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A Treasure Trove of Hypothalamic Neurocircuitries
Governing Body Weight Homeostasis
Claudia R. Vianna and Roberto Coppari
Department of Internal Medicine, Division of Hypothalamic Research, The University of Texas
Southwestern Medical Center, Dallas, Texas 75390-9077
Changes in physical activities and feeding habits have transformed the historically rare disease of
obesity into a modern metabolic pandemic. Obesity occurs when energy intake exceeds energy
expenditure over time. This energy imbalance significantly increases the risk for cardiovascular
disease and type 2 diabetes mellitus and as such represents an enormous socioeconomic burden
and health threat. To combat obesity, a better understanding of the molecular mechanisms and
neurocircuitries underlying normal body weight homeostasis is required. In the 1940s, pioneering
lesion experiments unveiled the importance of medial and lateral hypothalamic structures. In the
1980s and 1990s, several neuropeptides and peripheral hormones critical for appropriate feeding
behavior, energy expenditure, and hence body weight homeostasis were identified. In the 2000s,
results from metabolic analyses of genetically engineered mice bearing mutations only in selected
neuronal groups greatly advanced our knowledge of the peripheral/brain feedback-loop modalities by which central neurons control energy balance. In this review, we will summarize these
recent progresses with particular emphasis on the biochemical identities of hypothalamic neurons
and molecular components underlying normal appetite, energy expenditure, and body weight
homeostasis. We will also parse which of those neurons and molecules are critical components of
homeostatic adaptive pathways against obesity induced by hypercaloric feeding. (Endocrinology
152: 11–18, 2011)
rain-mediated control of energy intake and expenditure keeps body weight within normal values. Even a
small change in this homeostatic balance, as, for example,
a slight daily increase in food intake and/or reduction in
energy expenditure in the long run leads to increased body
weight (1). There are different degrees of increased body
weight in humans; the World Health Organization defines
adults with a body mass index (BMI; body weight in kilograms divided by the square of the height in meters)
between 25 and 29.9 kg/m2 as overweight and those with
higher BMIs as obese. Frighteningly, in 2005 approximately 400 million adults were classed as obese. Because
of its serious comorbidities (e.g. heart disease, diabetes),
obesity is therefore a huge threat to human health. Unfortunately, primary defects underlying obesity are still
poorly understood, except for very rare monogenic forms
that have been well-characterized in rodents and humans
B
ISSN Print 0013-7227 ISSN Online 1945-7170
Printed in U.S.A.
Copyright © 2011 by The Endocrine Society
doi: 10.1210/en.2010-0778 Received July 8, 2010. Accepted October 1, 2010.
First Published Online November 10, 2010
(2). Due to the rapid surge in the incidence of obesity seen
in industrialized and rapidly developing countries in
which consumption of calorie-rich food is also a common
habit, it has been postulated that chronic feeding on these
diets is a critical factor in the pathogenesis of obesity (3).
This contention is experimentally supported because
chronic hypercaloric feeding causes energy imbalance in
mammalian organisms (including nonhuman primates)
(4). However, some individuals appear to be very resistant
from, whereas others very sensitive to, dietary obesity,
suggesting a large variability in the robustness of homeostatic mechanisms against energy imbalance brought
about by overnutrition (5).
The contention that mammals (including humans) have
evolved mechanisms geared for positive energy balance as
Abbreviations: AgRP, Agouti-related peptide; ARH, arcuate nucleus; BMI, body mass index;
DMH, dorsomedial hypothalamic nucleus; FoxO, Forkhead box O; HT2CR, 5-hydroxytryptamine 2C serotonin receptor; IR, insulin receptor; LEPR, leptin receptor; LHA, lateral hypothalamic area; MC3R, melanocortin-3 receptor; MC4R, melanocortin-4 receptor; NF-␬B,
nuclear factor-␬B; IKK, inhibitory-␬B kinase; NPY, neuropeptide Y; POMC, proopiomelanocortin; PTP1B, protein tyrosine phosphatase 1B; PVH, paraventricular nucleus; SIM1,
single-minded 1; VMH, ventromedial nucleus; SHP2, tyrosine phosphatase-2; SIRT1, sirtuin
1; SOCS-3, suppressor of cytokine signaling-3.
Endocrinology, January 2011, 152(1):11–18
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Vianna and Coppari
Neurocircuitries Governing Metabolic Homeostasis
a means to better cope with periods in which food may be
scarce or even not available has been put forth. In modern
obesogenic environments the aforementioned anabolic
pathways have been suggested to underlie the excessive
body weight gain seen in many obese subjects, an idea
known as the thrifty gene hypothesis (6). However, this
hypothesis seems to be at odds with the fact that mammals
allowed to eat ad libitum do not normally develop obesity
and that even when fed on hypercaloric diets, mammals
attempt to resist obesity by triggering adaptive metabolic
responses (e.g. reduced food intake and increased energy
expenditure) (7–9). These results would suggest that mammals have a body weight set point and that mechanisms to
defend it are activated when the brain detects changes in
body energy status. Why then do so many people develop
obesity? To address this question, we will need to better
understand the following factors: 1) the signals underlying
body weight homeostasis, 2) the identities of the neuronal
populations that translate these signals into coordinated
food intake and energy expenditure, and 3) what causes
these homeostatic mechanisms to malfunction in obesogenic environments. To date, the answers to the aforementioned questions exist but are yet to be satisfactory. In
this review, we will summarize this knowledge and discuss
how this information may be instrumental for developing
novel and more effective antiobesity strategies.
