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AMPK: a metabolic gauge regulating whole-body

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Review

AMPK: a metabolic gauge regulating

whole-body energy homeostasis
Ricardo Lage1,2, Carlos Dieguez1,2, Antonio Vidal-Puig3 and Miguel Lopez1,2
1

Department of Physiology, School of Medicine, University of Santiago de Compostela, 15782, Santiago de Compostela, Spain
CIBER Fisiopatologa de la Obesidad y Nutricion (CIBERobn), Spain
3
Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrookes Hospital, University of Cambridge, CB2 0QQ,
Cambridge, UK
2

AMP-activated protein kinase (AMPK) is the downstream

component of a kinase cascade that acts as a gauge of
cellular energy levels. Over the last few years, accumulating evidence has demonstrated that AMPK is also
involved in the regulation of energy balance at the
whole-body level by responding to hormones and nutrient signals, which leads to changes in energy homeostasis. The physiological relevance of this new role of AMPK
is demonstrated by the fact that impairment of AMPK
function is associated with metabolic alterations, insulin
resistance, obesity, hormonal disorders and cardiovascular disease. Here, we summarize the role of AMPK in the
regulation of energy homeostasis. Understanding this
key enzyme and its tissue-specific regulation will provide
new targets for the treatment of metabolic disorders.
Regulation of energy homeostasis: the obesity
pandemic
Maintaining energy balance depends on the efficiency of
tightly regulated mechanisms of energy intake and expenditure. Obesity is ultimately the result of a chronic positive
imbalance between these two factors, a state where excess
fat accumulation in the white adipose tissue (WAT) causes
adverse health problems [1,2]. Increasing levels of obesity
have become one of the main health problems in both the
occidental and developing world, and this is a major
economic issue for these societies. The main concern over
obesity is its association with insulin resistance, type 2
diabetes, steatosis and a range of other disorders that have
generally been known as the metabolic syndrome [13]. For
this reason, during the last two decades much research
effort has centered on identifying the molecular mechanisms that control energy balance, as well as suitable therapeutic targets.
Besides the well-established role of nutrients, hormones and hypothalamic microcircuits (Box 1), recent
evidence has demonstrated that basic cellular metabolic
pathways have a major role in the regulation of wholebody energy homeostasis. Among them, much interest
and research has been focused on the AMP-activated
protein kinase (AMPK) pathway, a master sensor and
regulator of energy homeostasis at the cellular level [46].
During the last six years, accumulating evidence has
demonstrated that AMPK is also involved in the regulation of energy balance at the whole-body level by respond-

ing to hormonal and nutrient signals in both peripheral

tissues and the central nervous system (CNS) and modulating metabolism, feeding behavior and energy expenditure accordingly [46]. In this review, we will
summarize what is known about AMPK and energy
balance, discuss the pathophysiological implications of
this pathway and propose further avenues of research.
Understanding the AMPK cascade and its tissue-specific
regulation will provide new targets for the treatment
of obesity, insulin resistance, endocrine disorders and
cardiovascular disease.

Glossary
Adipokines: also known as adipocytokines, are a group of cytokines (cell-to-cell
signaling proteins) secreted by white adipose tissue (WAT). More than fifty
adipokines with diverse structures have already been discovered, and they can
be classified according to their functional role: appetite and energy balance,
immunity, insulin sensitivity, angiogenesis, blood pressure, lipid metabolism
and homeostasis. Among others, leptin, adiponectin (Adpn), resistin (RSTN),
tumor necrosis factor-a (TNF-a), interleukin 6 (IL-6), plasminogen activator
inhibitor 1 (PAI-1) and retinol binding protein 4 (RBP4) are adipokines.
AMP-activated protein kinase (AMPK): a serine/threonine protein kinase
composed of a catalytic subunit (a1 or a2) and two regulatory subunits (b1
or b2 and g1, g2 or g3). AMPK is activated by phosphorylation at Thr172 of the a
subunit, a process catalyzed by LKB1 or Ca2+/calmodulin-dependent protein
kinase kinase a (CaMKKa) and CaMKKb (especially the latter). AMPK is
allosterically activated by AMP. AMPK is the downstream component of a
kinase cascade that acts as a gauge of cellular energy levels, being activated by
increased AMP associated with low ATP.
ARC: arcuate hypothalamic nucleus, also called arcuate nucleus of the
hypothalamus.
Ca2+/calmodulin-dependent protein kinase kinase a (CaMKKa) and CaMKK(:
CaMKK is a serine/threonine protein kinase that is upstream of Ca2+/
calmodulin-dependent protein kinase (CaMK) and that is modulated by
calcium/calmodulin (Ca2+/CaM) complexes. Recent evidence has demonstrated
CaMKKs (especially CaMKKb) to be new upstream kinases that phosphorylate
AMPK at Thr172 in an AMP-independent manner.
DMH: dorsomedial hypothalamic nucleus, also called dorsomedial nucleus of
the hypothalamus.
LHA: the lateral hypothalamic area.
LKB1: a serine/threonine protein kinase that requires binding of mouse protein
25 (MO25) and Ste20-related adaptor protein (STRAD) for its activity. LKB1 is
the main upstream kinase of AMPK, phosphorylating it at Thr172. Mutations
that cause inactivation of the gene encoding LKB1 cause PeutzJeghers
syndrome, a dominantly inherited cancer predisposition syndrome, indicating
that LKB1 acts as a tumor suppressor.
Neuropeptide: a peptide found in neural tissue. There are about 100 different
neuropeptides (the number is continuously increasing), which are released by
different populations of neurons in the mammalian brain. Neuropeptides act
mainly as neuromodulators, but they also function as neurotransmitters and
hormones.
PVH: paraventricular hypothalamic nucleus, also called paraventricular
nucleus of the hypothalamus.
VMH: ventromedial hypothalamic nucleus, also called ventromedial nucleus of
the hypothalamus.

E-mail addresses: m.lopez@usc.es, miguellp@usc.es.

