2011 PHYS REV Leptina e o Controle Do Sistema Nervoso Central

Physiol Rev 91: 389 – 411, 2011;
doi:10.1152/physrev.00007.2010.
Leptin and the Central Nervous System Control

of Glucose Metabolism
GREGORY J. MORTON AND MICHAEL W. SCHWARTZ
Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington,

Seattle, Washington
I. Introduction 389
A. Model of CNS control of energy and glucose homeostasis 390
B. Adiposity signals: insulin and leptin 391
II. Leptin Signaling 391
A. Jak-STAT pathway 391
B. IRS-PI3K pathway 392
III. Central Nervous System-Mediated Effects of Leptin on Glucose Metabolism 393
A. Leptin and glucose metabolism 393
B. Sites and CNS mechanisms underlying leptin action on glucose metabolism 395
C. Role of hypothalamic PI3K: insight from CNS insulin action 396
D. CNS nutrient-sensing 397
E. Leptin-sensitive neuronal subsets 397
F. Effect of CNS leptin to regulate glucose metabolism 400
G. Extrahypothalamic neurocircuits involved in leptin regulation of insulin sensitivity 401
H. Indirect effects of CNS leptin on glucose metabolism 402
V. Perspectives 403
A. Leptin resistance and obesity pathogenesis 403
B. Physiological relevance 405
VI. Concluding Remarks 405
Morton GJ, Schwartz MW. Leptin and the Central Nervous System Control of Glucose Metabolism. Physiol Rev
91: 389 – 411, 2011; doi:10.1152/physrev.00007.2010.—The regulation of body fat stores and blood glucose levels is
critical for survival. This review highlights growing evidence that leptin action in the central nervous system plays
a key role in both processes. Investigation into underlying mechanisms has begun to clarify the physiological role
of leptin in the control of glucose metabolism and raises interesting new possibilities for the treatment of diabetes
and related disorders.
I. INTRODUCTION for a better understanding of how body weight and glu-

cose metabolism are regulated is compelling, as such
Obesity, insulin resistance, and type 2 diabetes are information is essential if we are to develop new strate-
growing health concerns, and the incidence and preva- gies for the safe and effective treatments for obesity and
lence of these diseases are increasing worldwide (175). In type 2 diabetes.
the United States alone, more than two-thirds of adults In studies dating back to the 19th century, the French
are classified as either overweight or obese, while more physiologist Claude Bernard observed that puncturing the
than 23 million people have been diagnosed with type 2 floor of the fourth ventricle (“piqure diabetique”) induced
diabetes (117). These numbers are expected to increase in diabetes (18), suggesting that the brain plays an important
the foreseeable future with costs for obesity in the United role in the control of blood glucose. Following the dis-
States alone well in excess of $100 billion per year (156, covery of insulin in the early 20th century (8), however,
175). Obesity is associated with increased morbidity, be- research into the regulation of glucose metabolism fo-
cause it is a major risk factor for diabetes, cardiovascular cused primarily on insulin secretion and on its action in
disease, and cancer. Diabetes, in turn, greatly increases peripheral tissues such as liver, muscle, and adipose tis-
the risk of heart disease and both macro- and microvas- sue. One result of this research effort is clear evidence,
cular disease (175, 202). Given these statistics, the need accumulated over the last 40 years, that obesity is asso-
www.prv.org 389
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Copyright © 2011 American Physiological Society. All rights reserved.
390 LEPTIN AND GLUCOSE METABOLISM
ciated with insulin resistance in these tissues and that this

insulin resistance is a cardinal feature of type 2 diabetes
(125). Consequently, pharmaceutical strategies for the
treatment of type 2 diabetes have tended to focus on
either increasing insulin secretion or improving insulin
sensitivity. Yet while a large literature provides insight
into the pathogenesis of obesity-associated insulin resis-
tance, a parallel body of evidence suggests that the CNS
plays an important role in the regulation of glucose me-
tabolism and that dysfunction of this control system may
contribute to metabolic consequences of obesity (161).
A. Model of CNS Control of Energy and

Glucose Homeostasis
The brain continuously transduces input from neu-

ral, hormonal, and nutrient-related signals into re-
sponses that maintain both energy and glucose homeo-
stasis. Afferent signals such as the hormones insulin
and leptin convey information to the brain regarding
long-term energy stores, while information regarding
short-term energy availability is conveyed by nutrient-
related signals such as glucose and free fatty acids
(FFA). In response to this input, the brain makes adjust-
ments to output systems that control food intake, energy
expenditure, hepatic insulin sensitivity, and glucose up-
take (Fig. 1). To restore homeostasis in the face of re-
duced energy stores or energy availability for example,
the brain initiates responses that promote both positive
energy balance (i.e., increased food intake and reduced FIG. 1. Model of CNS regulation of glucose homeostasis. The CNS
energy expenditure) and increased nutrient availability integrates signals from both long-term energy stores (e.g., leptin) and
short-term availability (nutrients; e.g., free fatty acids) and orchestrates
(increased endogenous glucose production). Conversely, responses that coordinate hepatic glucose production, peripheral glu-
in times of nutrient abundance and excess energy storage, cose uptake, and insulin secretion to maintain glucose homeostasis.
the brain initiates responses that both promote negative
energy balance and limit endogenous glucose production.
In view of anatomical overlap in brain areas involved in protective mechanism for survival (164). In 1953, Ken-
energy homeostasis and glucose metabolism, dysfunction nedy (92) first hypothesized that body adiposity was reg-
along a single neuroregulatory pathway can potentially ulated by circulating factors released in proportion to
predispose to both obesity and type 2 diabetes; remedying adipose tissue mass that acted in the brain to maintain
such a defect could therefore be of benefit in the treat- energy balance. While there was a concerted effort by
ment of both disorders. The goal of this review is to researchers to identify circulating factors involved in en-
highlight recent advances in our understanding of the ergy homeostasis, it wasn’t until 1994, when Zhang et al.
CNS mechanisms governing glucose metabolism, with a (212) successfully identified and cloned the ob gene and
special focus on the adipocyte hormone leptin. demonstrated that it is expressed selectively in adipose
A large and compelling body of evidence supports tissue and encodes a peptide hormone that was subse-
the hypothesis that hormonal signals generated in propor- quently termed “leptin,” mutation of which caused obesity
tion to body fat stores act in the CNS via a negative- in the ob/ob mouse. Not long thereafter, the leptin recep-
feedback loop to promote energy homeostasis. Early sup- tor was cloned, its expression was demonstrated in the
port for this model was based on the adaptive response to hypothalamus and other tissues (183), and the db muta-
conditions characterized by negative energy balance and tion was localized to this gene locus (100). As expected,
weight loss. These include the increase of food intake and either intraperitoneal or intracerebroventricular adminis-
reduction of energy expenditure induced by energy depri- tration of leptin, reduced food intake, and body weight in
vation or chronic energy restriction that enables the effi- ob/ob mice, whereas db/db mice failed to respond (30, 76,
cient recovery of lost weight, comprising an important 141, 192). Taken together, these data provided compelling
Physiol Rev • VOL 91 • APRIL 2011 • www.prv.org