Peripheral signals underlying body weight
homeostasis
The activity of metabolically relevant brain neurons is
affected by several hormones, the circulating amounts of
which reflect the status of body energy stores. These peptides are secreted by specialized endocrine cells mainly
found in adipose tissue, pancreas, stomach, and small intestine and include the following. Leptin is secreted by
adipocytes (fat cells) proportionally to the body fat mass,
and its adipostatic actions are chiefly mediated by hypothalamic, midbrain, and caudal brain stem neurons (10).
This hormone exerts a pivotal role for body weight homeostasis as demonstrated by the fact that deficiency in
leptin receptors (LEPRs) signaling causes severe obesity,
owing to reduced energy expenditure and augmented food
intake (hyperphagia) (11). Another hormonal signal
contributing to body energy balance is insulin, a peptide
secreted from pancreatic ␤-cells that also circulates in
proportion to adipose mass (12). Interestingly, insulin’s
peripheral and brain actions on energy balance appear
to be diametrically opposite from each other. In fact,
insulin’s effect on liver, skeletal muscle, and adipose
tissue is anabolic as insulin promotes the storage of
chemical energy in these tissues (13). However, when
Endocrinology, January 2011, 152(1):11–18
insulin is delivered intracerebroventricularly it exerts
catabolic effects (12).
Further genetic evidences support this bifurcation of
central vs. peripheral insulin’s actions on energy balance
as brain-specific deletion of insulin receptor (IR) has been
shown to engender increased adiposity (14). Other hormonal signals include peptide YY, glucagon-like peptide
1, and oxyntomodulin (produced by endocrine L cells in
the gut), the secretion of which augments postprandially
(15) and ghrelin (secreted by gastrointestinal endocrine
cells lining the stomach and proximal small intestine), the
circulating amounts of which rise before and fall after
meals (16). In addition to hormones, the brain also directly
responds to fluctuations in circulating metabolites levels
(e.g. fatty acids and glucose). For example, an increase in
long-chain fatty acyl-CoAs in the cytoplasm of brain cells
causes inhibition of food intake, suggesting that neuronal
lipid-sensing mechanisms also contribute to safeguarding
normal energy balance (17). Changes in blood glucose
levels affect the activity of hypothalamic neurons governing body weight, as for example the leptin- and insulinresponsive proopiomelanocortin (POMC) neurons (18).
Nevertheless, despite glucostatic and lipostatic theories
have been put forth, strong genetic evidences bolstering
the contention that changes in blood lipids and/or glucose
levels underlie long-term energy balance are still lacking.
Lastly, the brain (and in particular the caudal brain
stem neurons) also receives neural afferent inputs regarding the status of energy balance (19). Below we will mainly
focus on genetic evidences supporting that hormonalsensing mechanisms in hypothalamic neurons are key for
coordinated energy balance. We thus suggest other manuscripts that have dealt with roles on eating exerted by
hedonic and visceral afferents systems, both of which are
also key components of the circuitry underlying body
weight homeostasis (2, 10, 19 –21).
Hypothalamic neurons underlying body weight
homeostasis
The hypothalamus is a tiny brain structure that occupies the ventral portion of the diencephalon, the borders of
which are the optic chiasm (rostrally), the optic tracts and
cerebral peduncles (laterally), and the mammillary bodies
(caudally). Several nuclei are found within the hypothalamus. Here we touch on those that have been shown to be
important for coordinated body energy balance. The first
important clues about the physiological relevance of hypothalamic neurons on energy balance were obtained in
the 1940s by Hetherington and Ranson (22). They showed
that destruction of ventromedial hypothalamic areas including the ventromedial (VMH) and arcuate (ARH) nuclei leads to hyperphagia and obesity. Conversely, lesion
Endocrinology, January 2011, 152(1):11–18
of lateral hypothalamus causes reduced food intake and
weight loss. The dual centers concept originated from
these very important findings indicates the ventromedial
hypothalamus as the satiety and the lateral hypothalamus
as the phagic center. In light of recent findings, this concept
needs slight revision. Indeed, it is now known that neurons
within the same hypothalamic structure may serve opposite metabolic functions. One example of the complexity
of these hypothalamic circuitries is the central melanocortin system.
Two distinct populations of neurons that belong to this
system are POMC and agouti-related peptide (AgRP) neurons. Despite that these cells are located next to each other
in the ARH, POMC, and AgRP neurons have opposite
effects on energy balance (23). Interestingly, ␣-MSH (secreted from POMC neurons) activates, whereas AgRP inhibits melanocortin-3 and -4 receptors (MC3R and MC4R).
As a consequence, ␣-MSH suppresses feeding and body
weight gain, whereas AgRP promotes positive energy balance (24 –27). Noteworthy, POMC and AgRP neurons are
diversely regulated by leptin as this hormone stimulates
POMC neurons at the action potential (e.g. leptin depolarizes and hence increases POMC neurons firing rate)
(28) and the transcriptional level (e.g. LEPR signaling induces Pomc gene expression) (29 –32). In contrast, leptin
inhibits AgRP neurons as lack of LEPR signaling or fasting-induced hypoleptinemia leads to increased hypothalamic Agrp mRNA levels, an effect that is reversed by
exogenous leptin administration (33–35). Whether leptin
directly hyperpolarizes and decreases AgRP neurons firing
is yet to be established. Of note, ablation of AgRP neurons
in adult mice leads to anorexia (36 –38). Thus, AgRP neurons are metabolically relevant phagic neurons residing in
a previously considered satiety center.
The lateral hypothalamus also contains neurons, the
effects of which appear to be opposite to what Hetherington and Ranson’s results would have suggested. For example, orexins (also known as hypocretins) are neuropeptides secreted by a group of neurons only found in the
lateral hypothalamic area (LHA) (39). The orexin system
is made of two neuropeptides (orexin-A and orexin-B that
are the products of the same preproorexin gene) and their
cognate receptors (orexin receptor types 1 and 2) (39).