1471-4914/$ see front matter 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.molmed.2008.09.007 Available online 1 November 2008

539

Review

Trends in Molecular Medicine Vol.14 No.12

Box 1. Hypothalamic regulation of food intake

The hypothalamus is the brain region located below the thalamus. It
comprises the major portion of the ventral diencephalon and is
organized in anatomically defined neuronal clusters, called nuclei,
forming interconnected neuronal circuits via axonal projections. The
hypothalamus controls an immense number of bodily functions;
among them, the regulation of endocrine axes and body weight
homeostasis are particularly important. Hypothalamic nuclei respond to nutrients and hormones by modifying the expression of
specific neurotransmitters and neuromodulators, resulting in
changes in energy intake and expenditure [2,15]. The arcuate
hypothalamic nucleus (ARC) is considered to be the master
hypothalamic center for feeding control. Two distinct neuronal
populations in the ARC integrate peripheral nutritional and feeding
signals. One set of neurons expresses the orexigenic (feedingpromoting) neuropeptides agouti-related protein (AgRP) and neuropeptide Y (NPY). These neurons mostly project to other second
order neurons located in other hypothalamic nuclei, such as the
paraventricular hypothalamic nucleus (PVH). A second ARC population of neurons expresses the anorexigenic (feeding inhibiting)
products of proopiomelanocortin (POMC), the precursor of (melanocyte stimulating hormone (a-MSH) and the cocaine and
amphetamine regulated transcript (CART). This set of neurons
projects more broadly within the central nervous system (CNS) to
secondary hypothalamic nuclei such as the dorsomedial hypothalamic nucleus (DMH), the lateral hypothalamic area (LHA) and the
perifornical area (PFA), as well as the PVH. Dorsal to the ARC lays
the ventromedial hypothalamic nucleus (VMH), which mainly
receives projections from AgRP/NPY and CART/POMC neurons in
the ARC. Additionally, the VMH neurons project their axons to the
ARC, DMH and LHA, as well as to brainstem regions, such as the
nucleus of the solitary tract (NTS).
Hypothalamic neurons respond to peripheral signals, such as
glucose, leptin, ghrelin, adiponectin, resistin and insulin, by
modifying the synthesis of neuropeptides. When energy intake
exceeds expenditure, the expression of orexigenic neuropeptides,
such as AgRP and NPY, decreases. Conversely, the expression
anorexigenic neuropeptides, such as CART and POMC, increases.
Opposite changes occur when energy expenditure exceeds intake
[2,15].

AMPK, a master cellular energy gauge: structure and

regulation
AMPK is a highly evolutionarily conserved serine/threonine kinase, and orthologs of the AMPK subunits are found
in all eukaryotic species, such as Snf1 kinase in yeast [4,6].
At the molecular level, AMPK is a heterotrimer complex
comprising a catalytic a subunit, with a conventional
serine/threonine protein kinase domain, and two regulatory subunits, b and g. In mammals, each subunit is
encoded by multiple genes (a1, a2, b1, b2, g1, g2, g3),
which results in 12 possible combinations of AMPK complex (Figure 1). The a subunit contains an N-terminal
kinase domain and a C-terminal domain involved in complex formation with b and g subunits. The b subunits
contain conserved C-terminal domains that are sufficient
on their own to form a complex with a and g.
Both AMPK and Snf1 are activated via phosphorylation
by upstream kinases. The main upstream AMPK kinase is
the tumor suppressor LKB1 (see Glossary), which phosphorylates AMPK at Thr172 [46] (Figure 1). Several data
have recently demonstrated that LKB1 is constitutively
active [7] and have also determined the existence of nonLKB1 AMPK kinases. Based on the evidence that: (i)
multiple AMPK kinase (AMPKK) activities are found by
chromatography; (ii) in cells lacking LKB1, such as HeLa
540

Figure 1. Structure and regulation of AMP-activated protein kinase (AMPK). AMPK

is a heterotrimer complex consisting of a catalytic ( subunit and two regulatory
subunits, b and g. AMPK is the downstream component of a kinase cascade that
acts as a gauge of cellular energy levels, being activated through increased
phosphorylation of Thr172 within the catalytic a subunit caused by the upstream
tumor suppressor LKB1 and Ca2+/calmodulin-dependent protein kinase kinase
(CaMKK; especially CaMKKb). Recently, it has been reported that transforming
growth factor-b-activated kinase (TAK1) activates AMPK in yeast and rodents.
Protein phosphatase-2Ca (PP2Ca) dephosphorylates AMPK. Under conditions of
increased AMP, dephosphorylation of AMPK by PP2Ca is inhibited; because LKB1
is constitutively active, inhibition of the dephosphorylation reaction increases
phosphorylation at Thr172 and activation of AMPK. In addition to activation by
phosphorylation, AMPK is allosterically activated by AMP. A new mechanism of
modulation through ubiquinitation-mediating degradation has emerged recently
through a complex formed between cell-death-inducing like-effector A (Cidea) and
the AMPK( subunit. At the cellular level, AMPK is a counter-regulatory mechanism
that switches off (red line) ATP-consuming processes and switches on (green
arrow) catabolic processes that produce ATP. At the whole-body level, the
regulation in AMPK activity leads to changes in energy expenditure and feeding.

cells, A549 cells and murine embryo fibroblasts derived

from LKB1/ mice, there is some basal AMPK activity as a
result of Thr172 phosphorylation; and (iii) homology studies, three groups have recently identified Ca2+/calmodulin-dependent protein kinase kinase a (CaMKKa) and, in
particular, CaMKKb as new upstream kinases that phosphorylate AMPK in an AMP-independent manner, indicating that AMPK might have a role in Ca2+-mediated
signal transduction pathways [810] (Figure 1). Current
evidence has also demonstrated that transforming growth
factor-b-activated kinase (TAK1, also known as mitogenactivated protein kinase kinase kinase-7 [MAP3K7]) activates in vitro AMPK activity and also in vivo Snf1 activity
in yeast and AMPK activity in rodents [11] (Figure 1).
In addition to activation by phosphorylation, AMPK is
allosterically activated by AMP. In fact, AMPK is the
downstream component of a kinase cascade that acts as
a gauge of cellular energy levels, being activated by
increased AMP associated with low ATP [46]. The g
subunits of AMPK present a sequence motif of 60 residues repeated four times, which is known as a CBS