GREGORY J. MORTON AND MICHAEL W. SCHWARTZ 391
initial support for the hypothesis that an adipose-tissue Janus kinase-2 (Jak2) is activated (69), resulting in the
derived circulating factor acts in the CNS to regulate phosphorylation of three tyrosine residues on LepRb
energy balance and that maintenance of normal body fat (Tyr985, Tyr1077, Tyr1138) that in turn recruit and activate a
stores is dependent on the integrity of this endocrine distinct set of downstream signaling proteins. Phosphor-
system. The clinical relevance of this work was confirmed ylation of Tyr985 recruits SH2 domain-containing phospha-
by evidence that severe obesity results in humans as well tase-2 (SHP-2) to LepRb, leading to the activation of the
as in mouse models from mutation of genes encoding extracellular signal regulated (ERK) signaling pathway in
either leptin (118, 212) or its receptor (100, 110, 181). cultured cells, as well as the recruitment of suppressor of
cytokine signaling-3 (SOCS-3), a negative regulator of
LepRb signaling (6, 21, 22). In contrast, phosphorylation
B. Adiposity Signals: Insulin and Leptin of Tyr1138 recruits signal transduction and activator of
transcription-3 (STAT3), which is then itself phosphory-
Several lines of evidence support the hypothesis that lated on tyrosine residues by Jak2 allowing it to dimerize
in addition to leptin, the pancreatic hormone insulin also and translocate to the nucleus where it functions as a
acts in the brain as an “adiposity negative-feedback sig- transcription factor (6, 23, 186). Among the genes tran-
nal.” Both hormones circulate at levels that vary in pro- scriptionally induced by STAT3 is SOCS-3, which causes
portion to body fat stores (4, 39), and both enter the CNS negative-feedback inhibition of leptin signaling by binding
in proportion to their plasma level (160), where they act to Tyr985 of LepRb to block its signaling (Fig. 2). Phos-
on their respective receptors expressed in key brain areas phorylation of Tyr1077 and Tyr1138 promotes the recruit-
that control energy balance, glucose metabolism, and au- ment, phosphorylation, and transcriptional activation of
tonomic function (10, 11, 53). Administration of either STAT5 (71), and leptin may also activate signals gener-
peptide into the brain reduces food intake and body ated by Jak2 phosphorylation that are independent of
weight (30, 76, 200), while conversely, deficiency of either tyrosine phosphorylation sites on LepRb.
hormone or their respective receptors in the CNS results To determine the functional significance of each of
in hyperphagia, weight gain, and insulin resistance (27, these LepRb tyrosine residues in vivo, an approach was
174, 183, 212). In humans subjected to weight loss due to taken to generate homologously targeted “knock-in” mice
energy restriction, administration of leptin at doses that whereby sequences encoding substitution mutants of spe-
maintain preweight loss plasma levels blocks the reduc- cific LepRb phosphorylation sites replace the endogenous
tion of sympathetic nervous system (SNS) activity and Lepr allele. Mice bearing a mutant LepRb gene in which
metabolic rate characteristic of the weight-reduced state Tyr1138 is replaced by a serine residue (s/s mice) are
(151). Taken together, these data support the hypothesis unable to recruit STAT3 and are characterized by hy-
that energy homeostasis involves negative-feedback sig- perphagia, obesity (14), and reduced energy expenditure
nals that circulate in proportion to body fat and act cen- (12), suggesting that the Tyr1138-STAT3 pathway plays a
trally to inhibit food intake on the one hand, and to crucial role in the regulation of energy homeostasis (12,
increase energy expenditure on the other. Although this 14). However, the phenotype of these s/s mice does not
review focuses primarily on leptin, its many areas of completely mimic that of either ob/ob or db/db mice with
overlap with the actions of insulin in the brain warrant a respect to glucose metabolism, immune function, or re-
focus on both hormones. production (13, 14), implying that other LepRb signals
must also contribute to leptin action.
II. LEPTIN SIGNALING To determine the contribution of LepRb Tyr985 to
leptin action in vivo, mice were generated in which the
endogenous LepRb allele was replaced with a mutant in
A. Jak-STAT Pathway which a serine residue is substituted for Tyr985. In con-
trast to the hyperphagic, obese phenotype of animals
The leptin receptor contains an extracellular ligand- mutant for Tyr1138, mutation of Tyr985 in these (l/l) mice
binding domain, a single transmembrane domain, and a resulted in a lean phenotype characterized by reduced
cytoplasmic signaling domain and is member of the inter- food intake and adiposity as well as increased leptin
leukin (IL)-6 receptor family of class 1 cytokine receptors sensitivity (24). These results support data from cultured
(182). Among the various isoforms of LepR, only the cells (22), suggesting that Tyr985 attenuates leptin action
“long,” or “signaling” form, LepRb, appears to be compe- in vivo, presumably by serving as the SOCS-3 binding site
tent for intracellular signal transduction and is critical for (24). Since SOCS-3 can also be induced via the IKK␤-
energy homeostasis. This assertion is based in part on NF␬␤ pathway during cellular inflammation, this mecha-
evidence that mice that lack only LepRb (e.g., db/db mice) nism can contribute to leptin resistance in this setting
exhibit a phenotype similar to leptin-deficient ob/ob mice (211) and has been implicated in the pathogenesis of
(100). Upon leptin binding to LepRb, the tyrosine kinase diet-induced obesity (DIO) (87, 119, 211). What remains

of STAT5 in mice (via RIP-cre or Nestin-cre) causes a

mild-obesity phenotype (101). However, in addition to
leptin, several other cytokines and growth factors activate
STAT5 including granulocyte macrophage colony stimu-
lating factor (GM-CSF), prolactin, and growth hormone,
amongst others (101). Second, the use of RIP-cre and
Nestin-cre deletes some, but not all, LepRb-expressing
neurons as well as deleting many non-LepRb-expressing
neurons. Generation of mice bearing LepRb Tyr1077 sub-
stitution will help to clarify the physiological role of lep-
tin-mediated STAT5 signaling.
To investigate the potential role in leptin action for
signals activated by Jak2 independent of LepRb phos-
phorylation, homologous recombination was used to re-
place Lepr with a truncated LepRb mutant (LepRb⌬65)
(150). These ⌬/⌬ mice exhibit a phenotype that resembles
db/db mice where energy homeostasis, neuroendocrine,
and immune function are concerned, but also are charac-
terized by a delayed progression to diabetes, suggesting
a modest improvement in glucose homeostasis (150).
Taken together, these findings suggest that Jak2-autono-
mous LepRb signals are insufficient to mediate most of
the physiological actions of leptin.
Studies from knock-in mice have therefore offered
important insight into the physiological contribution of
specific tyrosine residues on LepRb to leptin action in
vivo. Although leptin clearly activates the Jak-STAT path-
way in mediobasal hypothalamus (186), and although this
pathway is clearly critical for leptin regulation of energy
homeostasis (14), leptin also elicits neuronal responses in
a time frame of seconds to minutes that cannot be ex-
plained by STAT3-mediated changes of gene transcrip-
tion. For instance, in electrophysiological studies using
FIG. 2. Leptin receptor signaling. Leptin binding to LepRb mediates freshly prepared hypothalamic slices, leptin rapidly
activation of the tyrosine kinase Janus kinase-2 (Jak2), resulting in
phosphorylation of three tyrosine residues (Tyr985, Tyr1077, Tyr1138).
changes the membrane potential and firing rate of neu-
Phosphorylation of Tyr985 recruits SHP-2, leading to the activation of the rons (42, 176), and leptin-induced inhibition of food in-
ERK pathway, and also binds to suppressor of cytokine signaling-3 take is observed within an hour. These observations
(SOCS-3), a negative regulator of LepRb signaling. Phosphorylation of
Tyr1077 mediates signal transduction and activator of transcription-5
prompted a search for leptin-activated signal transduction
(STAT5). Phosphorylation of Tyr1138 recruits and activates STAT3 and mechanisms additional to the Jak-STAT pathway.
STAT5. Activation of STAT3 leads to increased SOCS-3 expression,
which acts as a negative-feedback inhibitor of leptin signaling, in part, by
binding to Tyr985 of LepRb. In addition, hypothalamic inflammation is
also induced during high-fat feeding and increases SOCS-3 expression.
B. IRS-PI3K Pathway
Similar to SOCS-3, protein tyrosine phosphatase (PTP) 1B may also
inhibit LepRb signaling via dephosphorylation of Jak2.
Similarities between insulin and leptin action in the
CNS prompted investigation of the hypothesis that intra-
uncertain based on the phenotype of both s/s and l/l mice cellular signaling by insulin and leptin converge in key
is the extent to which Tyr1077 and/or Jak2-dependent sig- neuronal subsets at the level of the insulin receptor sub-
nals independent of LepRb tyrosine phosphorylation me- strate-phosphatidylinositol-3-OH kinase (IRS-PI3K) path-
diate leptin action in vivo. way (Fig. 3). Initial support for this hypothesis was pro-
Recent evidence suggests that leptin is capable of vided by electrophysiological studies in which leptin and
activating STAT5 in the hypothalamic arcuate nucleus insulin were shown to hyperpolarize a subset of “glucose-
(ARC) in vivo (126), in addition to cultured cells (71), responsive” neurons in the ARC via activation of the
raising the possibility that LepRb-STAT5 signaling con- ATP-sensitive potassium channel (KATP) (176, 177) via a
tributes to the physiological actions of leptin. This hy- mechanism that was blocked by a PI3K inhibitor (116,
pothesis is supported by evidence that neuronal deletion 177). Other early studies showed that like insulin, leptin

activates the IRS-PI3K pathway in the hypothalamus, and ingly, genome-wide scans have identified the SH2B1 gene
pharmacological inhibition of PI3K activity in the brain locus as an obesity risk allele in human populations (195).
blocks the ability of leptin to reduce food intake (129, Leptin has also been reported to activate nutrient-sensing
130). A potential mechanism linking the leptin receptor to enzymes including AMP-activated protein kinase (AMPK)
IRS-PI3K signaling involves the protein SH2B1 (103), (115) and mammalian target of rapamycin (mTOR) signal-
which appears to facilitate Jak2-mediated IRS phosphor- ing pathways (41), although neither the neuronal subsets
ylation in response to leptin receptor activation. Interest- nor the molecular mechanism involved have been eluci-
dated.
We note here that although leptin and insulin both
have the potential to activate IRS-PI3K signaling in neu-
rons and other cell types, both the subcellular localization
and intracellular consequences of this activation can dif-
fer substantially depending on cell type and on whether
activation is mediated by leptin versus insulin. Stated
differently, the assertion that similarities in the behavioral
or metabolic actions of insulin and leptin in the brain
reflect convergence of intracellular signaling via PI3K or
other transduction mechanisms is an oversimplification,
and additional studies are needed to better understand
neuronal responses to these hormones and their conse-
quences for energy homeostasis and glucose metabolism
(157). Progress made using mouse genetics in this effort is
discussed in section IIIE.
III. CENTRAL NERVOUS SYSTEM-MEDIATED

EFFECTS OF LEPTIN ON
GLUCOSE METABOLISM
A. Leptin and Glucose Metabolism
In addition to the well-established role played by

leptin in the regulation of energy homeostasis (198),
growing evidence implicates leptin in glucose homeosta-
sis as well, particularly in the control of peripheral tissue
insulin sensitivity. The earliest evidence for such a role
FIG. 3. Leptin and insulin signal transduction pathways in the CNS.