Although intracranial orexin injection acutely stimulates
appetite, a null mutation in preproorexin gene leads to
obesity (40, 41). This obesity is likely not the consequence
of narcolepsy (a major phenotype caused by orexin deficiency) (40, 41) as suggested by the fact that narcoleptic
humans lacking orexin have higher BMIs compared
with orexin-intact narcoleptics (42). Moreover, enhanced orexigenic signaling suppresses food intake and
body weight gain in part by augmenting leptin sensitivity
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(43). Thus, orexin-expressing neurons exert actions that
are typical of satiety neurons, even though they are located
in the LHA, a previously considered phagic center (22).
Collectively these results indicate that distinct neuronal
groups exerting opposite actions on energy balance coexist within a specific hypothalamic nucleus. Therefore,
from a pharmacological prospective, the metabolic outcomes of stimulation (or inhibition) of neurons within a
hypothalamic structure are likely the summation of events
triggered by the simultaneous stimulation (or inhibition)
of phagic and satiety neurons.
In addition to ARH and LHA, VMH neurons have also
been shown to be of particular importance. For example,
aberrant VMH development causes obesity (44). Also,
loss of LEPR signaling only in neurons expressing steroidogenic factor 1 (a transcription factor expressed only by
VMH neurons within the brain) (45, 46) causes mild obesity (7). Because VMH neurons also project to ARH
POMC neurons (47), it is very likely that VMH and ARH
neurons communicate (directly and/or indirectly) to each
other as part of the intricate hypothalamic neuronal web
underlying normal energy balance. Neurons in the paraventricular nucleus (PVH) are also indispensable for normal energy balance because hyperphagia occurs after the
PVH is damaged (48). Moreover, obesity develops in mice
(and humans) heterozygous for a null mutation in singleminded 1 (Sim1), a gene encoding for a transcription factor required for PVH development (49, 50). Furthermore,
POMC and AgRP neurons project to the PVH, a site of
abundant MC4R expression (51–53).
Interestingly, neurons coexpressing MC4R and SIM1
have been shown to mediate the anorectic effects induced
by central melanocortin signals (51). The dorsomedial hypothalamic nucleus (DMH) is another site of importance
because energy imbalance is caused by DMH lesion (54).
Similarly to the PVH, ARH, LHA, and VMH, the DMH
also contains leptin-responsive neurons (55). The biochemical signature(s) of DMH neurons has been elusive,
and this lack of knowledge has greatly impaired the ability
to genetically dissect the physiological relevance of specific
genes in specialized DMH neurons. However, due to the
fact that DMH neurons are metabolic-sensing cells projecting to metabolically relevant sites (e.g. PVH and ARH)
(56), it is tantalizing to suggest that metabolic-sensing
mechanisms in DMH neurons are also important for body
weight homeostasis.
The use of the Cre/LoxP technology has been instrumental in assigning metabolic roles to specific genes in
biochemically defined neuronal groups. For example, several POMC neuron- and/or AgRP neuron-specific genetic
mutations affecting body weight homeostasis have been
reported. In 2004 the group of Lowell and colleagues has
14
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Neurocircuitries Governing Metabolic Homeostasis
Endocrinology, January 2011, 152(1):11–18
TABLE 1. ARH neuron-specific mutations affecting body weight homeostasis
Neuron
Mutation
Diet
Food
intake
Energy
expenditure
Adiposity
Reference(s)
POMC
POMC
POMC
POMC
POMC
POMC
POMC
POMC
POMC
AgRP
AgRP
AgRP
AgRP
Lepr KO
SIRT1 KO
Shp2 KO
Lepr and IR KO
Socs3 KO
PTP1B KO
5-HT2CR React
FoxO1 KO
IR KO
Lepr KO
STAT3 CA
IKK␤ KO
Vgat KO
SC and HC
HC
SC and HC
SC
HC
HC
SC and HC
SC and HC
SC
SC
SC and HC
HC
SC and HC
–
–
–
–
–
–
–
?
–
–
Œ
Œ
–
–
–
?
Œ
?
Œ
Œ
Œ
Œ
Œ
–
Œ
(29, 57)
(9)
(58)
(66)
(59)
(58)
(69)
(70)
(57, 66)
(62)
(76)
(78)
(78)
–, Unchanged; Œ, increased; , decreased; ?, not measured; SC, standard diet; HC, hypercaloric diet; KO, knockout; React, reactivated; CA,
constitutively active; STAT3, signal transducer and activator of transcription 3; Vgat, vesicular GABA transporter.
shown that LEPR signaling in POMC neurons is required
for normal energy balance because its absence causes mild
obesity (29) owing to reduced energy expenditure (57)
(Table 1). A similar energy imbalance occurs when domain-containing protein tyrosine phosphatase-2 (SHP2; a
positive regulator of LEPR signaling) is knocked out only
in POMC neurons (58) (Table 1). Also, deletion of the
protein deacetylase sirtuin 1 (SIRT1) only from POMC
neurons leads to leptin resistance and consequentially to
hypersensitivity to dietary obesity (9) (Table 1). Conversely, enhanced leptin sensitivity only in POMC neurons
protects against diet-induced obesity. For example, highcalorie-fed mice bearing POMC-neuron-specific ablation
of suppressor of cytokine signaling-3 (SOCS-3; a negative
regulator of LEPR signaling) display a lean phenotype owing to increased energy expenditure (59) (Table 1).
Another negative regulator of leptin signaling is the
protein tyrosine phosphatase 1B (PTP1B); similarly to the
metabolic outcomes of POMC neuron-specific SOCS-3
deletion, high-calorie-fed mice lacking PTP1B only in
POMC cells are also more resistant to developing obesity
via a mechanism that includes increased energy expenditure (58) (Table 1). The result that both abolished/impaired or enhanced LEPR signaling in POMC neurons
does not cause altered food intake is somewhat unexpected, mainly because previous results from nonneuronspecific experiments strongly suggested that leptin’s anorectic effects were mediated by POMC neurons (60, 61).