Review

Trends in Molecular Medicine

Vol.14 No.12

Table 1. Targets of AMPK and their biologic effects

Lipid metabolism

Organ/tissue

Target enzyme

Liver

Acetyl-CoA carboxylase-1/a
Malonyl-CoA decarboxylase
Fatty acid synthase
HMG-CoA reductase
Acetyl-CoA carboxylase-1/(

Immediate effect
(direct or indirect)
Enzyme activity#
Enzyme activity"
Transcription#
Enzyme activity#
Enzyme activity#

Fatty acid synthase

Transcription#

Acetyl-CoA carboxylase-2/b
Malonyl-CoA decarboxylase
Hormone-sensitive lipase a
Malonyl-CoA decarboxylase
GLUT4

Enzyme activity#
Enzyme activity"
Activation by PKA#
Enzyme activity"
Translocation to cell
membrane"
Expression"
Enzyme activity"
Enzyme activity#
Enzyme activity"
Expression#

Hypothalamus

Muscle
Adipose tissue
Glucose metabolism

Muscle

Heart
Liver

Mitochondrial
biogenesis/function

Pancreatic b cell
Muscle

Hexokinase
Glycogen synthase
6-phosphofructo-2-kinase
Phosphoenolpyruvate
carboxykinase
Glucose-6-phosphatase
?
Transcription factor NRF1
Co-activator PGC1a
UCP3

Expression#
Insulin release#
Expression"
Expression"
Expression"

Metabolic effect

Refs

Fatty acid synthesis#

Fatty acid synthesis#
Fatty acid synthesis#
Cholesterol synthesis#
Fatty acid synthesis#
Fatty acid oxidation"
Fatty acid synthesis#
Prevents decrease of
malonyl-CoA
Fatty acid oxidation"
Fatty acid oxidation"
Lipolysis# a
Fatty acid oxidation"
Glucose uptake"

[5,15,101]
[5,15,71]
[5,15,96]
[5,102]
[55,56,65,68,72,75,76]

Glycolytic flux"
Glycogen synthesis#
Glycolysis"
Gluconeogenesis#

[22,105]
[3235]
[5,106,107]
[28,29]

Gluconeogenesis#
Plasma insulin#
Mitochondrial biogenesis"
Mitochondrial biogenesis"
Mitochondrial proton leak"

[28,29]
[108,109]
[25,110]
[25]
[111]

[56,72]

[103]
[70,71]
[1618]
[71]
[22,104,105]

Key: ", stimulation; #, inhibition.

a
The role of AMPK in the regulation is complex and recent data have challenged the idea that AMPK inhibits lipolysis through direct phosphorylation of hormone-sensitive
lipase (HSL) and by the blocking of protein kinase A (PKA)-induced HSL activation [1921].

(cystathionine-b-synthase) domain; these domains are

involved in the nucleotide binding of either AMP or ATP
in a mutually exclusive manner [46]. AMP-promoted
phosphorylation by upstream kinases was considered for
a long time as an essential mechanism regulating AMPK,
even more important than allosteric activation itself. However, recent data have challenged that idea, demonstrating
that AMP does not promote phosphorylation by either

LKB1 or CaMKKb [7,12,13]. On the basis of these data,

a new model of AMPK regulation has been recently
suggested. The first part of the model describes AMP-dependent activation; under conditions of increased AMP,
dephosphorylation of AMPK by protein phosphatase-2Ca
(PP2Ca) is inhibited, and because LKB1 is constitutively
active [7], inhibition of the dephosphorylation reaction
increases phosphorylation at Thr172 and activation of

Figure 2. Roles of AMP-activated protein kinase (AMPK) in the control of whole-body energy metabolism. The figure shows the main metabolic effects of AMPK in different
tissues. Activation of AMPK (green arrows) stimulates energy-generating pathways in several tissues while inhibiting (red lines) energy-consuming pathways. AMPK
activation promotes fatty acid oxidation and glucose uptake in skeletal muscle and heart. Conversely, in the liver, AMPK activity inhibits fatty acid and cholesterol synthesis.
Lipogenesis is also reduced in adipose tissue by AMPK activation. The role of AMPK in lipolysis is complex. Former evidence demonstrated that in adipocytes, AMPK
inhibits lipolysis; however, recent data have confronted that idea (see the section entitled AMPK regulates lipid metabolism in the main text). AMPK inhibits insulin
secretion from pancreatic b cells. Finally, hypothalamic AMPK has a key role in the regulation of food intake.

541

Review
AMPK. This occurs in addition to the allosteric activation
of AMPK by AMP. The second part of the model decribes
Ca2+-dependent activation; increases in Ca2+ lead to activation of CaMKKb, which increases Thr172 phosphorylation and activation of AMPK. This mechanism can occur
without an increase in AMP [7] (Figure 1). Finally, recent
data have revealed a new mechanism that modulates
AMPK independently of AMP and phosphorylation or
dephosphorylation processes. Cell-death-inducing likeeffector A (Cidea) forms a complex with the b subunit of
AMPK, which elicits an ubiquitination-mediated degradation of AMPK, reducing its activity [14] (Figure 1).
Roles of AMPK in peripheral tissues: metabolic
pathways regulated by AMPK
The classical view of AMPK, as described above, is as an
intracellular energy gauge that modulates the energy
balance within the cell. Thus, in many tissues, activated
(phosphorylated) AMPK acts as a counter-regulatory
mechanism that switches off ATP-consuming processes
while switching on catabolic processes that produce ATP