A: activation of the insulin receptor induces tyrosine phosphorylation of
insulin receptor substrate (IRS) proteins, which in turn activate phos-
phatidylinositol 3-kinase (PI3K), an enzyme that phosphorylates phos-
phatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-
trisphosphate (PIP3) and activates several downstream molecules in-
cluding 3-phosphoinositide-dependent protein kinase 1 (PDK1), protein
kinase B (PKB; also referred to as Akt), and mammalian target of
rapamycin (mTOR). B: leptin binding to the extracellular domain of the
LepRb activates Janus kinase-2 (JAK2), leading to binding and tyrosine
phosphorylation of STAT3, which dimerizes, translocates to the nucleus,
and activates transcription of target genes SOCS-3, which can attenuate
both insulin and leptin receptor signaling. Like insulin, leptin signaling
can also activate PI3K, and downstream targets, presumably via tyrosine
phosphorylation of IRS proteins by Jak2. Although leptin and insulin
both have the potential to activate IRS-PI3K signaling in neurons and
other cell types, important differences in the response to these two
hormones exist. These likely arise from divergent roles for PI3K signal-
ing within a given cell type due to differences in the intracellular
microdomain in which PI3K signaling is activated, or from distinct cell
subpopulations that respond to either leptin or insulin, but not both
(e.g., POMC neurons). PTEN, phosphatase and tensin homolog.

comes from studies in mice with genetic leptin deficiency Another model of leptin deficiency is that which oc-
(ob/ob mouse) or leptin receptor deficiency (db/db mouse curs in uncontrolled insulin-deficient diabetes (uDM), in-
or fa/fa rat). Such animals exhibit not only hyperphagia duced by the loss of insulin-secreting beta-cells. As the
and obesity, but insulin resistance and diabetes as well synthesis and storage of fat requires insulin, weight gain
(37, 57, 181, 212). While increased food intake and body cannot occur in uDM, despite elevated food intake,
adiposity clearly contribute to impaired glucose metabo- known as “diabetic hyperphagia,” in this setting. Conse-
lism in these rodent models, several observations suggest quently, uDM is characterized by both hyperglycemia and
that leptin regulates glucose metabolism independently of hyperphagia (102), with progressive loss of body fat
its effects on energy balance. Not only is caloric restric- stores, and with a dramatic reduction of circulating levels
tion limited in its ability to improve insulin sensitivity and of leptin as well as insulin (78). Since the excess calories
hyperglycemia in animals with genetic leptin or leptin- consumed cannot be stored as fat, they contribute to
receptor deficiency (122, 203), leptin administration to hyperglycemia and are ultimately lost through the urine,
leptin-deficient mice or humans ameliorates hyperglyce- and the ensuing diuresis causes dehydration leading to
mia and hyperinsulinemia (60, 141) even when differences increased water intake (108). Although insulin deficiency
of food intake are controlled by pair-feeding (80, 158). is primarily responsible for hyperglycemia and weight
Severe insulin resistance and diabetes are also ob- loss in uDM, at least some of the beneficial effects of
served in genetic disorders characterized by reduced lep- insulin treatment may in fact arise from an associated
tin levels due to disorders of adipose tissue development. increase of leptin action since plasma leptin levels are
Such conditions, termed “lipodystrophy,” can result from normalized by insulin treatment in uDM rats (78). Simi-
any of several mutations that impair adipogenesis and larly, reduction in the plasma level of both leptin and
thus severely limit the capacity to store triglyceride. In insulin is implicated in the pathogenesis of diabetic hy-
humans, the two most common genetic lipodystrophies perphagia in rats treated with streptozotocin (STZ) (173),
are congenital generalized lipodystrophy (CGL), a condi- a chemical agent that selectively destroys pancreatic
tion in which body fat is absent from birth, and familial
beta-cells. A role for leptin deficiency in the hyperphagia
partial lipodystrophy (FPL), where the loss of body fat is
characteristic of uDM was established by preventing the
progressive and variable, occurring during childhood and
fall in plasma leptin levels by systemic administration of
puberty (172). In addition to genetic lipodystrophy, ac-
exogenous leptin at a dose that maintains normal physi-
quired lipodystrophies also have been described (and are
ological plasma leptin levels in rats with STZ-induced
more common), including acquired partial lipodystrophy
diabetes (173).
(APL), acquired generalized lipodystrophy (AGL), and that
Similarly, leptin deficiency has recently been impli-
induced by highly active antiretroviral therapy (HAART)
cated in the progressive insulin resistance and associated
containing human immunodeficiency virus (HIV)-1 protease
inhibitors in HIV-infected patients. neuroendocrine derangements seen in uDM. Systemic ad-
A pathophysiological sequence of events shared in ministration of exogenous leptin at a dose that maintains
common by these lipodystrophic disorders is that the loss normal physiological plasma leptin levels prevented the
of adipocytes and the inability to store fat leads to accu- development of severe, progressive insulin resistance in
mulation of excess nutrients (including triglyceride) in rats with uDM, an effect that could not be explained by
liver, muscle, and other tissues, causing metabolic impair- leptin-induced changes of food intake or body weight
ment. Several lines of evidence from both humans and (68). Moreover, the mechanism underlying this effect ap-
rodent models suggest that leptin deficiency contributes peared to preferentially involve the liver, as physiological
to insulin resistance and diabetes in this setting (139, 168, leptin replacement in uDM reduced hepatic triglyceride
169). For one, transplantation of body fat from wild-type content and gluconeogenic gene expression, and also re-
animals improves insulin sensitivity in a mouse model of stored normal insulin signal transduction in liver, but not
lipodystrophy, whereas transplantation of fat from ob/ob in skeletal muscle or white adipose tissue (WAT). This
mice has no effect (38, 63). As in leptin-deficient mice, the intervention also normalized circulating levels of gluca-
diabetes phenotype of these lipodystrophic mice is also gon and corticosterone, both of which are elevated in
ameliorated by leptin administration via a mechanism uDM. Thus leptin deficiency plays a key role in neuroen-
that is, at least in part, independent of its effect on food docrine disturbances linked to hyperglycemia in uDM. Yet
intake and body weight (64, 168). In humans, leptin ther- physiological leptin replacement only modestly reduced
apy has been examined in several clinical trials in patients blood glucose levels in this setting (68), demonstrating
with lipodystrophy, and these have demonstrated signifi- that factors beyond leptin deficiency (and elevated levels
cant improvements in glycemia, dyslipidemia, and hepatic of glucagon and corticosterone) are sufficient to explain
steatosis (89, 90, 139, 142). At present, congenital lipodys- hyperglycemia in this model. Thus, although prevention
trophy is the only clinical condition for which a compel- of leptin deficiency may ameliorate insulin resistance and
ling indication for leptin therapy has been established. related endocrine disorders and hence confer benefit to

humans with diabetes, this intervention seems unlikely to nous leptin increased glucose turnover and glucose up-
substantially improve hyperglycemia in and of itself. take but decreased hepatic glycogen content (91). In ob/ob
Interestingly, hyperleptinemia induced by either pharma- mice, intravenous leptin also increased glucose turnover
cological leptin administration (34) or with adenoviral and stimulated glucose uptake in brown adipose tissue
gene therapy (210) fully ameliorates hyperglycemia in (BAT), brain, and heart but not in skeletal muscle or WAT
STZ-induced diabetic rats, even in the face of extremely (29). Among several lines of evidence implicating the
low plasma insulin levels. Although the mechanism un- brain in the actions of leptin on glucose metabolism is the
derlying this effect requires additional study, it may in- observation that the effect is similar whether leptin is
volve a suppression of hepatic glucose production (HGP). administered intravenously or via intracerebroventricular
In normal individuals, insulin-induced suppression of infusion (at much lower doses) in both rats (106) and
HGP is critical for the control of blood glucose levels. mice (91). Despite clear evidence that leptin has direct
Consequently, in uDM, glucose production is unre- actions on pancreatic beta-cells, skeletal muscle, fat, and
strained, and therefore contributes importantly to dia- other tissues, low-dose intracerebroventricular adminis-
betic hyperglycemia. Several lines of evidence suggest tration of leptin corrects the insulin resistance and diabe-
that hyperglucagonemia contributes to the hyperglyce- tes phenotype of both leptin-deficient ob/ob and lipodys-
mia in uDM, at least in part by driving the hepatic trophic mice (2). Similarly, intracerebroventricular ad-
expression of the gluconeogenic genes, glucose-6-phos- ministration of leptin normalizes blood glucose levels in
phatase (G6Pase) and phosphoenolpyruvate kinase STZ-diabetic rats at doses that are ineffective when ad-
(Pepck) (47, 123). ministered peripherally (43, 82, 104, 190). Moreover, we
This hypothesis was articulated by Yu et al. (210), recently found that continuous infusion of leptin directly
who reported that the antidiabetic effects of leptin in into the brain normalizes blood glucose levels in STZ-
STZ-induced diabetes are accompanied by normalization induced diabetic rats via a mechanism that cannot be
of elevated glucagon levels. Moreover, glucagon receptor- explained by reduced food intake, increased urinary glu-
null mice remain normoglycemic following treatment cose losses, or a recovery of pancreatic beta-cells. In-
with alloxan to induce uDM, suggesting that intact gluca- stead, leptin action in the brain potently suppressed he-
gon signaling is required for diabetic hyperglycemia and patic glucose production while increasing tissue glucose
hence that the leptin-mediated decrease of plasma gluca- uptake despite persistent, severe insulin deficiency (67).
gon levels may mediate its effects on blood glucose (191). This leptin action is distinct from its previously reported
Although this hypothesis merits further study, the obser- effect to increase insulin sensitivity in the liver (66, 146)
vation that in rats with STZ-induced uDM, hyperglycemia and offers compelling evidence of a novel mechanism
is only slightly improved by physiological leptin replace- through which the brain normalizes diabetic hyperglyce-
ment despite normalized plasma glucagon levels (68) sug- mia without the need for insulin (67). Taken together,
gests that the latter cannot fully explain the hypoglycemic these data provide compelling evidence that the CNS
effect of pharmacological leptin administration in this mediates key effects of leptin on glucose metabolism.
setting. Collectively, these data suggest that deficient en- Using in situ hybridization and immunohistochem-
dogenous leptin signaling underlies at least some mani- ical techniques, leprb mRNA and protein have both
festations of uDM and raise the intriguing possibility that been detected in several hypothalamic areas involved
leptin therapy may one day constitute a useful adjunct to in the control of energy balance and autonomic func-
insulin in diabetes treatment. tion, including the ARC, ventromedial nucleus (VMH),
and dorsomedial nucleus (DMN), with lesser amounts in
the paraventricular nucleus (PVN) and the lateral hypo-
B. Sites and CNS Mechanisms Underlying Leptin thalamic area (LHA) (10, 53). Beyond the hypothalamus,
Action on Glucose Metabolism functional leptin receptors are expressed in the hip-
pocampus, hindbrain [including the nucleus of the soli-
To determine the mechanism by which leptin influ- tary tract (NTS)], pyriform cortex and other olfactory
ences glucose metabolism, the acute effects of a pharma- processing areas, and in mesolimbic areas involved in
cological dose of leptin on peripheral and hepatic insulin reward including the ventral tegmental area (VTA) and
action were studied using the euglycemic-hyperinsuline- substantia nigra (SN) (61, 72).
mic clamp technique. In nondiabetic rats, an acute intra- To investigate the role of the ARC in the action of
venous leptin infusion enhanced insulin’s ability to sup- leptin on peripheral glucose metabolism, gene targeting
press glucose production without affecting glucose up- and gene therapy techniques have been used to selec-
take. This enhanced insulin-mediated suppression of tively restore leptin signaling to this brain area in leptin
glucose production was due to a marked suppression of receptor-deficient animals. Coppari et al. (40) studied
hepatic glycogenolysis, whereas gluconeogenesis was mice in which the endogenous Lepr allele was replaced by
paradoxically increased (152). In wild-type mice, intrave- a mutant construct through which gene expression is