Results from studies using mice lacking LEPR in other
biochemically defined neurons have now led to the wellaccepted contention that leptin’s actions on body weight
are not mediated by a single neuronal population but by
multiple hypothalamic and extrahypothalamic neuronal
groups (7, 29, 62, 63). On the other hand and somewhat
unexpected, reactivation of LEPR in ARH POMC neurons completely rescues the hyperglycemia phenotype
caused by LEPR signaling deficiency (64, 65). Altogether
these results led to a paradigm shift: LEPR in ARH POMC
neurons play only marginal roles on body weight homeostasis (contrary to what was previously suggested)
(60, 61) but are key for mediating the antidiabetic actions
of leptin (64, 65).
The idea that POMC neurons are also important for
controlling glucose balance is further bolstered by other
findings. For example, glucose sensing in POMC neurons
is dispensable for body weight balance but is required for
normal glucose tolerance (18). Moreover, deletion of both
LEPR and IR in POMC neurons causes overt hepatic insulin resistance, whereas IR deletion alone has no effects
on glucose/body weight homeostasis (57, 66). However,
because POMC neurons are established regulators of food
intake as demonstrated by the fact that Pomc gene deletion
causes hyperphagia and obesity, whereas intracerebroventricular delivery of ␣-MSH potently suppresses food
intake (67, 68), other inputs to POMC neurons must underlie coordinated feeding. One of these inputs is serotonin because reactivation of 5-hydroxytryptamine 2C serotonin receptor (5-HT2CR) only in POMC neurons
normalizes the hyperphagia and obesity phenotypes displayed by 5-HT2CR-null mice (69) (Table 1). Forkhead
box O (FoxO)-1 transcription factor in POMC neurons is
also indispensable for appropriate food intake because
POMC neuron-specific deletion of FoxO1 leads to increased ␣-MSH levels and an anorectic phenotype (70)
(Table 1).
AgRP neurons also express neuropeptide Y (NPY) (71).
Ablation of the Npy and/or AgRP gene does not result in
altered body weight and food intake (72) despite the fact
that intracranial injection of either one of these neuropeptides potently stimulates hyperphagia and body weight
gain (73, 74). However, the consequence of AgRP/NPY
neuron ablation in adulthood includes hypophagia and
Endocrinology, January 2011, 152(1):11–18
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FIG. 1. Potential antiobesity molecular targets in metabolically relevant hypothalamic
neurons. POMC and AgRP/NPY neurons are critical for coordinated energy balance. In green
are depicted molecules that positively regulate, whereas in red are the ones that negatively
affect metabolic sensing in these neurons. Pharmacologically mediated activation of SIRT1
and SHP2 in POMC neurons combined with the inhibition of SOCS3 and PTP1B in POMC and
NF-␬B/IKK␤ in AgRP neurons may be an effective approach to reverse energy imbalance
brought about by hypercaloric feeding.
reduced body weight (36 –38, 75). These results indicate
that, in addition to AgRP and NPY, other molecules secreted by these neurons must be critical for normal energy
balance. Recently one of these molecules has been identified: the neurotransmitter ␥-aminobutyric acid. Indeed,
mutant mice unable to secrete ␥-aminobutyric acid from
AgRP/NPY neurons display reduced body weigh due to
increased energy expenditure without changes in food intake (8) (Table 1). Because these mutants eat normally (8),
other yet-to-be-identified factor(s) produced by AgRP/
NPY neurons must exert potent orexigenic actions. Further strengthening an important role for AgRP neurons on
body weight regulation are results from mice in which a
constitutively active signal transducer and activator of
transcription 3 (a downstream signaling molecule of LEPR
signaling) is selectively expressed in AgRP/NPY neurons,
a mutation that causes resistance to dietary obesity (76).
On the other hand, ablation of LEPR only in these neurons
leads to mild obesity (62) (Table 1).
What causes energy imbalance in obesogenic
environments?
Little is known about the molecular mechanisms by
which hypercaloric feeding causes energy imbalance.
However, impaired responsiveness to changes in circulating hormonal and substrate levels in hypothalamic neurons is a hallmark defect brought on by hypercaloric
feeding (18, 77), a defect that likely contributes to the
pathogenesis of dietary obesity. For example, obese subjects are hyperleptinemic, suggesting that leptin resistance
underlies, at least in part, their metabolic imbalance. At
the molecular level, both, impaired leptin transport from
blood to brain and altered LEPR signaling underlie leptin
15
resistance (77). Of note, chronic hypercaloric feeding stimulates nuclear factor-␬B (NF-␬B)/inhibitory-␬B kinase
(IKK)-␤ inflammatory pathways in hypothalamus, an effect that impairs normal metabolic sensing in hypothalamic
neurons (78). Interestingly, mice lacking IKK␤ only in AgRP/NPY neurons
appear to be protected from diet-induced leptin resistance and hence obesity (Table 1), suggesting that endogenously and/or exogenously mediated
NF-␬B/IKK␤ inhibition in these cells
may be an effective antiobesity strategy
(78) (Fig. 1).
Conclusions
We have come a long way from Hetherington and Ranson’s findings suggesting that medial and lateral hypothalamic neurons are critical regulators of appetite,
metabolic rate, and body weight homeostasis (22). Indeed, we now know the biochemical identities of some of
these neurons (e.g. POMC, AgRP/NPY, SIM1, steroidogenic factor 1, orexin expressing neurons) and the nature
of some of the peripheral signals that regulate the activity
of these specialized cells (e.g. leptin, insulin, ghrelin, glucose, fatty acids, etc.). Also, some of the intracellular molecular components required for translating these peripheral signals into normal body weight have been identified.