Trends in Molecular Medicine Vol.14 No.12

and restore the AMP:ATP ratio [46]. Next, we will

describe the role of AMPK in the control of whole-body
energy homeostasis in different tissues and organs, which
is also summarized in Table 1.
AMPK regulates lipid metabolism
AMPK is a key modulator of lipid metabolism (Table 1,
Figures 2 and 3). In fact, one of the best characterized
targets for AMPK is the fatty acid synthesis pathway (Box
2) in the liver and hypothalamus. Activated AMPK phosphorylates and inhibits acetyl-CoA carboxylase (ACC)
activity and decreases fatty acid synthase (FAS) expression while activating malonyl-CoA decarboxylase (MCD),
thereby reducing the flux of substrates in the fatty acid
anabolic pathway [5,15]. In liver and hypothalamus and in
muscle during exercise contraction, activated AMPK not
only inhibits fatty acid synthesis but also activates fatty
oxidation by reducing the levels of malonyl-CoA, the product of ACC, which is a potent allosteric inhibitor of
carnitine palmitoyltransferase 1 (CPT1), the enzyme
importing long chain fatty acyl-CoA into the mitochondria

Figure 3. Mechanisms of AMP-activated protein kinase (AMPK) regulation in the hypothalamus. In the hypothalamus, positive energy balance signals inhibit AMPK
phosphorylation and activation and negative energy balance signals stimulate AMPK phosphorylation and activation. These signals are integrated and probably progress
through alterations in the tumor suppressor LKB1 and the Ca2+/calmodulin-dependent protein kinase kinase b (CaMKKb) pathways. A series of metabolic events, such as
regulation of fatty acid synthesis, and gene transcription events, such as transcription of the neuropeptide Y (npy) gene, is started that eventually leads to an inhibition or
stimulation of food intake.

542

Review
Box 2. Fatty acid synthesis and fatty acid oxidation
Fatty acid synthesis is a metabolic pathway that synthesizes fatty
acids. Under lipogenic conditions, excess glucose in the cell is first
converted to pyruvate via glycolysis in the cytoplasm. Pyruvate
enters the mitochondria and is converted to acetyl-CoA and
transported as citrate from mitochondria into cytoplasm. ATP citrate
lyase (ACL) then reconverts citrate to acetyl-CoA. Acetyl-CoA
carboxylase (ACC) catalyzes the carboxylation of acetyl-CoA to
malonyl-CoA in an ATP-dependent manner. Acetyl-CoA and malonyl-CoA are then used as the substrates for the production of
palmitate by the seven-enzymatic reactions catalyzed by fatty acid
synthase (FAS) at the expense of NADPH. The synthesis step of
malonyl-CoA is a reversible regulated mechanism, and malonyl-CoA
decarboxylase (MCD) converts malonyl-CoA back to acetyl-CoA. The
resulting saturated fatty acid molecule produced by FAS can be
desaturated to form unsaturated fatty acids, triglyceride molecules
for storage or a range of phospholipids and derivatives for
membrane and signaling functions [5,15]. Alternative fatty acids
can also be further metabolized depending on requirements. The
oxidative degradation of fatty acids is called fatty acid oxidation. The
fatty acid is first activated in the outer mitochondrial membrane in a
reaction catalyzed by long-chain fatty acyl-CoA synthetase. Next, by
the action of carnitine palmitoyltransferase 1 and 2 (CPT1 and CPT2),
the fatty acid is translocated to the mitochondrial matrix, where
oxidation takes place [5,15]. The complete oxidation of a palmitic
acid molecule (C16:0) yields 129 molecules of ATP.

for fatty acid b-oxidation (Box 2 and Figure 3) [5,15]. The

role of AMPK in lipolysis is complex. Former evidence
demonstrated that in adipocytes, AMPK inhibits lipolysis
through direct phosphorylation of hormone-sensitive
lipase (HSL) and by the blocking of protein kinase A
(PKA)-induced HSL activation [1618]. However, recent
data conflict with this idea, showing that (i) activation of
AMPK through a cAMP-dependent mechanism is required
for activation of lipolysis in 3T3-L1 cells [19], (ii) AMPK
modulates adrenaline-induced lipolysis in isolated adipocytes [20] and (iii) AMPK stimulates lipolysis in adipocytes via phosphorylation of HSL [21]. Further work will
be necessary to clarify the exact role of AMPK in lipolysis.
Finally, concomitant inactivation of ACC and hydroxymethyl-3-glutaryl-CoA (HMG-CoA) reductase in hepatocytes by AMPK inhibits cholesterol synthesis [5].
AMPK regulates glucose homeostasis
Glucose homeostasis is maintained by a balance between
hepatic glucose production and glucose uptake by peripheral tissues. AMPK also exerts a potent effect on glucose
metabolism (Table 1 and Figure 2). Activation of AMPK by
muscle contraction enhances glucose uptake through the
translocation of glucose transporter 4 (GLUT4) to the cell
membrane and also through the regulation of Glut4 gene
expression [22]. Interestingly, this effect shows dependence of the fiber type, with AMPK increasing glucose
uptake in fast-twitch (glycolytic) muscles, such as epitrochlearis, but not in slow-twitch (oxidative) soleus [23,24].
AMPK activation also increases hexokinase II expression
[22]. In parallel with these effects, AMPK is required for
mitochondrial biogenesis in muscle in response to dietinduced chronic energy deprivation, an effect associated
with increased expression of nuclear respiratory factor 1
(NRF-1) and peroxisomal proliferator-activated receptor g
(PPARg) coactivator 1 (PGC-1) [25]. Similar effects can be

