Regulation Of Body Weight Homeostasis Research Articles

Shp2 signaling in Pomc neurons is important for leptin's actions on blood pressure, energy balance and glucose homeostasis.

Previous studies showed that Src homology‐2 tyrosine phosphatase (Shp2) is an important regulator of body weight homeostasis. We examined if deletion of Shp2 in proopiomelanocortin (Pomc) neurons attenuate the chronic cardiovascular and metabolic responses to leptin. Mice with Shp2 deleted in Pomc neurons (Shp2/Pomc‐Cre, n=7) and control mice (Shp2flox/flox, n=9) were implanted with telemetry probes for measurement of 24‐hr mean arterial pressure (MAP) and venous catheters for leptin infusion. After a 5‐day baseline period, mice received leptin infusion (2 μg/kg/day, iv) for 7 days. Shp2/Pomc‐Cre mice were slightly heavier (34±1 vs 31±1 g), but consumed the same amount of food (3.9±0.3 vs 3.8±0.2 g) compared to control mice. Leptin infusion reduced food intake by 30% and raised MAP by 5 mmHg in control mice, whereas Shp2/Pomc‐Cre mice exhibited attenuated responses on food intake (~18%) and MAP (2 mmHg). Leptin infusion decreased insulin and glucose levels in control mice (12±1 to 6±1 μU/ml and 142±12 to 81±8 mg/100 ml) while no changes were observed in Shp2/Pomc‐Cre mice. Leptin also increased energy expenditure by 16% in control mice and only 7% in Shp2/Pomc‐cre mice. These results indicate that Shp2 signaling in Pomc neurons is important in mediating the long‐term appetite and blood pressure actions of leptin and for the ability of leptin to reduce insulin and glucose levels. (NHLBI‐PO1HL51971/ AHA SDG5680016)

Action of Neurotransmitter: A Key to Unlock the AgRP Neuron Feeding Circuit

The current obesity epidemic and lack of efficient therapeutics demand a clear understanding of the mechanism underlying body weight regulation. Despite intensive research focus on obesity pathogenesis, an effective therapeutic strategy to treat and cure obesity is still lacking. Exciting studies in last decades have established the importance of hypothalamic agouti-related protein-expressing neurons (AgRP neurons) in the regulation of body weight homeostasis. AgRP neurons are both required and sufficient for feeding regulation. The activity of AgRP neurons is intricately regulated by nutritional hormones as well as synaptic inputs from upstream neurons. Changes in AgRP neuron activity lead to alterations in the release of mediators, including neuropeptides Neuropeptide Y (NPY) and AgRP, and fast-acting neurotransmitter GABA. Recent studies based on mouse genetics, novel optogenetics, and designer receptor exclusively activated by designer drugs have identified a critical role for GABA release from AgRP neurons in the parabrachial nucleus and paraventricular hypothalamus in feeding control. This review will summarize recent findings about AgRP neuron-mediated control of feeding circuits with a focus on the role of neurotransmitters. Given the limited knowledge on feeding regulation, understanding the action of neurotransmitters may be a key to unlock neurocircuitry that governs feeding.

An Obligate Role of Oxytocin Neurons in Diet Induced Energy Expenditure

Oxytocin neurons represent one of the major subsets of neurons in the paraventricular hypothalamus (PVH), a critical brain region for energy homeostasis. Despite substantial evidence supporting a role of oxytocin in body weight regulation, it remains controversial whether oxytocin neurons directly regulate body weight homeostasis, feeding or energy expenditure. Pharmacologic doses of oxytocin suppress feeding through a proposed melanocortin responsive projection from the PVH to the hindbrain. In contrast, deficiency in oxytocin or its receptor leads to reduced energy expenditure without feeding abnormalities. To test the physiological function of oxytocin neurons, we specifically ablated oxytocin neurons in adult mice. Our results show that oxytocin neuron ablation in adult animals has no effect on body weight, food intake or energy expenditure on a regular diet. Interestingly, male mice lacking oxytocin neurons are more sensitive to high fat diet-induced obesity due solely to reduced energy expenditure. In addition, despite a normal food intake, these mice exhibit a blunted food intake response to leptin administration. Thus, our study suggests that oxytocin neurons are required to resist the obesity associated with a high fat diet; but their role in feeding is permissive and can be compensated for by redundant pathways.