blocked by insertion of a “floxed” stop cassette (Leprneo/neo for the ability of insulin to inhibit food intake (129). While
mice). Microinjection of a virus expressing cre recombi- insulin is well known for its actions in peripheral tissues
nase was then used in these mice to restore Lepr expres- such as liver, muscle, and fat in the control glucose me-
sion in a brain region-specific manner. With this ap- tabolism, several studies identify a role for insulin action
proach, unilateral, selective restoration of leptin signaling in the brain as well. For example, mice with neuron-
to the ARC was found to have only modest effects on food specific deletion of either the insulin receptor (IR) or
intake and body weight, while it markedly improved hy- insulin receptor substrate-2 (IRS-2) are characterized by
perinsulinemia and normalized blood glucose levels (40). mild obesity and insulin resistance (27, 97, 105). More-
We developed a complementary approach using the leptin over, while selectively restoring insulin receptors to the
receptor-deficient Koletsky (fak/fak) rat, in which genetic liver and pancreas of insulin receptor-deficient mice res-
obesity arises from a point mutation that results in the cues them from perinatal lethality, restoration of insulin
absence of all forms of the leptin receptor (181). These signaling to the brain as well prevents the development of
animals are characterized by obesity, hyperphagia, insulin diabetes (136).
resistance, and glucose intolerance but are not hypergly- Using a complementary approach, Koch and col-
cemic (57). Using adenoviral gene therapy, we found that leagues acutely inactivated insulin receptor signaling ei-
selective restoration of leptin receptor signaling to the ther in all tissues including brain (IR⌬wb) or in a manner
ARC significantly improved peripheral insulin sensitivity that was restricted to peripheral tissues (IR⌬per) (95). The
via a mechanism that was not dependent on reduced food IR⌬per mouse model used cre-recombinase fused to the
intake or body weight (122). Furthermore, the effect of estrogen receptor to acutely induce insulin receptor defi-
leptin signaling in the ARC to improve insulin sensitivity ciency in peripheral tissues, through peripheral adminis-
was attenuated by intracerebroventricular administration tration of the synthetic estrogen receptor antagonist ta-
of the PI3K inhibitor LY294002, while it was mimicked by moxifen. To acutely induce insulin receptor deficiency in
ARC-directed expression of a constitutively active mutant both peripheral tissues and brain, a second mouse model
of Akt/protein kinase B (PKB), a key downstream medi-
was created using conditional RNAi-mediated gene
ator of PI3K (122). These findings suggest that leptin
knockdown through the expression of a ubiquitous IR-
signaling limited to the ARC is sufficient to promote nor-
specific shRNA under the transcriptional control of the
mal insulin sensitivity and that the neuronal signaling
human H1/U6 promoter that contains a tetracycline-oper-
mechanism underlying this leptin effect involves PI3K.
ated sequence (tetO). Upon doxycycline administration,
the tetracycline repressor (tetR) which silences the
C. Role of Hypothalamic PI3K: Insight From CNS shRNA is sequestered from the promoter, allowing ubiq-
Insulin Action uitous transcription of the IR shRNA. With the use of each
of these elegant approaches, inducible inaction of the IR
The hypothesis that PI3K signaling contributes to the in both peripheral tissues and brain consistently causes a
effects of hypothalamic leptin action on glucose metabo- more pronounced diabetes phenotype than when recep-
lism is further supported by studies in which the endog- tor deletion occurs in peripheral tissues alone, thus im-
enous leptin receptor was replaced with a mutant allele plicating neuronal insulin action in the control of glucose
(leprS1138) that prevents LepRb-STAT3 signaling without homeostasis (95).
affecting other transduction pathways. As expected, these Consistent with a role for CNS insulin action in the
mice exhibit hyperphagia and obesity, yet their impair- control of glucose metabolism, either intrahypothalamic
ment of glucose metabolism is mild compared with either administration of antisense oligonucleotides to reduce
ob/ob or db/db mice (13). Furthermore, since defective insulin receptor signaling or local infusion of the PI3K
glucose metabolism in these mice is prevented by chronic inhibitor, LY294002, causes hepatic insulin resistance in
caloric restriction (13), whereas this does not occur in rats (132). Conversely, administration of insulin into ei-
calorically restricted db/db mice (203), leptin receptor- ther the third ventricle or the mediobasal hypothalamus
mediated STAT3 signaling appears to be critical for en- improves insulin sensitivity via enhanced suppression of
ergy homeostasis, but not for glucose homeostasis. Lep- hepatic glucose production, with no effect on glucose
tin-stimulated PI3K signaling likely contributes to this uptake (135). Moreover, these effects of insulin are
mechanism, based on findings noted above (122), and is blocked by infusion of the PI3K inhibitor and also appear
consistent with recent evidence that Jak2-mediated sig- to require activation of KATP channels (135, 145). Simi-
nals that are independent of LepRb tyrosine phosphory- larly, increasing hypothalamic PI3K signaling, a major
lation contribute to the modulation of glucose homeosta- intracellular mediator of insulin action, by local overex-
sis by leptin (150). pression of IRS-2 increases peripheral insulin sensitivity
Like leptin, insulin also activates the IRS-PI3K path- in rats with uDM induced by STZ (65). Collectively, these
way in hypothalamic neurons, and PI3K is also required studies suggest that neuronal PI3K signaling is an impor-

tant determinant of glucose metabolism and that the CNS gies to determine the functional role of each of these
action of insulin is mediated via this mechanism. leptin-sensitive neuronal subsets in the actions of leptin
on glucose metabolism, energy balance, immune function,
and reproduction (128).
D. CNS Nutrient-Sensing
Two of the most well-characterized leptin-sensitive
neuronal populations implicated in the regulation of food
In addition to insulin and leptin, the CNS is capable
intake, energy expenditure, and glucose metabolism are
of sensing and responding to input from nutrient-related
contained within the hypothalamic ARC. One of these
signals. Several lines of evidence suggest that one hypo-
subsets expresses neuropeptide Y (NPY) and agouti re-
thalamic signal of nutrient availability is the intracellular
lated peptide (AgRP), peptides that stimulate food intake
accumulation of long-chain fatty acyl-CoA (LCFA) mole-
and inhibit energy expenditure, thereby promoting posi-
cules. Consistent with this hypothesis, pharmacological
tive energy balance (75, 153, 178). As these NPY/AgRP
interventions designed to block LCFA oxidation by in-
neurons are inhibited by both leptin and insulin, reduced
creasing malonyl CoA levels [e.g., oleic acid, fatty acid
neuronal input from these hormones (as occurs, for ex-
synthase (FAS) inhibitor] in the CNS reduce food intake
ample, during fasting and uDM) increases hypothalamic
and HGP (99, 107, 133, 147), while conversely, pharmaco-
expression of these peptides (158, 163).
logical interventions that reduce hypothalamic malonyl
Adjacent to these cells is a neuronal subset that
CoA levels cause obesity and insulin resistance (79). Nu-
expresses proopiomelanocortin (POMC). Unlike NPY/
trient-sensing involved in the CNS plays an important role
AgRP neurons, POMC neurons are stimulated by leptin
in the regulation of energy balance and glucose metabo-
(33, 162), whereas the effects of insulin are more complex
lism and is described in greater detail elsewhere (31, 98).
and context dependent (35, 204). The POMC cleavage
The enzyme AMPK is a ubiquitous fuel sensor that is
product ␣-melanocyte stimulating hormone (␣-MSH) is
activated when cellular fuel availability is low. AMPK
released by these neurons and acts on melanocortin re-
phosphorylates and inhibits acetyl CoA carboxylase
ceptors (Mc3r/Mc4r) to inhibit food intake, increase en-
(ACC), preventing the conversion of acetyl CoA to malo-
ergy expenditure, and promote weight loss (59). There-
nyl CoA, leading to a fall in malonyl CoA levels (179). This,
fore, in conditions of reduced leptin signaling (e.g., fasting
in turn, increases energy utilization (e.g., fat oxidation) by
or diet-induced weight loss), POMC neurons are inhibited
disinhibiting the enzyme carnitine palmitoyltransferase-1
while NPY/AgRP neurons are activated, a combination of
(CPT-1) (154). In the hypothalamus, AMPK activity is sensi-
responses that promote positive energy balance and the
tive not only to changes of nutrient (e.g., glucose) availabil-
recovery of lost weight. Hence, NPY/AgRP neurons stim-
ity, but is inhibited by central administration of either insulin
ulate feeding not only by releasing NPY, and thereby
or leptin (115, 208). Furthermore, inhibition of hypothalamic
activating Y1 and Y5 receptors, but by reducing melano-
AMPK (using an adenovirus expressing the dominant nega-
cortin signaling via release of AgRP, an endogenous mela-
tive form of AMPK) lowers food intake and HGP, while
nocortin-3/4 receptor antagonist (137, 171). Moreover,
increasing hypothalamic AMPK has the opposite effect (113,
NPY/AgRP neurons inhibit POMC neurons through re-
209), mimicking some hypothalamic actions of leptin and
lease of the inhibitory neurotransmitter GABA (42), and
insulin. These findings collectively implicate cellular nutri-
recent work suggests that loss of GABAergic signaling by
ent-sensing mechanisms as downstream mediators of at
AgRP neurons projecting to the parabrachial nucleus
least some leptin and insulin effects.
causes profound anorexia (201).
While each of these two neuronal subpopulations
E. Leptin-Sensitive Neuronal Subsets is critical for normal energy homeostasis, both also
appear to be important in the regulation of glucose
Since its discovery, the neuronal mechanism(s) by homeostasis. Central administration of both NPY and
which leptin acts in the brain has been an area of intense the melanocortin-3/4 receptor antagonist SHU9119
focus. Peripheral administration of leptin activates neu- causes insulin resistance and glucose intolerance via
ronal populations throughout the brain, as measured ei- mechanisms independent of their effects on food intake
ther by pSTAT3 activation (a marker of LepRb activation) (1, 109, 188). Conversely, chronic central administra-
or induction of c-fos expression (which can occur both in tion of the melanocortin agonist melanotan II (MTII)
“first-order” neurons activated directly by leptin and in has the opposite effect (134).
“second-order” neurons in a leptin-activated circuit), in- Several additional studies have sought to clarify the
cluding regions throughout the hypothalamus such as the role of leptin signaling via the Jak-STAT and the IRS-PI3K
ARC, VMH, PVN, LHA, and dorsomedial hypothalamus pathway in ARC neurons. Electrophysiological studies
(DMH), and extrahypothalamic areas including the VTA, first demonstrated that both insulin and leptin activate
NTS, and thalamus, among others (50, 52, 186). Ongoing ATP-sensitive potassium channels and thereby hyperpo-
studies have employed mouse genetics and other strate- larize a subset of “glucose-responsive” neurons via a

