amplification, it can be expected that such individuals
therefore reacts to the body weight increase by indirectly react to obesity in a special way.
increasing the burden on the LHPA system. People with a leptin amplifier mechanism react to the
In conclusion, the development of obesity occurs in two increase in serum leptin by increasing glucose allocation to
stages: (1) an initial setpoint reduction and (2) a compensa- the brain (see Fig. 5f). In an impressive experiment,
tory feedback-response of the LHPA system. In other words, Akira Mizuno and coworkers of the Takushima University
the brain in the first phase competes too little for energy in Japan were able to demonstrate the leptin-mediated
resources with the body periphery. In the second phase it feedback-effect on glucose allocation. The researchers
sees a growing, more forceful competitor in the periphery, treated vagotomized animals with leptin and examined
so that ultimately it has to compete even more with the body their insulin production under glucose loading. Leptin
periphery for energy. suppressed insulin secretion almost completely. The team
then carried out the same experiment with animals that were
3.4. Type 2 diabetes mellitus also sympathectomized; here, a renormalized insulin
secretion was shown. The experiment showed that leptin,
A setpoint change of the LHPA system can lead to the via the hypothalamus and its sympathetic efferents, can
development of obesity. The way in which the organism suppress insulin secretion and with that glucose allocation to
reacts to this metabolic load depends greatly on its genetic muscle and adipose tissue. That means in reverse that leptin
background [268]. concentrations increasing with body mass can promote
glucose allocation to the brain. It was recently shown that
Case 7: Pedro, a 40 year-old Mexican factory worker, had the melanocortin system can amplify this leptin feedback
suffered a severe accident at work 10 years previously. He effect even further; centrally applied melanocortin agonists
was in a coma for five days, was operated on repeatedly for inhibit insulin secretion [272]. Individuals with a marked
leptin amplification mechanism therefore react to the brain uses limbic plasticity to stabilize the self-
increasing leptin with a particularly strong activation of allocation process in the long run. After a stressful
glucose allocation to the brain. experience, such a newly achieved consolidation and
How does the body mass change with increased glucose stabilization of the self-allocation process may allow the
allocation to the brain? brain to reappraise its energy demand strategies. Fourth,
An increased glucose allocation to the brain coincides alterations in glucose allocation can be compensated by
with an increased sympatho-adrenally mediated lactate changes in food intake or by utilization of alternate
formation in the muscle [163 – 165]. Additional glucose and substrates such as lactate or ketones. Alternative strategies
lactate for the brain allows the body to reduce food intake of the brain to safeguard its energy needs can result in
while still guaranteeing the energy supply of the brain. A diseases such as obesity or type 2 diabetes mellitus.
decrease in appetite and food intake results in less energy These four basic tenets summarize the essentials of the
reaching the muscle and adipose tissues. An inhibited new theory: refutal of any of these tenets should lead to a
glucose uptake into the peripheral tissues results in an major questioning of the validity of the theory. From these
increased blood glucose concentration. If the blood glucose basic tenets we built various ramifications and in each
concentrations exceed the renal threshold, glucosuria case proposed molecular mechanisms to explain them.
occurs. In this way significant amounts of glucose can be The theory itself is not bound to one particular mechanism
eliminated (at 250 mg/dl blood glucose there is an approx. or another to explain these secondary aspects. For example,
10 g/l glucosuria). Such a glucose loss represents an we have proposed BDNF and its receptors as one
additional burden to the regulatory system. As such an mechanism underlying plasticity, but we cannot rule out
increased allocation to the brain coincides with both that another factor was more involved. If this were true,
appetite inhibition and glucosuria, and both can lead to a however, it would not actually jeopardize the theory.
negative energy balance. A population-based study from The presented theory also includes a newly discovered
Arizona has indeed shown that amongst patients not taking general principle of how two receptors can originate a
insulin after a type 2 diabetes mellitus is diagnosed, a long- setpoint in biological systems: High and low affinity
lasting decrease in weight is observed [273]. receptors bind to a ligand and after so doing they generate
In conclusion, a type 2 diabetes mellitus can arise in two a signal that results in an increase or decrease of ligand
phases: (1) an initial setpoint-reduction and (2) an increased concentrations, respectively. This ‘principle of balance’
feedback-mediated regulatory response of the LHPA describes the molecular mechanisms of setpoint signal
system. In the first phase the brain competes too little with generation which is essential for defining the ideal behavior
the body periphery so that obesity arises. With certain of a biological feedback control system.
genetic predispositions the brain reacts in a second phase Unlike traditional models, the paradigm presented by us
particularly strongly to the increase in body weight and fundamentally changes the hierarchy of the regulated
restricts the further growth of its peripheral competitor. parameters and places the brain’s energy needs at the
Interestingly, there is a certain analogy between the highest level. The size of the adipose tissue or muscle mass
development of type 2 diabetes mellitus and anorexia therefore becomes a secondary regulatory goal. According
nervosa. With anorexia nervosa, ketone bodies alleviate the to these concepts, obesity and type 2 diabetes represent
regulatory system as additional energy carriers. The ketone brain diseases with defects in neuroendocrine functions.
bodies prevent the body mass from falling below a certain Attempts to prevent or treat obesity can be successful only
critical mass. During the development of diabetes mellitus when these basic aspects are taken into account.
the organism loses energy through glucosuria (elimination
of energy-carriers). The ‘flowing through’ (in Greek
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The Selfish Brain: Competition For Energy Resources

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Neuroscience and Biobehavioral Reviews 28 (2004) 143–180

The selfish brain: competition for energy resources

* Corresponding author. Tel.: þ 49-451-500-3546; fax: þ49-451-500-4807.

2.2. Load of the brain-supplying regulatory system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155

1. Introduction transportation mechanisms across the blood – brain barrier

1. Increased glucose allocation to the brain due to stress from fasting.

2.2.1.3. Economics of the alternative brain-specific sub-

2.3.3. Memory formation during sleep

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