These molecules enhance (e.g. SIRT1, SHP2) whereas
other antagonize (e.g. SOCS-3, PTP1B) metabolic sensing
in POMC neurons (Fig. 1). From a pharmacological perspective, activation of SIRT1 and SHP2 and inhibition of
SOCS-3 and PTP1B selectively in POMC neurons combined with suppression of NF-␬B/IKK␤ in AgRP neurons
may therefore be an effective approach that in obesogenic
environment could reestablish normal body weight (Fig.
1). It must be noted, however, that two major problems
need to be overcome if antiobesity therapies are to be effective. First, due to significant overlaps between brain
circuitries controlling feeding and hedonic/reward pathways, ideal antiobesity drugs must target the former but
not the latter. One example of the limitation of the use of
drugs targeting both pathways is represented by the inverse agonists at the cannabinoid receptor 1. Clinical trials
at final phases were recently halted because of psychotropic side effects elicited by these drugs (79 – 81). Second,
to target only specific molecules in specific neurons, ways
to deliver drugs in a neuron-selective manner must be developed; these approaches are theoretically feasible yet
still beyond our capabilities. In summary, there is urgency
16
Vianna and Coppari
Neurocircuitries Governing Metabolic Homeostasis
for developing effective antiobesity therapies. Our
progresses in understanding mechanisms underlying body
weight homeostasis have already provided potential molecular targets in defined neuronal groups. Harnessing
these molecules in these neurons could be an effective and
long-lasting antiobesity approach.
Acknowledgments
We thank Giorgio Ramadori, Teppei Fujikawa, and Jason
Anderson (all members of the Coppari laboratory) for helpful
discussions and critical reading of the manuscript.
Address all correspondence and requests for reprints to: Dr.
Roberto Coppari, Department of Internal Medicine, Division of
Hypothalamic Research, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Room Y6220C, Dallas, Texas 75390-9077. E-mail: roberto.coppari@
utsouthwestern.edu.
This work was supported by American Heart Association
(Scientist Development Grant to R.C.) and National Institutes of
Health Grant DK080836 (to R.C.).
Disclosure Summary: The authors have nothing to disclose.
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21.
References
1. Spiegelman BM, Flier JS 2001 Obesity and the regulation of energy
balance. Cell 104:531–543
2. O’Rahilly S 2009 Human genetics illuminates the paths to metabolic
disease. Nature 462:307–314
3. Obici S 2009 Minireview: molecular targets for obesity therapy in
the brain. Endocrinology 150:2512–2517
4. McCurdy CE, Bishop JM, Williams SM, Grayson BE, Smith MS,
Friedman JE, Grove KL 2009 Maternal high-fat diet triggers lipotoxicity in the fetal livers of nonhuman primates. J Clin Invest 119:
323–335
5. Enriori PJ, Evans AE, Sinnayah P, Jobst EE, Tonelli-Lemos L, Billes
SK, Glavas MM, Grayson BE, Perello M, Nillni EA, Grove KL,
Cowley MA 2007 Diet-induced obesity causes severe but reversible
leptin resistance in arcuate melanocortin neurons. Cell Metab
5:181–194
6. Neel JV 1999 The “thrifty genotype” in 1998. Nutr Rev 57:S2–S9
7. Dhillon H, Zigman JM, Ye C, Lee CE, McGovern RA, Tang V,
Kenny CD, Christiansen LM, White RD, Edelstein EA, Coppari R,
Balthasar N, Cowley MA, Chua Jr S, Elmquist JK, Lowell BB 2006
Leptin directly activates SF1 neurons in the VMH, and this action by
leptin is required for normal body-weight homeostasis. Neuron 49:
191–203
8. Tong Q, Ye CP, Jones JE, Elmquist JK, Lowell BB 2008 Synaptic
release of GABA by AgRP neurons is required for normal regulation
of energy balance. Nat Neurosci 11:998 –1000
9. Ramadori G, Fujikawa T, Fukuda M, Anderson J, Morgan DA,
Mostoslavsky R, Stuart RC, Perello M, Vianna CR, Nillni EA,
Rahmouni K, Coppari R 2010 SIRT1 deacetylase in POMC neurons
is required for homeostatic defenses against diet-induced obesity.