mechanism that requires PI3K (176, 177). Consistent with crodomain in which PI3K signaling is activated. Thus,
this, leptin inhibits the firing rate of NPY/AgRP neurons while it has been established that anorexia induced by
(189), while simultaneously depolarizing POMC neurons intracerebroventricular leptin can be blocked by inhibit-
(42), and also activates PI3K signaling in the latter cells ing PI3K signaling using a pharmacological approach
(204). In contrast to leptin, however, insulin hyperpolar- (130), the contribution of the PI3K signaling pathway in
izes and silences both AgRP and POMC neurons (96) and specific hypothalamic neurons to leptin regulation of en-
activates PI3K signaling in both these neuronal popula- ergy balance and glucose metabolism has been less clear.
tions (204). In POMC neurons, therefore, both insulin and To address this conundrum, Elmquist and colleagues
leptin activate PI3K signaling, but leptin leads to mem- (197) recently provided both histological and electrophys-
brane depolarization and an increase in firing rate, iological evidence that leptin and insulin act in distinct
whereas insulin evidently has the opposite effects. Com- subpopulations of POMC cells, rather than acting on the
plicating matters further, leptin reduces PI3K signaling in same subset of POMC cells. This conclusion is based on
AgRP cells, whereas insulin increases it (204), yet both evidence that the subset of POMC cells in which leptin-
hormones inhibit AgRP neuronal firing. Consequently, it induced c-fos activity is detected is separate from those
has been difficult to reconcile how two different hor- POMC neurons that express the insulin receptor, and they
mones share the same signaling cascade yet have oppo- confirmed that acute effects of insulin in POMC cells
site effects on neuronal firing. To further clarify the role differ from that of leptin in ways that suggest an anatom-
of various intracellular signaling transduction mecha- ical separation of insulin- and leptin-responsive POMC
nisms in leptin action in vivo, Cre-LoxP technology has cells (197). These data support a model in which “cross-
been utilized to delete leptin receptors, STAT3, or com- talk” between insulin and leptin involves A distinct sub-
ponents of the IRS-PI3K pathway in each of these neuro- population of POMC cells, rather THAN convergent signal
nal populations. transduction in the same neurons (Fig. 3, A and B).
Mice with selective deletion or inactivation of either Taken together, these findings offer a plausible ex-
the insulin receptor or IRS-2 in POMC cells (35, 96) explanation for how both insulin and leptin activate the
hibit no obesity phenotype, unlike what is observed with same intracellular signaling enzyme, PI3K, yet have diver-
pan-neuronal deletion of these proteins. When both sub- gent effects on POMC neuronal activity. To further clarify
units of PI3K (p85␣, p110␣) were deleted from POMC the physiological roles of insulin and leptin signaling in
neurons in mice, leptin failed to depolarize and increase POMC neurons, mice lacking both leptin and insulin recep-
the firing rate of these neurons, and insulin’s ability to tors in POMC neurons (Pomc-Cre, Leprflox/flox IR flox/flox
hyperpolarize POMC neurons was similarly abolished. mice) were compared with mice lacking either insulin
However, while the anorexic effects of leptin were receptors alone or leptin receptors alone in these cells
blunted in these mice, body weight was not altered (84). (83). Consistent with previous reports, body weight was
To further examine the role of the IRS-PI3K pathway in not affected by deletion of insulin receptors alone in
POMC neurons on energy and glucose homeostasis, stud- POMC neurons (96), whereas mice lacking leptin recep-
ies were conducted in which signaling molecules down- tors from POMC neurons exhibit a mild-obesity pheno-
stream of PI3K were deleted selectively in these cells. type (5). However, the combined deletion of insulin re-
Following its activation, PI3K phosphorylates phos- ceptors and leptin receptors in POMC neurons amelio-
phatidylinositol 4,5-bisphosphate (PIP2) to phosphatidyl- rated the obesity phenotype of mice lacking leptin
inositol 3,4,5-trisphosphate (PIP3) and activates several receptors from POMC neurons (83). While previous stud-
downstream molecules including 3-phosphoinositide-de- ies had reported either no effect (5) or only a mild effect
pendent protein kinase 1 (PDK1) and protein kinase B on glucose homeostasis in male mice lacking leptin re-
(PKB; also referred to as Akt) (Fig. 3A). While selective ceptors in POMC neurons (165), female mice lacking both
inactivation of PDK1 in POMC neurons caused a mild- insulin receptors and leptin receptors in POMC neurons
obesity phenotype (15), selective inactivation of the PIP3 exhibited marked hepatic insulin resistance, as measured
phosphatase PTEN (phosphatase and tensin homolog) in using the euglycemic-hyperinsulinemic clamp technique
these neurons unexpectedly caused a mild-obesity pheno- (83), suggesting that actions of both insulin and leptin on
type, despite increased PIP3 signaling (143). Yet deletion discrete subpopulations of POMC neurons act synergisti-
of PTEN in all leptin receptor-expressing cells (e.g., cally to suppress HGP.
POMC cells along with many other cell types) protects While leptin-induced activation of STAT3 is critical
against DIO and improves insulin resistance during high- for normal energy homeostasis (12, 14), selective deletion
fat (HF) feeding (144). These seemingly contradictory of STAT3 in either POMC (205) or NPY/AgRP (70) neu-
findings remain incompletely explained, but may reflect rons results in a mild-obesity phenotype, as occurs when
multiple, divergent roles for PI3K signaling within a given leptin receptors are selectively deleted from these cells
cell subpopulation, and divergent effects of leptin versus (5, 46, 187). Conversely, overexpression of STAT3 in
insulin arising due to differences in the intracellular mi- AgRP neurons results in a lean phenotype that is resistant

to DIO due to an increase in locomotor activity and in many other hypothalamic areas, as well as in extrahy-
energy expenditure (112). Deletion of leptin receptors pothalamic sites that likely contribute to leptin’s anorec-
from both NPY/AgRP and POMC ARC neurons results in tic effects (Fig. 4). Consequently, leptin receptors must be
a phenotype that is nearly additive with respect to the restored widely throughout the CNS using several neuron-
increase of body weight and adiposity observed following specific promoters to normalize obesity, fertility, and glu-
deletion of leptin receptors from individual neuronal sub- cose metabolism in db/db mice (44).
sets, but the overall effect is still modest compared with The impact of leptin signaling in POMC neurons on
obesity caused by leptin deficiency (187). This outcome is energy homeostasis and glucose metabolism was also
not surprising, given that leptin receptors are expressed recently investigated by Bjorbaek and colleagues (88) by
FIG. 4. CNS neurocircuits regulating energy and glucose homeostasis. A number of hypothalamic and extrahypothalamic sites have been
implicated in the action of leptin to regulate energy and glucose homeostasis. The hypothalamic ARC contains neuropeptide Y and agouti-related
peptide (NPY/AgRP) neurons that stimulate food intake and are inhibited by leptin, and proopiomelanocortin (POMC) neurons that reduce food
intake and are stimulated by leptin. NPY/AgRP neurons also inhibit POMC neurons via synaptic release of the neurotransmitter GABA. ARC, arcuate
nucleus; LepRb, leptin receptor; Mc3r/Mc4r, melanocortin-3/4 receptor; VMH, ventromedial hypothalamus; LHA, lateral hypothalamic area; PVN,
paraventricular nucleus; DMH, dorsomedial hypothalamus; VTA, ventral tegmental area; NTS, nucleus of the solitary tract.