Trends in Molecular Medicine

Vol.14 No.12

observed in skeletal muscle after activation of AMPK with

AICAR (5-amino-4-imidazole carboxamide riboside) [26].
Finally, it has been demonstrated that mitochondrial biogenesis in response to chronic activation of AMPK was
decreased in old rats, suggesting that aging-associated
reductions in AMPK activity might be an important contributing factor to the reduced mitochondrial function and
impaired intracellular lipid metabolism associated with
aging [27].
Gluconeogenesis is a metabolic pathway that results in
the generation of glucose from non-carbohydrate carbon
substrates, such as pyruvate, lactate, glycerol and glucogenic amino acids. The vast majority of gluconeogenesis
takes place in the liver and, to a smaller extent, in the
cortex of kidneys. This process occurs during periods of
fasting, starvation or intense exercise [5]. AMPK regulates
hepatic gluconeogenesis by inhibiting the transcription of
phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) [28,29]. Thus, liver-specific
AMPKa2- and LKB1-knockout (KO) mice exhibit glucose
intolerance and fasting-induced hyperglycemia, presumably because of elevated gluconeogenesis associated with
increased PEPCK and G6Pase activity. This effect is
mediated by inhibition by phosphorylation of the transcriptional coactivador transducer of regulated cAMP response
element-binding protein activity 2 (TORC2), a recently
discovered zinc finger transcription factor called AREBP
and the immediate early transcription factor Egr1 (early
growth response 1), a known transcriptional activator of
dual specificity protein phosphatase 4 (Dusp4, also known
as MAP kinase phosphatase 2 [MKP-2]) [30,31].
AMPK also regulates glycogen metabolism. In skeletal
muscle, AMPK activation phosphorylates glycogen
synthase (GS), decreasing its activity and thus reducing
glycogen synthesis [32,33]. The molecular mechanisms
underlying this effect, and particularly the mechanisms
of glycogen synthesis after exercise (glycogen supercompensation), are complex and involve the interaction of
multiple regulatory factors, including major roles for
AMPKg subunits (especially g2 and g3) [34,35]. Finally,
in both rat and human muscle, there is also evidence that
high cellular glycogen content represses activation of
AMPK [33].
Overall, these data suggest that AMPK plays a fundamental part in modulating glucose and lipid metabolism.
Next, we will describe how AMPK integrates the effect of
peripheral hormones on those metabolic pathways.
AMPK mediates the metabolic effects of hormones in
peripheral tissues
Peripheral tissues have emerged as key players in energy
metabolism through the release of substrates and hormones, such as insulin, adipokines (leptin, adiponectin
[Adpn], resistin [RSTN]), ghrelin, thyroid hormones, endocannabinoids and glucocorticoids, all of which are involved
in metabolism and insulin sensitivity. Many of the metabolic effects of these hormones are mediated by AMPK. In
this section, we will review the actions of some of these
hormones on AMPK in peripheral tissues. The effect on
hypothalamic neurons will be discussed in greater detail in
the following section.
543

Review
Leptin
Leptin is the classical adipokine and has a crucial role in
the regulation of feeding, energy expenditure and neuroendocrine control (for an extensive review, see Ref. [36]).
The first evidence linking leptin and AMPK came from the
seminal work of Kahns group, who demonstrated that
peripheral leptin administration stimulated the phosphorylation and activation of the AMPKa2 in skeletal
muscle, leading to inhibition of fatty acid synthesis and
stimulation of fatty acid oxidation and glucose uptake [37].
Interestingly, this effect shows: (i) a time-dependent frame
(early activation of AMPK occurs by leptin acting directly
on muscle, whereas later activation depends on leptin
functioning through the hypothalamic melanocortinsympathetic axis and a adrenergic receptors in muscle) [37,38];
and (ii) dependence of the type of fiber [39]. At the molecular level, the leptins effects on fatty acid oxidation are
mediated by AMPK via two mechanisms: (i) the direct
effect of AMPKa2 on ACCb (ACC-2) and (ii) the stimulation of PPARa [37,40]. Activated AMPKa2 containing
the b1 subunit is retained in the cytoplasm, where it
phosphorylates ACC-2/b and thereby stimulates fatty acid
oxidation. By contrast, AMPKa2 containing the b2 subunit
is translocated to the nucleus, where it induces PPARa
gene transcription [40].
The pathophysiological relevance of leptin effects on
muscle AMPK is intriguing. It has been recently reported
that diet-induced obesity (DIO) impairs the AMPK and
ACC response to leptin in muscle (and also in the hypothalamus, see below) [41,42]. In addition, in vitro data have
demonstrated that in myotubes from obese subjects, elevated suppressor of cytokine signaling-3 (SOCS-3) expression suppresses leptin-dependent AMPK signaling and
fatty acid oxidation [43]. Importantly, the high-fat diet
(HFD)-induced attenuation of AMPK and ACC phosphorylation is restored by central treatment with the melanocortin agonist melanotan II (MT-II) [38]. Finally, it has
been recently proposed that leptin effects on muscle
thermogenesis could also be mediated by AMPK [44];
further work will be required to address this hypothesis.
Adiponectin (Adpn)
Adpn is an insulin-sensitizing white adipocyte-secreted
molecule that improves glucose uptake and fatty acid
oxidation in muscle, reduces hepatic glucose production
and enhances insulin sensitivity at the whole-body level. In
contrast to leptin, its secretion and plasma concentration
are inversely related to adiposity. Plasma Adpn concentrations are decreased in obese and type 2 diabetes [45].
Adpn stimulates the phosphorylation of AMPK in liver and
muscle, and this is the molecular mechanism that mediates the above-described actions [46,47]. The effects of
Adpn on AMPK are extensively linked to other tissues.
Adpn inhibits hypertrophic signaling in the myocardium
through activation of AMPK signaling. In keeping with
this observation, Adpn-deficient mice display cardiac
hypertrophy, heart failure and increased mortality [48].
The pathological relevance of these data is interesting and
suggests a potential role for the AdpnAMPK interaction
in the treatment of heart disease. Indeed, it has been
recently reported that Adpn protects against myocardial
544