Cell Metab 12:78 – 87
10. Saper CB, Chou TC, Elmquist JK 2002 The need to feed: homeostatic and hedonic control of eating. Neuron 36:199 –211
11. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
Endocrinology, January 2011, 152(1):11–18
1994 Positional cloning of the mouse obese gene and its human
homologue. Nature 372:425– 432
Woods SC, Lotter EC, McKay LD, Porte Jr D 1979 Chronic intracerebroventricular infusion of insulin reduces food intake and body
weight of baboons. Nature 282:503–505
Unger RH, Orci L 2010 Paracrinology of islets and the paracrinopathy of diabetes. Proc Natl Acad Sci USA 107:16009 –16012
Brüning JC, Gautam D, Burks DJ, Gillette J, Schubert M, Orban PC,
Klein R, Krone W, Müller-Wieland D, Kahn CR 2000 Role of brain
insulin receptor in control of body weight and reproduction. Science
(New York, NY) 289:2122–2125
Stanley S, Wynne K, Bloom S 2004 Gastrointestinal satiety signals
III. Glucagon-like peptide 1, oxyntomodulin, peptide YY, and pancreatic polypeptide. Am J Physiol Gastrointest Liver Physiol 286:
G693–G697
Nogueiras R, Tschöp MH, Zigman JM 2008 Central nervous system regulation of energy metabolism: ghrelin versus leptin. Ann NY
Acad Sci 1126:14 –19
Obici S, Feng Z, Arduini A, Conti R, Rossetti L 2003 Inhibition of
hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production. Nat Med 9:756 –761
Parton LE, Ye CP, Coppari R, Enriori PJ, Choi B, Zhang CY, Xu C,
Vianna CR, Balthasar N, Lee CE, Elmquist JK, Cowley MA, Lowell
BB 2007 Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity. Nature 449:228 –232
Powley TL, Chi MM, Schier LA, Phillips RJ 2005 Obesity: should
treatments target visceral afferents? Physiol Behav 86:698 –708
Myers Jr MG, Münzberg H, Leinninger GM, Leshan RL 2009 The
geometry of leptin action in the brain: more complicated than a
simple ARC. Cell Metab 9:117–123
Coll AP, Farooqi IS, O’Rahilly S 2007 The hormonal control of food
intake. Cell 129:251–262
Hetherington AW, Ranson SW 1940 Hypothalamic lesions and adiposity in the rat. Anat Rec 78:149 –172
Cone RD 2005 Anatomy and regulation of the central melanocortin
system. Nat Neurosci 8:571–578
Coll AP, Farooqi IS, Challis BG, Yeo GS, O’Rahilly S 2004 Proopiomelanocortin and energy balance: insights from human and
murine genetics. J Clin Endocrinol Metab 89:2557–2562
Fan W, Boston BA, Kesterson RA, Hruby VJ, Cone RD 1997 Role
of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 385:165–168
Ollmann MM, Wilson BD, Yang YK, Kerns JA, Chen Y, Gantz I,
Barsh GS 1997 Antagonism of central melanocortin receptors in
vitro and in vivo by agouti-related protein. Science (New York, NY)
278:135–138
Cone RD, Lu D, Koppula S, Vage DI, Klungland H, Boston B, Chen
W, Orth DN, Pouton C, Kesterson RA 1996 The melanocortin receptors: agonists, antagonists, and the hormonal control of pigmentation. Rec Prog Horm Res 51:287–317; discussion 318
Cowley MA, Smart JL, Rubinstein M, Cerdán MG, Diano S,
Horvath TL, Cone RD, Low MJ 2001 Leptin activates anorexigenic
POMC neurons through a neural network in the arcuate nucleus.
Nature 411:480 – 484
Balthasar N, Coppari R, McMinn J, Liu SM, Lee CE, Tang V, Kenny
CD, McGovern RA, Chua Jr SC, Elmquist JK, Lowell BB 2004
Leptin receptor signaling in POMC neurons is required for normal
body weight homeostasis. Neuron 42:983–991
Schwartz MW, Seeley RJ, Woods SC, Weigle DS, Campfield LA,
Burn P, Baskin DG 1997 Leptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral arcuate nucleus.
Diabetes 46:2119 –2123
Thornton JE, Cheung CC, Clifton DK, Steiner RA 1997 Regulation
of hypothalamic proopiomelanocortin mRNA by leptin in ob/ob
mice. Endocrinology 138:5063–5066
Mizuno TM, Kleopoulos SP, Bergen HT, Roberts JL, Priest CA,
Mobbs CV 1998 Hypothalamic pro-opiomelanocortin mRNA is
Endocrinology, January 2011, 152(1):11–18
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
reduced by fasting and [corrected] in ob/ob and db/db mice, but is
stimulated by leptin. Diabetes 47:294 –297
Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, MaratosFlier E, Flier JS 1996 Role of leptin in the neuroendocrine response
to fasting. Nature 382:250 –252
Schwartz MW, Baskin DG, Bukowski TR, Kuijper JL, Foster D,
Lasser G, Prunkard DE, Porte Jr D, Woods SC, Seeley RJ, Weigle DS
1996 Specificity of leptin action on elevated blood glucose levels and
hypothalamic neuropeptide Y gene expression in ob/ob mice. Diabetes 45:531–535
Stephens TW, Basinski M, Bristow PK, Bue-Valleskey JM, Burgett
SG, Craft L, Hale J, Hoffmann J, Hsiung HM, Kriauciunas A,
MacKellar W, Rosteck Jr PR, Schoner B, Smith D, Tinsley FC,
Zhang XY, Heiman M 1995 The role of neuropeptide Y in the
antiobesity action of the obese gene product. Nature 377:530 –532
Gropp E, Shanabrough M, Borok E, Xu AW, Janoschek R, Buch T,
Plum L, Balthasar N, Hampel B, Waisman A, Barsh GS, Horvath
TL, Brüning JC 2005 Agouti-related peptide-expressing neurons are
mandatory for feeding. Nature neuroscience 8:1289 –1291
Luquet S, Perez FA, Hnasko TS, Palmiter RD 2005 NPY/AgRP
neurons are essential for feeding in adult mice but can be ablated in
neonates. Science (New York, NY) 310:683– 685
Bewick GA, Gardiner JV, Dhillo WS, Kent AS, White NE, Webster
Z, Ghatei MA, Bloom SR 2005 Post-embryonic ablation of AgRP
neurons in mice leads to a lean, hypophagic phenotype. FASEB J
19:1680 –1682
Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka
H, Williams SC, Richardson JA, Kozlowski GP, Wilson S, Arch JR,
Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu
WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M 1998
Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92:573–585
Hara J, Beuckmann CT, Nambu T, Willie JT, Chemelli RM, Sinton
CM, Sugiyama F, Yagami K, Goto K, Yanagisawa M, Sakurai T
2001 Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30:345–354
Hara J, Yanagisawa M, Sakurai T 2005 Difference in obesity phenotype between orexin-knockout mice and orexin neuron-deficient
mice with same genetic background and environmental conditions.