reactivating leptin signaling selectively in POMC neurons F. Effect of CNS Leptin to Regulate
of mice that otherwise lack leptin receptors. Expression Glucose Metabolism
of leptin receptors selectively in POMC neurons of
Leprdb/db mice (HA-LRb/Pomc-Cre/Leprdb/db) reduced Investigation into how leptin signaling in the brain
food intake and body weight, while normalizing blood improves peripheral insulin sensitivity has been ham-
glucose levels independently of changes in energy bal- pered to some extent by divergent outcomes from studies
ance (88). These data provide further evidence that leptin that employed a pharmacological approach in normal
signaling in POMC neurons plays an important role in animals versus those using a gene therapy approach in
leptin’s ability to regulate glucose metabolism. Similarly, animals that lack leptin receptors. In normal rats, intra-
while mice with selective inactivation of the insulin re- cerebroventricular leptin administration stimulates he-
ceptor in AgRP neurons maintain a normal body weight, patic gluconeogenesis, but fails to affect overall hepatic
they exhibit hepatic insulin resistance, implying a role for glucose production owing to a simultaneous decrease of
insulin action in AgRP-expressing cells in the mainte- glycogenolysis (106). Subsequent studies demonstrated
nance of normal liver insulin sensitivity (96). that the effect of intracerebroventricular leptin on gluco-
In addition to leptin action in ARC neurons, several neogenesis and expression of the gluconeogenic enzyme
lines of evidence suggest that the VMH also plays an Pepck were blocked when activation of neuronal melano-
important role in leptin’s effects on glucose metabolism. cortin signaling was inhibited using the melanocortin-3/4-
Neurons in the VMH express the leptin receptor (53), are receptor antagonist SHU9119, while leptin suppression of
activated by leptin (as measured by induction of either glycogenolysis remained intact, resulting in a net de-
pSTAT3 or c-Fos) (124), and leptin rapidly depolarizes crease of glucose production (73). Thus pharmacological
and increases the firing rate of steroidogenic factor-1 leptin stimulation of gluconeogenesis appears to involve a
(SF-1)-containing neurons in this brain area (180). In ad- melanocortin-dependent pathway while leptin inhibition
dition, microinjection of leptin directly into the VMH pro- of glycogenolysis is proposed to occur via a melanocortin-
motes glucose uptake in peripheral tissues via a mecha- independent pathway. In addition, the acute effects of
nism involving the SNS (77, 114), whereas selective dele- hypothalamic leptin signaling on liver glucose flux require
tion of leptin receptors from SF-1-positive neurons results leptin receptor signaling through STAT3 (28). Since intra-
in an obese, insulin-resistant phenotype, an effect that is cerebroventricular leptin infusion reverses insulin resis-
exaggerated when leptin receptor deficiency is present in tance induced in rats by short-term exposure to a HF diet
both POMC and VMH neurons (20, 46). Neurons in the by reducing both glycogenolysis and gluconeogenesis
VMH are implicated in the regulation of melanocortin (146), these data suggest that the metabolic response of
signaling (180), whereas melanocortins also regulate the normal rats to intracerebroventricular leptin is context-
function of VMH neurons. For example, brain-derived dependent, and furthermore, that CNS responses may
neurotrophic factor (BDNF)-containing neurons in the contribute to the pathogenesis of peripheral insulin resis-
VMH are regulated by both nutritional state and by Mc4r tance during HF feeding.
signaling (206). Furthermore, mice with reduced expres- Recent work has begun to clarify how hypothalamic
sion of the BDNF receptor TrkB exhibit a phenotype leptin action affects peripheral glucose metabolism. Using
characterized by obesity, hyperphagia, and increased the euglycemic-hyperinsulinemic clamp technique to
body length, similar to that of Mc4r-deficient mice, and measure changes of glucose metabolism induced by re-
leptin administration induces Bdnf expression in the VMH storing leptin receptor signaling to the ARC of leptin
(206). Given that a subset of VMH neurons send strong receptor-deficient Koletsky rats, improved insulin sensi-
excitatory inputs to POMC neurons in the ARC (180), tivity was shown to involve enhanced insulin-induced
these data implicate a subset of VMH neurons as compo- suppression of glucose production, rather than changes of
nents of the melanocortin pathway and suggest that leptin glucose uptake (66). These effects of restored ARC leptin
signaling in this brain area participates in the control of signaling were associated with enhanced insulin signal
glucose metabolism. transduction via PI3K in liver, but not skeletal muscle, and
The VMH is also implicated in the control of glucagon were also associated with reduced hepatic expression of
secretion. Studies dating back to the 1960s and 1970s dem- key gluconeogenic genes, G6Pase and Pepck (66). Thus
onstrated that electric stimulation of the VMH increases leptin action in the ARC increases peripheral insulin sen-
glucagon secretion, promotes liver glycogen breakdown, sitivity primarily via effects on the liver, and like insulin,
and raises blood glucose levels via the autonomic nervous this effect is PI3K dependent and involves inhibition of
system (166, 167). Moreover, VMH neurons are critical for hepatic gluconeogenic gene expression.
sensing and responding to hypoglycemia (111). Thus leptin One potential mechanism whereby leptin could alter
signaling in the VMH offers a plausible mechanism to ex- hepatic insulin sensitivity is via inhibition of the hepatic
plain leptin-mediated normalization of hyperglycemia and enzyme stearoyl-coenzyme A desaturase 1 (SCD-1), which
hyperglucagonemia in STZ-induced diabetes (210). catalyzes the synthesis of monounsaturated fatty acids

(MUFA; such as oleic acid) from saturated FFA (e.g., in plasma insulin or glucose levels (91). The hypothal-
palmitate, stearate) and is essential for de novo lipogen- amus is implicated in these effects since microinjection
esis. Hepatic Scd-1 mRNA levels are markedly increased of leptin directly into the VMH increases insulin-inde-
in ob/ob mice, an effect implicated in the dramatic in- pendent glucose uptake in skeletal muscle, heart, and
crease of hepatic triglyceride synthesis and steatosis char- BAT (114) via a mechanism involving the sympathetic
acteristic of these animals (36). Since intracerebroventric- nervous system (SNS) (77). The observation that these
ular (as well as systemic) leptin treatment inhibits hepatic effects of leptin were blocked by the Mc3/4r antagonist
Scd-1 gene expression via a mechanism that cannot be SHU9119 suggests that this effect of leptin is dependent
attributed to reduced food intake, leptin regulation of on activation of melanocortin receptors (185). In com-
hepatic Scd-1 gene expression may involve a central site parison, leptin injection into the ARC increases glucose
of action (36). Moreover, hepatic insulin resistance in- uptake only in BAT, while injection into either the LHA
duced by HF feeding is blocked by reducing hepatic (114), DMH, or PVN has no effect (185). These findings
SCD-1 expression using antisense oligodeoxynucleotides support a model in which autonomic responses trig-
(ASO) (74), and whole-body Scd-1 deficient mice are pro- gered by leptin action in the brain play a key role in
tected against DIO and its metabolic sequelae. In addition, changes of peripheral glucose metabolism.
introduction of SCD-1 deficiency in lipodystrophic aP2- One attractive candidate for mediating the effect of
nSREBP-1c mice corrects hepatic steatosis, although it central leptin action on systemic glucose clearance is
does not ameliorate diabetes (2), and loss of SCD-1 in via autonomic activation of AMPK in peripheral tissues.
ob/ob mice reduces body weight and hepatic steatosis but AMPK is a master sensor of cellular energy expressed
worsens diabetes (62). Thus, although SCD1 regulation in key metabolic tissues including liver, skeletal mus-
likely contributes to effects of leptin on hepatic triglycer- cle, adipose tissue, and hypothalamus (179) and is ac-
ide and lipoprotein synthesis, its role in leptin regulation tivated when fuel availability is reduced, as during
of hepatic glucose metabolism is uncertain. exercise, which in turn stimulates fat oxidation while
Another potential mediator of leptin control of glu- increasing glucose uptake in muscle via an insulin-
cose metabolism is IGF-binding protein-2 (IGFBP2). With independent mechanism (154). Moreover, recent evi-
the use of microarrays, hepatic expression of Igfbp2 was dence suggests leptin action in the hypothalamus acti-
shown to be upregulated by leptin, and IGFBP2 plasma vates AMPK in skeletal muscle via a mechanism involv-
levels were also increased following leptin treatment in ing the sympathetic branch of the autonomic nervous
both ob/ob and wild-type mice (80). Moreover, adenoviral- system (115).
induced overexpression of IGFBP2 normalized blood glu- However, the mechanism whereby leptin signaling in
cose levels in ob/ob mice via improved hepatic insulin the CNS communicates to peripheral tissues to stimulate
sensitivity, accompanied by reduced hepatic expression glucose uptake is not well understood. To identify the
of the gluconeogenic genes, G6Pase and Pepck, along with neural circuits whereby leptin promotes glucose uptake
a significant reduction of hepatic steatosis (80). Overex- in skeletal muscle, a recent study used LepRb-GFP re-
pression of IGFBP2 also reduced blood glucose levels in porter mice in combination with muscle-specific injec-
models of leptin and insulin resistance/deficiency includ- tion of an mRFP-expressing pseudorabies virus (PRV)
ing agouti, DIO, and STZ-induced diabetic mice. However, (3). They found that while injection of PRV in muscle
the question of whether IGFBP2 is required to mediate led to PRV labeling within multiple areas of the hypo-
effects of leptin on glucose metabolism remains unan- thalamus and hindbrain, the only area of colocalization
swered, and the mechanism whereby leptin induces between leptin receptor expressing cells and muscle-
Igfbp2 is also unknown. Additional uncertainty stems derived PRV was within the NTS and the retrochias-
from early observations that insulin is a major inhibitory matic area (RCh) (3), an area that projects to leptin-
regulator of hepatic Igfbp2, such that expression of the sensitive neurons in the intermediolateral (IML) nu-
latter is markedly increased in animals with insulin-defi- cleus of the spinal cord (51). While populations may yet
cient diabetes (67, 68, 194). Since insulin treatment of exist in other brain areas, these data implicate that the
diabetic rodents lowers both HGP and Igfbp2 gene ex- NTS and RCh are key sites whereby leptin action in the
pression (26, 138, 194), the notion that IGFBP2 plays a brain activates autonomic relays that affect skeletal
major role in leptin-mediated inhibition of HGP seems muscle.
counterintuitive. Additional studies are warranted to ad-
dress these questions.
In addition to effects on HGP, at pharmacological G. Extrahypothalamic Neurocircuits Involved in
doses, central administration of leptin in normal ani- Leptin Regulation of Insulin Sensitivity
mals increases whole body glucose turnover and glu-
cose uptake in peripheral tissues including skeletal One mechanism proposed to explain how leptin re-
muscle, heart, and BAT, but not WAT, without changes duces food intake is by enhancing the CNS response to