Trends in Molecular Medicine Vol.14 No.12

ischemiareperfusion injury through an AMPK-dependent

mechanism [49]. Adpn also activates AMPK in WAT,
increasing glucose uptake independently of the insulin
signaling pathway [50]; whether AMPK induces the translocation of GLUT4 to the membranes of adipocyte is
unknown.
Resistin (RSTN)
RSTN is an adipocyte-derived hormone [51,52] that generally seems to have opposite effects to those of Adpn: RSTN
promotes insulin resistance, stimulates glucose production, decreases fatty acid uptake and metabolism in
skeletal muscle, impairs adipocyte differentiation and promotes inflammation [5153]. RSTN expression, as well as
other adipokines, is markedly affected by nutritional and
metabolic status, being decreased by food deprivation and
increased in obesity and insulin resistance [51,52]. Contrary to leptin and Adpn, RSTN reduces hepatic AMPK
activation, suggesting a role in glucose production [54].
Ghrelin
Ghrelin is a hormone that is produced mainly in the
stomach and that has orexigenic properties; it is thus
linked to weight gain and adiposity [55,56]. Ghrelin inhibits AMPK in liver and WAT and so increases gluconeogenesis and lipogenesis [55,57]. Recent data suggest that
AMPK mediates the beneficial effects of ghrelin on cardiovascular function, such as the reduction of myocyte apoptosis [55]. However, ghrelin does not modulate AMPK in
skeletal muscle [55,57].
Endocannabinoids
Endocannabinoids, such as anandamide and 2-arachydoglycerol, are lipid-like molecules acting on cannabinoid
receptor type-1 (CB1) and -2 (CB2). Besides their psychological effects, endocannabinoids stimulate feeding and de
novo fatty acid synthesis and gluconeogenesis in peripheral tissues [58]. Endocannabinoids inhibit AMPK activity
in the liver and WAT and thus promote fat accumulation
and weight gain. Similarly to ghrelin, it has been recently
proposed that AMPK mediates the favorable effects of
endocannabinoids on the ischemic heart, such as the
reduction in infarct size in the myocardium [55]. Contrary
to their action in liver, WAT and heart, endocannabinoids
do not modulate AMPK in skeletal muscle [55].
Thyroid hormones
Thyroid hormones (T4 and T3) play a fundamental part in
regulating energy homeostasis and metabolism through
their actions on the CNS and periphery [59]. Thyroid
hormones exert short-term non-genomic actions on AMPK
and, interestingly, these actions show a tissue-specific
pattern. Thus, in skeletal (but not in cardiac) muscle, T3
treatment activates AMPK via intracellular Ca2+ mobilization and CaMKKb activation, and increased AMPK
activity in turn decreases the levels of malonyl-CoA (as
a consequence of ACC inactivation) and stimulates mitochondrial fatty acid oxidation [60,61]. Conversely, T3
decreases AMPK activation in liver [60]. The physiological
relevance of these actions is unclear, but recent data
indicate that T3-induced AMPK activation in muscle is

Review
associated with increased expression of PGC1a [60],
suggesting that this mechanism might be important in
mediating hormone-induced increases in mitochondrial
biogenesis. The role of AMPK in the orexigenic actions
of thyroid hormones is still not fully explored. Very recent
data have demonstrated that T3 stimulates feeding by
increasing hypothalamic AMPK [62].Whether this effect
could be linked to the feeding alterations observed in
thyroid status disorders, such as hyperthyroidism and
hypothyroidism [59], will require further investigation.
Ciliary neurotrophic factor (CNTF)
CNTF promotes weight loss, improves glucose tolerance
and reduces feeding [63]. A recent study has demonstrated
that CNTF increases fatty acid oxidation and reduces
insulin resistance in skeletal muscle by activating AMPK
independently of signaling through the brain. Interestingly, these effects are not suppressed by diet-induced or
genetic models of obesity, which indicates a new potential
therapeutic target [64].
Hypothalamic AMPK: a newly emerged regulator of
food intake
Up to this point, we have mainly focused on peripheral
AMPK, which acts as a key sensor of energy balance by
integrating nutritional and hormonal signals with modulation of the metabolism. However, current data are also
showing that AMPK acts in hypothalamic neurons, linking
metabolic status to classical neuropeptide and neurotransmitter systems, which ultimately regulate feeding, and the
evidence is as follows. AMPK is expressed in several key
hypothalamic nuclei, such as the ARC, PVH, VMH and
LHA (see Glossary) [56,6567]. Regulation of AMPK in the
hypothalamus is part of the adaptive changes observed
during physiological regulation of feeding. Fasting
increases AMPK activity in multiple hypothalamic regions
and refeeding inhibits it [56,65,68]. Activation of AMPK in
the hypothalamus increases feeding and body weight gain,
whereas inhibition of hypothalamic AMPK activity promotes hypophagia and weight lost [56,65,68].
AMPK is a key modulator of the hypothalamic fatty acid
metabolic pathway (Box 2 and Figure 3). Activated AMPK
phosphorylates and inhibits ACC and decreases FAS
mRNA expression via a sterol regulatory element binding
protein-1 (SREBP1)-dependent mechanism [56]. The net
result of this effect is a marked decrease in malonyl-CoA
levels, which stimulates CPT1 activity and thus increases
feeding [55,56,68,69]. There is evidence that AMPK also
controls the activity of MCD in peripheral tissues, such as
liver, muscle and adipose tissue [70,71]; however, there are
no data linking hypothalamic AMPK and MCD.
The crucial importance of the different components of
this hypothalamic AMPKmalonyl-CoACPT1 axis [56,72]
in the control of energy homeostasis is demonstrated by the
fact that it mediates the effects of the peripheral and
central signals that regulate feeding. Anorectic signals,
such as leptin, insulin, glucagon-like peptide-1 (GLP-1),
CNTF and melanocortin receptor agonists, inhibit hypothalamic AMPK, resulting in increased ACC activity
[65,68,7377] (Figure 3). It has been proposed that insulin
deficiency is one of the factors underlying hypothalamic