Neurosci Lett 380:239 –242
Nishino S, Ripley B, Overeem S, Nevsimalova S, Lammers GJ,
Vankova J, Okun M, Rogers W, Brooks S, Mignot E 2001 Low
cerebrospinal fluid hypocretin (orexin) and altered energy homeostasis in human narcolepsy. Ann Neurol 50:381–388
Funato H, Tsai AL, Willie JT, Kisanuki Y, Williams SC, Sakurai T,
Yanagisawa M 2009 Enhanced orexin receptor-2 signaling prevents
diet-induced obesity and improves leptin sensitivity. Cell Metab
9:64 –76
Majdic G, Young M, Gomez-Sanchez E, Anderson P, Szczepaniak
LS, Dobbins RL, McGarry JD, Parker KL 2002 Knockout mice
lacking steroidogenic factor 1 are a novel genetic model of hypothalamic obesity. Endocrinology 143:607– 614
Luo X, Ikeda Y, Parker KL 1994 A cell-specific nuclear receptor is
essential for adrenal and gonadal development and sexual differentiation. Cell 77:481– 490
Ikeda Y, Lala DS, Luo X, Kim E, Moisan MP, Parker KL 1993
Characterization of the mouse FTZ-F1 gene, which encodes a key
regulator of steroid hydroxylase gene expression. Mol Endocrinol
(Baltimore, Md) 7:852– 860
Sternson SM, Shepherd GM, Friedman JM 2005 Topographic mapping of VMH –⬎ arcuate nucleus microcircuits and their reorganization by fasting. Nat Neurosci 8:1356 –1363
Weingarten HP, Chang PK, McDonald TJ 1985 Comparison of the
metabolic and behavioral disturbances following paraventricularand ventromedial-hypothalamic lesions. Brain Res Bull 14:551–559
Holder Jr JL, Butte NF, Zinn AR 2000 Profound obesity associated
endo.endojournals.org
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
17
with a balanced translocation that disrupts the SIM1 gene. Hum
Mol Genet 9:101–108
Michaud JL, Rosenquist T, May NR, Fan CM 1998 Development
of neuroendocrine lineages requires the bHLH-PAS transcription
factor SIM1. Genes Dev 12:3264 –3275
Balthasar N, Dalgaard LT, Lee CE, Yu J, Funahashi H, Williams T,
Ferreira M, Tang V, McGovern RA, Kenny CD, Christiansen LM,
Edelstein E, Choi B, Boss O, Aschkenasi C, Zhang CY, Mountjoy K,
Kishi T, Elmquist JK, Lowell BB 2005 Divergence of melanocortin
pathways in the control of food intake and energy expenditure. Cell
123:493–505
Harris M, Aschkenasi C, Elias CF, Chandrankunnel A, Nillni EA,
Bjøorbaek C, Elmquist JK, Flier JS, Hollenberg AN 2001 Transcriptional regulation of the thyrotropin-releasing hormone gene by leptin and melanocortin signaling. J Clin Invest 107:111–120
Kishi T, Aschkenasi CJ, Lee CE, Mountjoy KG, Saper CB, Elmquist
JK 2003 Expression of melanocortin 4 receptor mRNA in the central
nervous system of the rat. J Comp Neurol 457:213–235
Bellinger LL, Bernardis LL 2002 The dorsomedial hypothalamic nucleus and its role in ingestive behavior and body weight regulation:
lessons learned from lesioning studies. Physiol Behav 76:431– 442
Elmquist JK, Ahima RS, Maratos-Flier E, Flier JS, Saper CB 1997
Leptin activates neurons in ventrobasal hypothalamus and brainstem. Endocrinology 138:839 – 842
Gautron L, Lazarus M, Scott MM, Saper CB, Elmquist JK 2010
Identifying the efferent projections of leptin-responsive neurons in
the dorsomedial hypothalamus using a novel conditional tracing
approach. J Comp Neurol 518:2090 –2108
Hill JW, Elias CF, Fukuda M, Williams KW, Berglund ED, Holland
WL, Cho YR, Chuang JC, Xu Y, Choi M, Lauzon D, Lee CE,
Coppari R, Richardson JA, Zigman JM, Chua S, Scherer PE, Lowell
BB, Brüning JC, Elmquist JK 2010 Direct insulin and leptin action
on pro-opiomelanocortin neurons is required for normal glucose
homeostasis and fertility. Cell Metab 11:286 –297
Banno R, Zimmer D, De Jonghe BC, Atienza M, Rak K, Yang W,
Bence KK 2010 PTP1B and SHP2 in POMC neurons reciprocally
regulate energy balance in mice. J Clin Invest 120:720 –734
Kievit P, Howard JK, Badman MK, Balthasar N, Coppari R, Mori
H, Lee CE, Elmquist JK, Yoshimura A, Flier JS 2006 Enhanced leptin
sensitivity and improved glucose homeostasis in mice lacking suppressor of cytokine signaling-3 in POMC-expressing cells. Cell
Metab 4:123–132
Schwartz MW, Woods SC, Seeley RJ, Barsh GS, Baskin DG, Leibel
RL 2003 Is the energy homeostasis system inherently biased toward
weight gain? Diabetes 52:232–238
Seeley RJ, Yagaloff KA, Fisher SL, Burn P, Thiele TE, van Dijk G,
Baskin DG, Schwartz MW 1997 Melanocortin receptors in leptin
effects. Nature 390:349
van de Wall E, Leshan R, Xu AW, Balthasar N, Coppari R, Liu SM,
Jo YH, MacKenzie RG, Allison DB, Dun NJ, Elmquist J, Lowell BB,
Barsh GS, de Luca C, Myers Jr MG, Schwartz GJ, Chua Jr SC 2008
Collective and individual functions of leptin receptor modulated
neurons controlling metabolism and ingestion. Endocrinology 149:
1773–1785
Hayes MR, Skibicka KP, Leichner TM, Guarnieri DJ, DiLeone RJ,
Bence KK, Grill HJ 2010 Endogenous leptin signaling in the caudal
nucleus tractus solitarius and area postrema is required for energy
balance regulation. Cell Metab 11:77– 83
Coppari R, Ichinose M, Lee CE, Pullen AE, Kenny CD, McGovern
RA, Tang V, Liu SM, Ludwig T, Chua Jr SC, Lowell BB, Elmquist
JK 2005 The hypothalamic arcuate nucleus: a key site for mediating
leptin’s effects on glucose homeostasis and locomotor activity. Cell
Metab 1:63–72
Huo L, Gamber K, Greeley S, Silva J, Huntoon N, Leng XH,
Bjørbaek C 2009 Leptin-dependent control of glucose balance and
locomotor activity by POMC neurons. Cell Metab 9:537–547
Könner AC, Janoschek R, Plum L, Jordan SD, Rother E, Ma X, Xu
C, Enriori P, Hampel B, Barsh GS, Kahn CR, Cowley MA, Ashcroft
18
67.