gut-derived satiety peptides, such as cholecystokinin hypothalamic leptin signaling to Koletsky rats on hepatic
(CCK) and glucagon-like peptide-1 (GLP-1) (196) that are insulin sensitivity were blocked by selective hepatic va-
released upon food ingestion and activate vagal afferent gotomy (66). However, selective hepatic vagotomy failed
fibers that terminate in the NTS (9, 25, 55, 121). Available to affect hepatic glucose metabolism in leptin receptor-
evidence suggests that leptin signaling in forebrain areas deficient Koletsky rats that did not receive leptin gene
such as the ARC activates a descending projection to the therapy, and previous studies have demonstrated that
NTS, which in turn enhances the hindbrain response to selective removal of vagal tone to the liver by itself in
input from CCK (122). Interestingly, a parallel neurocir- genetically normal rats has no effect on insulin-induced
cuit is implicated in the mechanism that links hypotha- suppression of HGP. Similarly, while abundant evidence
lamic leptin action to the control of hepatic insulin sen- suggests that vagal afferents play a critical role in the
sitivity, in which leptin-sensitive forebrain neurons regu- ability of gut-derived satiety signals, such as CCK, to
late the activity of neurons in the NTS and adjacent promote the termination of a meal, selective vagotomy by
dorsal motor nucleus of the vagus (DMX). Contained itself fails to affect energy homeostasis (19). Thus addi-
within the DMX are vagal motor neurons that supply tional studies are required to determine the physiological
the liver and other tissues, and their activity is tonically relevance of this circuit in the control of glucose metab-
regulated by input from the NTS. The NTS, in turn, olism.
receives input from both afferent vagal fibers and from
descending projections from the hypothalamus and
other brain areas (Fig. 5). H. Indirect Effects of CNS Leptin on
Consistent with this hypothesis, both local adminis- Glucose Metabolism
tration of insulin and inhibition of fat oxidation in the
ARC increase hepatic insulin sensitivity via a mechanism While several lines of evidence suggest that leptin
that requires intact hepatic vagal innervation, and also action in the brain improves glucose metabolism indepen-
activates hindbrain neurons within both the NTS and dent of its effects on energy homeostasis, the effect of
DMX (147). Moreover, the beneficial effects of restoring leptin to reduce food intake and body weight (and body
FIG. 5. Model of the hypothalamic regulation of hepatic glucose production. Leptin-sensing neurons in the hypothalamic ARC receive input
regarding energy stores, and in response to this input, pathways that increase hepatic vagal tone to the liver are activated, increasing hepatic insulin
sensitivity. ARC, arcuate nucleus; LepRb, leptin receptor; NTS, nucleus of the solitary tract; G6Pase, glucose-6-phosphatase; PEPCK, phospho-
enolpyruvate kinase.

fat mass) also likely contributes to the overall effects of stored as fat. These observations raise a fundamental
leptin to improve glucose metabolism, since weight loss paradox: if body fat is homeostatically regulated, then
as small as 5–10% can substantially improve insulin sen- increases of body fat should activate adaptive responses
sitivity in obese patients (16). involving increased leptin secretion that protect against
Yet another potential mechanism whereby leptin sig- weight gain. How, then, do obese individual’s maintain
naling in the brain can influence insulin action is via elevated weight in the face of elevated leptin levels?
effects on lipid metabolism. Infusion of leptin directly into One potential explanation is that under normal con-
the mediobasal hypothalamus during an euglycemic-hy- ditions, this homeostatic system defends against both
perinsulinemic clamp suppressed the expression of key weight loss and weight gain, but that common forms of
de novo lipogenic enzymes in WAT and also activated obesity develop due to genetic or acquired defects that
lipolysis and suppressed FFA uptake into this tissue (28). impair the response to elevated leptin levels (159). Obe-
Surprisingly, while the ability of hypothalamic leptin to sity in both humans and in rodents placed on a HF diet is
regulate food intake, glucose metabolism, and reproduc- characterized by hyperleptinemia, and the ability of leptin
tive function requires intact STAT3 signaling, these ef- to suppress food intake and reduce body weight is atten-
fects of leptin on adipose tissue metabolism are STAT3- uated (49, 81). Consistent with this observation, the abil-
independent, appearing instead to involve hypothalamic ity of leptin to activate pSTAT3, a marker of leptin signal-
PI3K and SNS outflow (28). ing (49), is impaired in rodent models of DIO, specifically
Pertinent to this discussion is the phenotype of mice in the hypothalamic ARC (56, 124). This concept is com-
in which PI3K signaling in leptin receptor-expressing neu- monly referred to as “leptin resistance” and is somewhat
rons in the CNS is increased by deleting PTEN using analogous to “insulin resistance,” whereby elevated insu-
cre-loxP technology, alluded to earlier. Selective PTEN lin levels are required to maintain blood glucose levels in
ablation in leptin-expressing neurons results in a pheno- the normal range. Indeed, the same cellular mechanisms
type characterized by reduced adiposity and increased that impair insulin signaling in tissues such as liver and
energy expenditure due, at least in part, to increased fatty muscle of obese individuals may also contribute to the
acid oxidation in WAT (144), associated with increased pathogenesis of leptin resistance.
sympathetic nerve activity to WAT and leading to a re- The identification of cellular mechanisms that can
modeling of WAT to take on characteristics of BAT, in- explain impaired leptin signaling in DIO is an area of
cluding increased mitochondrial content and UCP1 ex- intense current research. One model proposes that during
pression (144). positive energy balance and excess body fat gain, leptin
Leptin-mediated activation of the melanocortin path- resistance is caused by elevated plasma leptin levels,
way may contribute to these potent effects on adipose tissue resulting in chronic overstimulation of the leptin receptor
metabolism. Pharmacological inhibition of melanocortin re- and associated SOCS-3 induction (22, 54, 155). Consistent
ceptors in the CNS increases WAT lipid uptake, triglyceride with this hypothesis, heterozygous SOCS-3-deficient mice
synthesis, and fat accumulation, whereas activation of neu- display increased leptin sensitivity and are protected
ronal melanocortin receptors stimulates lipid mobilization against the development of obesity on a HF diet (87). This
independent of changes in food intake. Moreover, while effect appears to be neurally mediated, as neuron-specific
reduced melanocortin signaling promotes insulin sensitivity SOCS-3 conditional knockout mice exhibit a similar phe-
and glucose uptake in WAT, it reduces glucose utilization in notype (119), suggesting that in neurons, SOCS-3 plays a
BAT and muscle (131), favoring increased triglyceride syn- physiological role to favor positive energy balance and
thesis and storage in the body. weight gain. Moreover, mutation of LRb Tyr985 prevents
SOCS-3 action on the leptin receptor and thereby results
in mice which display increased leptin sensitivity, are
V. PERSPECTIVES
lean, and are resistant to DIO (24). An important consid-
eration in the interpretation of this work, however, is that
A. Leptin Resistance and Obesity Pathogenesis proinflammatory signaling induced in the hypothalamus
during HF feeding (see below) also increases SOCS-3
While absolute leptin deficiency causes obesity (118, expression. So while a compelling argument exists in
212), most obese humans and animal models exhibit ele- support of a causal role of hypothalamic SOCS-3 in the
vated circulating plasma leptin levels (39). This is not pathogenesis of common forms of leptin resistance,
surprising, given that leptin is synthesized and secreted by whether SOCS-3 induction is due to hyperleptinemia, pro-
adipocytes in direct proportion to total body fat mass inflammatory cellular responses, or some combination of
(39). Yet an abundant literature supports the hypothesis these awaits clarification.
that body fat is regulated by a negative-feedback loop Interestingly, mice expressing a constitutively active
described earlier that adjusts food intake and energy ex- version of STAT3 selectively in POMC neurons cause a
penditure as needed to promote the stability of body fuel hyperphagic, obese phenotype accompanied by central