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Vol.14 No.12

AMPK activation and the subsequent hyperphagia

observed in streptozotocin (STZ)-induced diabetic rats
[73]. The molecular mechanism that triggers this action
in the hypothalamus remains unclear, but recent data
obtained in the heart indicate that insulin effects on AMPK
might be mediated through an Akt-dependent mechanism
[78].
In contrast to anorectic hormones, orexigenic signals,
such as cannabinoids, glucocorticoids, Adpn, ghrelin, thyroid hormones and agouti-related protein (AgRP), activate
hypothalamic AMPK [55,56,62,68,72,7981] (Figure 3). In
relation to this, it has been recently reported that ghrelin
effects on feeding are mediated via the AMPKmalonylCoACPT1 axis [56,72] linked to uncoupling protein 2
(UCP2) [81]. RSTN, despite its anorectic effect, activates
hypothalamic AMPK [52] (Figure 3).
In addition to hormonal signals and neuropeptides,
hypothalamic AMPK is regulated by nutrients and intermediate metabolites. For example, AMPK activation in
several hypothalamic nuclei, such as the VMH, ARC and
PVH, seems to have prominent roles in hypoglycemia
sensing [82] and mediating counter-regulatory responses
[66,83]. Similarly, central administration of glucose suppresses AMPK activity in the hypothalamus [65]. a-Lipoic
acid, a cofactor of mitochondrial enzymes that has antioxidant and anorectic properties, also inhibits AMPK
activity in the hypothalamus [84]. Lastly, intracerebroventricular (ICV) administration of citrate elicits an anorexigenic response associated with inhibition of AMPK,
activation of ACC and subsequent increase in malonylCoA [85].
The integrative role of hypothalamic AMPK in wholebody energy homeostasis is demonstrated by the fact that
nutrient- and hormonal-induced alterations in hypothalamic AMPK activity correlate with changes in neuropeptide expression that occur mainly in the ARC (which
shows changes in the expression of, e.g., AgRP, neuropeptide Y [NPY] and proopiomelanocortin [POMC]
[52,56,65,80,8588]) but also in the LHA and PVH (which
show changes in the expression of, e.g., melanin-concentrating hormone [MCH] [65] and corticotrophin-releasing
hormone [CRH] [85], respectively) (Figure 3). The molecular mechanisms underlying neuropeptide AMPKmediated expression are still unclear, but some data
obtained via both in vivo and in vitro models have indicated roles for cAMP response element-binding protein
(CREB) [86], the mammalian target of rapamycin
(mTOR) pathway [89], the activation of muscarinic receptors [90] and UCP2 [81]. Altogether, these data suggest
the existence of several downstream pathways linking
AMPK with neuropeptides (Figure 3).
Finally, a recent study has demonstrated that CaMKKb
(CaMKK2) regulates in vivo AMPK activity and NPY
expression and modulates ghrelins action in the hypothalamus (Figure 3). Furthermore, CaMKKb KO mice
are protected against HFD-induced obesity, insulin resistance and glucose intolerance [91]. Further work will be
required to fully characterize the role of hypothalamic
CaMKKb in energy homeostasis and, more importantly,
to address whether it might be a suitable target for therapeutic intervention.
545

Review

Trends in Molecular Medicine Vol.14 No.12

Role of hypothalamic AMPK in the development of

obesity and disease-associated feeding disorders
A role of hypothalamic AMPK in energy balance is evident,
but its importance in the progression to obesity is uncertain. It has been recently demonstrated that impaired
responses of AMPK to leptin might be involved in leptin
resistance in obese states [42]. Several mouse models with
targeted deletions of different AMPK subunits have been
generated (for an extensive review, see Ref. [5]). Among
them, just the global AMPKa2 KO fed under HFD [92] and
the AMPKa2 KO in POMC neurons (POMCa2KO) fed
under standard and HFD show increased body weight
and fat [88,93]. Conversely, mice with selective ablation
of AMPKa2 in AgRP (AgRPa2 KO) neurons show an agedependent lean phenotype [88]. The lack of dramatic phenotypes in terms of body weight and food intake in AMPK
KOs might be caused by compensation by the remaining
catalytic subunits, that is, in the AMPKa2 KO mice,
AMPKa1 is upregulated [92]. However, further work is
required because recently it has been demonstrated that
the obese phenotype in POMCa2-KO mice is not caused by
compensatory upregulation of AMPKa1 [88]. The development of other mouse models specifically targeting AMPK
subunits in specific hypothalamic nuclei or neurons will
clarify the role of hypothalamic AMPK in the pathophysiology of obesity and the physiological response to peripheral hormones and metabolites. As an example, it was
recently reported that deletion of AMPKa2 in hypothalamic POMC and AgRP is essential for glucose sensing but
not for mediating the effects of leptin and insulin [88].
Recent papers have involved hypothalamic AMPK in
pathogenic processes. Thus, hypothalamic AMPK activation reverses cancer anorexia by blocking the expression
of interleukin 1b (IL-1b) and tumor necrosis factor-a (TNFa), thereby increasing lifetime [94]. Whether modulation of
hypothalamic AMPK might be a therapeutic target for the
treatment of cancer-induced anorexia will need further
research. Another recent study has reported that glucocorticoid excess increases AMPK signaling in the liver and
hypothalamus but decreases it in WAT and heart, indicating that impaired AMPK might be under the hyperphagia,
increased adiposity, steatosis and cardiac phenotype of
Cushing Syndrome [95].
Targeting the AMPK pathway
An important reason for the interest in AMPK is the fact
that it represents a potential target for the treatment of
type 2 diabetes (Table 2). Metformin, a drug that lowers
blood glucose levels via a decrease in hepatic gluconeogenesis, reduces circulating lipid levels and increases insulin
sensitivity in muscle and liver, activates AMPK by increasing Thr172 phosphorylation [96,97]. In the pancreatic bcell, metformin decreases mitochondrial ATP synthesis,
which results in impaired glucose sensitivity and inhibition of insulin release [98]. Thiazolidinediones (TZDs),