68.
69.
70.
71.
72.
73.
74.
Vianna and Coppari
Neurocircuitries Governing Metabolic Homeostasis
FM, Brüning JC 2007 Insulin action in AgRP-expressing neurons is
required for suppression of hepatic glucose production. Cell Metab
5:438 – 449
Yaswen L, Diehl N, Brennan MB, Hochgeschwender U 1999 Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin. Nat Med 5:1066 –1070
Tsujii S, Bray GA 1989 Acetylation alters the feeding response to
MSH and ␤-endorphin. Brain Res Bull 23:165–169
Xu Y, Jones JE, Kohno D, Williams KW, Lee CE, Choi MJ,
Anderson JG, Heisler LK, Zigman JM, Lowell BB, Elmquist JK 2008
5-HT2CRs expressed by pro-opiomelanocortin neurons regulate
energy homeostasis. Neuron 60:582–589
Plum L, Lin HV, Dutia R, Tanaka J, Aizawa KS, Matsumoto M, Kim
AJ, Cawley NX, Paik JH, Loh YP, DePinho RA, Wardlaw SL, Accili
D 2009 The obesity susceptibility gene Cpe links FoxO1 signaling in
hypothalamic pro-opiomelanocortin neurons with regulation of
food intake. Nat Med 15:1195–1201
Chen P, Li C, Haskell-Luevano C, Cone RD, Smith MS 1999 Altered
expression of agouti-related protein and its colocalization with neuropeptide Y in the arcuate nucleus of the hypothalamus during lactation. Endocrinology 140:2645–2650
Qian S, Chen H, Weingarth D, Trumbauer ME, Novi DE, Guan X,
Yu H, Shen Z, Feng Y, Frazier E, Chen A, Camacho RE, Shearman
LP, Gopal-Truter S, MacNeil DJ, Van der Ploeg LH, Marsh DJ 2002
Neither agouti-related protein nor neuropeptide Y is critically required for the regulation of energy homeostasis in mice. Mol Cell
Biol 22:5027–5035
Clark JT, Kalra PS, Crowley WR, Kalra SP 1984 Neuropeptide Y
and human pancreatic polypeptide stimulate feeding behavior in
rats. Endocrinology 115:427– 429
Rossi M, Kim MS, Morgan DG, Small CJ, Edwards CM, Sunter D,
75.
76.
77.
78.
79.
80.
81.
Endocrinology, January 2011, 152(1):11–18
Abusnana S, Goldstone AP, Russell SH, Stanley SA, Smith DM,
Yagaloff K, Ghatei MA, Bloom SR 1998 A C-terminal fragment of
Agouti-related protein increases feeding and antagonizes the effect
of alpha-melanocyte stimulating hormone in vivo. Endocrinology
139:4428 – 4431
Phillips CT, Palmiter RD 2008 Role of agouti-related protein-expressing neurons in lactation. Endocrinology 149:544 –550
Mesaros A, Koralov SB, Rother E, Wunderlich FT, Ernst MB, Barsh
GS, Rajewsky K, Brüning JC 2008 Activation of Stat3 signaling in
AgRP neurons promotes locomotor activity. Cell Metab 7:236 –248
El-Haschimi K, Pierroz DD, Hileman SM, Bjørbaek C, Flier JS 2000
Two defects contribute to hypothalamic leptin resistance in mice
with diet-induced obesity. J Clin Invest 105:1827–1832
Zhang X, Zhang G, Zhang H, Karin M, Bai H, Cai D 2008 Hypothalamic IKK␤/NF-␬B and ER stress link overnutrition to energy
imbalance and obesity. Cell 135:61–73
Addy C, Wright H, Van Laere K, Gantz I, Erondu N, Musser BJ, Lu
K, Yuan J, Sanabria-Bohórquez SM, Stoch A, Stevens C, Fong TM,
De Lepeleire I, Cilissen C, Cote J, Rosko K, Gendrano 3rd IN,
Nguyen AM, Gumbiner B, Rothenberg P, de Hoon J, Bormans G,
Depré M, Eng WS, Ravussin E, Klein S, Blundell J, Herman GA,
Burns HD, Hargreaves RJ, Wagner J, Gottesdiener K, Amatruda
JM, Heymsfield SB 2008 The acyclic CB1R inverse agonist
taranabant mediates weight loss by increasing energy expenditure
and decreasing caloric intake. Cell Metab 7:68 –78
Després JP, Golay A, Sjöström L 2005 Effects of rimonabant on
metabolic risk factors in overweight patients with dyslipidemia.
N Engl J Med 353:2121–2134
Di Marzo V 2008 Targeting the endocannabinoid system: to enhance or reduce? Nat Rev 7:438 – 455
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