insulin and leptin resistance (58), offering further (albeit be both necessary and sufficient for HF-induced obesity.
indirect) evidence that induction of SOCS-3 in these cells This notion does not exclude a pathogenic role for hyper-
impairs energy homeostasis. Moreover, while upregula- insulinemia, since both inflammatory signaling and leptin
tion of SOCS-3 selectively in POMC neurons causes leptin share in common the ability to induce SOCS-3.
resistance and obesity, somewhat surprisingly, overex- Further evidence of a role for SOCS-3 in the patho-
pression of SOCS-3 in leptin receptor-positive neurons did genesis of DIO stems from mice with cell-type specific
not (149). Thus SOCS-3 may play a cell type-specific role deletion of IKK␤ in AgRP neurons, which are protected
in the regulation of energy balance. Again, it is important against DIO and exhibit reduced expression of SOCS-3 in
to recognize that SOCS-3 is induced not only by pSTAT3, the mediobasal hypothalamus (211). Moreover, increasing
but also by inflammatory signaling through the IKK␤- SOCS-3 expression in the mediobasal hypothalamus using
NF␬〉 pathway, when interpreting these outcomes. a lentiviral approach blocked the protection against DIO
Similar to SOCS-3, the protein tyrosine phosphatase conferred by AgRP neuron-specific IKK␤ knockout
(PTP) 1B inhibits leptin and insulin signaling in cultured (211). Although the extent to which leptin resistance
cells and in vivo via dephosphorylation of Jak2 (48, 93). induced by hypothalamic inflammation depends on
Consistent with this, HF feeding increases PTP1B expres- SOCS-3 remains to be established, these data suggest
sion in the hypothalamus, and pharmacological inhibition that both hyperleptinemia and inflammation may con-
of PTP1B in the brain improves leptin sensitivity in aged tribute to central leptin resistance via an overlapping
leptin-resistant rats (120). Moreover, neuronal (17) or mechanism involving SOCS-3.
POMC-specific (7) PTP1B knockout mice are protected Yet another mechanism that may contribute to hypo-
from DIO and exhibit increased leptin sensitivity. These thalamic inflammation and central leptin and insulin re-
data suggest that both SOCS-3 and PTP1B are possible sistance is endoplasmic reticulum (ER) stress. Recent
mediators that contribute to reduced LepRb signaling in studies demonstrate that ER stress and the unfolded pro-
obesity. tein response (UPR) are activated in the hypothalamus of
A growing literature implicates cellular inflammation obese mice and that this effect is sufficient to inhibit
in the pathogenesis of obesity-associated metabolic im- leptin signaling (140). In support of the hypothesis that
pairment in peripheral tissues (85, 86, 170). Excess body ER stress is involved in pathways that mediate nutritional
adiposity has been associated with activation of macro- activation of hypothalamic IKK␤/NF-␬B, central adminis-
phages and associated inflammation in a variety of periph- tration of an ER stress inhibitor suppressed hypothalamic
eral tissues including WAT, liver, skeletal muscle, and the NF-␬B levels in HF-fed rats and lowered both food intake
vasculature and eventually is accompanied by increased and body weight in DIO animals (211). Conversely, induc-
circulating plasma levels of proinflammatory cytokines tion of ER stress in the brain of mice and rats increases
(193, 207). Recent evidence suggests that consumption of food intake and body weight and blocks the anorexic
a HF diet also induces inflammation in the hypothalamus, effects of insulin and leptin (140, 199). In addition, neu-
an effect that itself could favor weight gain by impairing ronal deletion of X-box binding protein-1 (XBP-1) in mice
the neuronal response to input from leptin and insulin increased food intake and body adiposity and is accom-
(184). Consistent with this notion, rats fed a HF diet for panied by hypothalamic leptin resistance (140).
20-wk exhibit both leptin resistance and hypothalamic To compare the contribution of hyperleptinemia ver-
inflammation, as measured by elevated mRNA and protein sus a HFD itself to the development of leptin resistance, a
levels of proinflammatory cytokines (tumor necrosis fac- recent study treated ob/ob mice with systemic leptin con-
tor-␣, IL-1␤, and IL-6), resulting from activation of IKK␤ tinuously at a dose designed to “clamp” plasma levels to
and JNK-1 (45, 148, 211). Beyond these correlative obser- that of wild-type controls fed standard chow (94). Follow-
vations, recent work has begun to assess whether hypo- ing the switch to a HF diet, wild-type and leptin-infused
thalamic inflammation is a cause of DIO, or is simply a ob/ob mice displayed similar weight gain despite markedly
consequence. higher plasma leptin levels in the former group (94).
Consistent with hypothalamic inflammation driving Moreover, wild-type mice exposed to a HF diet were
HF-induced obesity, activation of hypothalamic IKK␤/ resistant to the ability of leptin to reduce food intake and
NF-␬B signaling using a gene therapy approach promotes body weight and to induce hypothalamic pSTAT3 relative
hyperphagia and weight gain and reduces leptin and in- to leptin-infused ob/ob mice fed a HF diet. The authors’
sulin signaling in mice (211). Conversely, interventions concluded from these studies that hyperleptinemia is re-
that reduce hypothalamic inflammation, either by reduc- quired for the development of leptin resistance (94). How-
ing neuronal IKK␤ signaling using a gene therapy ap- ever, the important question of whether hyperleptinemia
proach (211) or by pharmacological administration of a is sufficient to induce leptin resistance was not examined
IKK␤ inhibitor, reduce food intake and body weight in in this study (since ob/ob mice did not receive leptin at
DIO animals (148) and maintain central leptin and insulin doses that induce hyperleptinemia) and perhaps more
sensitivity. Thus hypothalamic inflammation appears to importantly, the study design presumes that wild-type and

leptin-infused ob/ob mice are fundamentally indistinguish- based on evidence that under true physiological condi-
able where leptin sensitivity and energy homeostasis are tions, insulin action on the liver is mediated primarily via
concerned, despite clear evidence that ob/ob mice are a direct effect (32). While most investigators can agree
more sensitive to leptin than normal mice (30, 76). Addi- that the brain senses changes of circulating insulin levels,
tional studies are therefore needed to determine the ex- whether insulin action in the brain plays a physiological
tent to which elevated plasma leptin levels contribute to role in the day-to-day regulation of glucose production by
leptin resistance and associated weight gain during HF the liver or other tissues remains to be firmly established,
feeding. and the same may be said about the role of leptin in
One conclusion stemming from this area of science is glucose metabolism.
that viable mechanisms have finally emerged with the
potential to link altered hypothalamic function to sus-
tained weight gain in models of DIO (127). A second VI. CONCLUDING REMARKS
inference is that no single mechanism is likely predomi-
nant in the pathogenesis of obesity-associated leptin re- In conclusion, a large and growing literature supports
sistance and, like insulin resistance in peripheral tissues, the hypothesis that input to the CNS from afferent signals
it seems probable that numerous mechanisms contribute such as leptin is integrated with that from a variety of
in ways that are challenging to disarticulate. other hormonal and nutrient-related signals to coordinate
efferent responses that control food intake, energy expen-
diture, hepatic insulin sensitivity, and glucose uptake in
B. Physiological Relevance the service of energy and glucose homeostasis. Evidence
of substantial overlap in the CNS circuits that regulate
The regulation of blood glucose levels is a complex energy balance and those that regulate glucose metabo-
and highly integrated process involving the brain and lism raises the possibility that reduced secretion, sensing,
peripheral tissues. In this review, we have highlighted or responsiveness to these afferent signals promotes both
evidence that the adiposity signal leptin plays an impor- weight gain and insulin resistance. Therapies that target
tant role in the control not only of energy homeostasis, the CNS and restore sensitivity of neuronal circuits to key
but of glucose homeostasis as well, and that the CNS is afferent signals have the potential to improve currently
implicated in both leptin effects. Yet most approaches available treatments for obesity and diabetes.
used to investigate the role of leptin in glucose homeo-
ACKNOWLEDGMENTS
stasis employ either genetic models (e.g., ob/ob mice,
db/db mice, or fak/fak rats) or pharmacological doses of Address for reprint requests and other correspondence:
leptin in normal animals. While this research has gener- G. J. Morton, Dept. of Medicine, Univ. of Washington, UW Med-
icine at South Lake Union, 815 Mercer St., Box 358055, Seattle,
ated a wealth of information and has advanced our un-
WA 98195 (e-mail: gjmorton@u.washington.edu).
derstanding of how leptin acts in the CNS and how CNS
leptin action is communicated to the periphery, whether GRANTS
these leptin effects play a physiological role in glucose
This work was supported by National Institute of Diabetes
homeostasis on a minute-to-minute, hour-to-hour, and
and Digestive and Kidney Diseases Grants DK068384, DK083042,
day-to-day basis in genetically normal humans and animal and DK052989 (to M. W. Schwartz); the Nutrition Obesity Re-
models, and whether such effects are neurally mediated, search Center (DK035816); the Diabetes Endocrine Research
are key questions that remain incompletely answered. Center (P30 DK17047); and the Mouse Metabolic Phenotyping
Other technological considerations warrant com- Center (U24 DK076126) at the University of Washington. G. J.
ment. To examine the physiological mechanisms whereby Morton is supported by an American Heart Association Scientist
insulin inhibits HGP in vivo, many experiments employed Development Grant.
the pancreatic clamp, a technique that employs the infu-
sion of somatostatin to block endogenous insulin and DISCLOSURES
glucagon secretion, along with intravenous infusion of No conflicts of interest, financial or otherwise, are declared
insulin and glucagon to maintain basal levels. One limita- by the authors.
tion of this approach relates to the fact that endogenous
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2011 PHYS REV Leptina e o Controle Do Sistema Nervoso Central

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Physiol Rev 91: 389 – 411, 2011;

Leptin and the Central Nervous System Control

Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington,

I. INTRODUCTION for a better understanding of how body weight and glu-

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ciated with insulin resistance in these tissues and that this

A. Model of CNS Control of Energy and

The brain continuously transduces input from neu-

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of STAT5 in mice (via RIP-cre or Nestin-cre) causes a

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III. CENTRAL NERVOUS SYSTEM-MEDIATED

A. Leptin and Glucose Metabolism

In addition to the well-established role played by

FIG. 3. Leptin and insulin signal transduction pathways in the CNS.

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Physiol Rev • VOL 91 • APRIL 2011 • www.prv.org

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