such as rosiglitazone, improve insulin sensitivity through a

double mechanism based in the regulation of PPARg-activated genes and also by modulation of AMPK [5,97].
Rosiglitazone activates skeletal muscle AMPK by increasing the AMP:ATP ratio [97]. Recent pharmacological data
are suggesting that pharmacological targeting of AMPK
might be a potential treatment for obesity. C75, a FAS
inhibitor, reduces feeding via hypothalamic AMPK [86,99].
This effect is also observed after central administration of
compound C, a non-specific AMPK inhibitor in all tissues,
[56]. In terms of regulation of feeding, it is crucial to
perfectly define the exact place where these events take
place. Recent data obtained for our group, using stereotaxic
delivery of AMPK dominant negative adenoviruses,
suggest that the VMH is the key hypothalamic nucleus
for AMPK regulation of food intake [56].
Finally, it is interesting to note that besides AICAR,
which is the classical non-specific AMPK activator in many
tissues [6,16,26,29], a new AMPK activator a non-nucleoside compound, referred as A-769662, from the thienopyridone family has recently been identified and
characterized [29,100]. Treatment of ob/ob mice with A769662 reduces hepatic expression of PEPCK, G6Pase and
FAS, lowers plasma glucose, reduces body weight gain and
decreases both plasma and liver triglyceride levels [29],
suggesting that this drug or a similar one could be an
alternative approach for the treatment of type 2 diabetes
and other metabolic disorders.
Concluding remarks
Physiological, pharmacological and genetic data clearly
demonstrate that manipulating the activity of AMPK
and its upstream kinases, LKB1 and CaMKKb, in different
tissues has a profound impact on feeding, body weight,
glucose homeostasis and insulin sensitivity in rodents and
humans. In addition, recent studies have demonstrated
that impaired AMPK signaling promotes heart disease,
cancer-induced anorexia and the metabolic alterations of
Cushing Syndrome. Altogether, this evidence strengthens
the idea that, besides its role as cellular sensor, AMPK has
a crucial role in the regulation of energy balance at the
whole-body level, opening avenues for future therapeutic
and medical intervention not just for insulin resistance,
obesity and related disorders but also for feeding and
metabolic alterations associated with disease. However,
in our view, several questions remain to be answered (Box
3) before AMPK can be considered as a common target for
the treatment of the obesity and feeding alterations. What
is the molecular mechanism underlying AMPK-tissuespecific regulation by peripheral hormones? Do these hormones show a differential and tissue-specific effect on
AMPK, LKB1 and CaMKKs, or even on PP2Ca? What
would be the long-term consequences of targeting hypothalamic AMPK, a key regulator of glucose and lipid
metabolic pathways? Would this compromise neuronal

Table 2. Drugs targeting the AMPK pathway in different tissues

Drug
Metformin
Rosiglitazone
C75

Skeletal muscle
" [96]
" [97]

Key: ", stimulation; #, inhibition; , non-reported effect.

546

Liver
" [96]

" [86]

Pancreatic ( cell
" [98]

Hypothalamus

# [86]

Non-hypothalamic neurones

"/# [99]

Review
Box 3. Outstanding questions
What are the molecular mechanisms underlying AMPK-tissuespecific regulation by peripheral hormones? For example, leptin
activates AMPK in muscle, which promotes fatty acid oxidation [37],
but inhibits it in the hypothalamus, which ultimately inhibits feeding
[65]. Conversely, endocannabinoids and ghrelin inhibit AMPK in
liver and WAT, which promotes fatty acid synthesis [55,57], but
promote AMPK in the hypothalamus, which inhibits fatty acid
synthesis and ultimately stimulates feeding [5557,68,72,79,80].
Finally, resistin (RSTN) inhibits AMPK in liver [54] but activates it
in the hypothalamus [52]. Do these hormones show a differential
and tissue-specific effect on LKB1 and Ca2+/calmodulin-dependent
protein kinase kinases (CaMKKs) or even on protein phosphatase-2C
(PP2C)? Generation of tissue-specific LKB1-, CaMKK- and protein
PP2C-KO models, as well as tissue-specific AMPK activators and
inhibitors, will help to clarify these questions.
Current data have demonstrated that although leptin effect on
AMPK is present in the majority of hypothalamic nuclei [65], the
ghrelin orexigenic action is mediated by selective modulation of
AMPK activity in the VMH [56,72]. As a result of this, hypothalamic
malonyl-CoA decreases, carnitine palmitoyltransferase 1 (CPT1) is
activated and feeding increases [56,72]. Do other signals regulating
AMPK (such as endocannabinoids, glucocorticoids, adiponectin,
RSTN, insulin, glucagon-like peptide 1 [GLP-1] and ciliary neurotrophic factor [CNTF]) regulate hypothalamic AMPK in a nucleusspecific fashion?
Finally, peripheral AMPK has been demonstrated as a suitable
target for type 2 diabetes; however, what are the therapeutic
possibilities of targeting hypothalamic AMPK for obesity? Given
the housekeeping role of de novo lipogenesis, it would be necessary
to establish the long-term consequences of its pharmacological
modulation in neurons: would it affect neuron viability and
function?

viability and function? If so, the targeting of specific

neuronal populations via the generation of hypothalamic
nuclei-specific LKB1-, CaMKK- and PP2C-KO models, as
well as via tissue-specific AMPK pathway activators and
inhibitors, will be key next steps in this field that will help
to clarify these issues.
Acknowledgements
We thank Victoria Bonnici for editing the manuscript. This work has been
supported by grants from the Xunta de Galicia (C.D.,
PGIDIT06PXIB208063PR and M.L., GRC2006/66), Fondo
Investigationes Sanitarias (M.L., PI061700), Ministerio de Educacion y
Ciencia (C.D., BFU2005), European Union (C.D., LSHM-CT-2003
503041: Diabesity, http://www.eurodiabesity.org; and A.V-P., LSHM-CT2005018734: Hepadip, http://www.hepadip.org), Mutua Madrilena (C.D.
and M.L.), Medical Research Council (A.V-P.) and Wellcome Trust (A.VP.). CIBER de Fisiopatologa de la Obesidad y Nutricion is an initiative of
Instituto de Salud Carlos III (ISCIII).

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