Metabolic and appetite responses to fasting and refeeding in mice with Shp2 deletion in forebrain neurons

Previous studies showed that Src homology‐2 tyrosine phosphatase (Shp2) is an important regulator of body weight homeostasis. Whether Shp2 is involved in normal refeeding response after prolonged fasting is still unknown. In this study we examined whether mice with Shp2 deletion in forebrain neurons (Shp2/CamK2‐Cre mice) exhibit impaired appetite and metabolic responses to refeeding after 24‐hrs of fasting. Shp2/CamK2‐Cre (n=6) and control mice (Shp2flox/flox, n=5) at 22‐weeks of age were placed in a controlled apparatus to measure 24‐hr food intake (FI), oxygen consumption (VO2), and body core temperature (BT) before and after a 24‐hr fasting protocol. Shp2/CamK2‐Cre mice were heavier, hyperphagic (4.7±0.3 vs. 3.0±0.3 g), exhibited lower VO2, but similar BT. Fasting reduced body weight (52.0±3.8 to 48.6±3.6 and 32.9±2.2 to 30.3±2.4 g), VO2 (2154±135 to 1898±138 and 2424±197 to 2093±132 ml/kg/hr), and BT (36.5±0.2 to 35.4 ±0.2 and 36.2±0.0 to 35.5±0.1 oC) in Shp2/CamK2‐Cre and Shp2flox/flox mice. The increases in metabolic rate and appetite in response to refeeding were attenuated in Shp2/CamK2‐ Cre compared to control mice (VO2: +6 vs. +11% and FI: +6 vs. +54%). Our results demonstrate that in addition to promote obesity, Shp2 deletion in forebrain neurons is also involved in the normal FI and metabolic responses to refeeding after prolonged fasting. (NHLBI‐PO1HL51971/AHA SDG5680016)

Functional implications of limited leptin receptor and ghrelin receptor coexpression in the brain

The hormones leptin and ghrelin act in apposition to one another in the regulation of body weight homeostasis. Interestingly, both leptin receptor expression and ghrelin receptor expression have been observed within many of the same nuclei of the central nervous system (CNS), suggesting that these hormones may act on a common population of neurons to produce changes in food intake and energy expenditure. In the present study we explored the extent of this putative direct leptin and ghrelin interaction in the CNS and addressed the question of whether a loss of ghrelin signaling would affect sensitivity to leptin. Using histological mapping of leptin receptor and ghrelin receptor expression, we found that cells containing both leptin receptors and ghrelin receptors are mainly located in the medial part of the hypothalamic arcuate nucleus. In contrast, coexpression was much less extensive elsewhere in the brain. To assess the functional consequences of this observed receptor distribution, we explored the effect of ghrelin receptor deletion on leptin sensitivity. In particular, the responses of ad libitum-fed, diet-induced obese and fasted mice to the anorectic actions of leptin were examined. Surprisingly, we found that deletion of the ghrelin receptor did not affect the sensitivity to exogenously administrated leptin. Thus, we conclude that ghrelin and leptin act largely on distinct neuronal populations and that ghrelin receptor deficiency does not affect sensitivity to the anorexigenic and body weight-lowering actions of leptin.

Expanding neurotransmitters in the hypothalamic neurocircuitry for energy balance regulation

The current epidemic of obesity and its associated metabolic syndromes impose unprecedented challenges to our society. Despite intensive research on obesity pathogenesis, an effective therapeutic strategy to treat and cure obesity is still lacking. Exciting studies in last decades have established the importance of the leptin neural pathway in the hypothalamus in the regulation of body weight homeostasis. Important hypothalamic neuropeptides have been identified as critical neurotransmitters from leptin-sensitive neurons to mediate leptin action. Recent research advance has significantly expanded the list of neurotransmitters involved in body weight-regulating neural pathways, including fast-acting neurotransmitters, gamma-aminobutyric acid (GABA) and glutamate. Given the limited knowledge on the leptin neural pathway for body weight homeostasis, understanding the function of neurotransmitters released from key neurons for energy balance regulation is essential for delineating leptin neural pathway and eventually for designing effective therapeutic drugs against the obesity epidemic.

Hypothalamic Angptl4/Fiaf Is a Novel Regulator of Food Intake and Body Weight

OBJECTIVEThe angiopoietin-like protein 4 (Angptl4)/fasting-induced adipose factor (Fiaf) is known as a regulator of peripheral lipid and glucose metabolism. In the present study, we investigated the physiological role of Angptl4 in central regulation of body weight homeostasis.RESEARCH DESIGN AND METHODSHypothalamic Angptl4 expression levels were measured using immunoblot assay during feeding manipulation or after administration of leptin, insulin, and nutrients. The effects of Angptl4 on food intake, body weight, and energy expenditure were determined following intracerebroventricular (ICV) administration of Angptl4 in C57BL/6 mice. Food intake, energy metabolism, and feeding responses to leptin, insulin, and nutrients were compared between Angptl4-null mice and their wild littermates. Finally, the relationship of hypothalamic AMP-activated protein kinase (AMPK) and Angptl4 was studied.RESULTSHypothalamic Angptl4 expression levels were increased upon food intake or administration of leptin, insulin, and nutrients. Furthermore, central administration of Angptl4 suppressed food intake and body weight gain but enhanced energy expenditure. These effects were mediated via suppression of hypothalamic AMPK activities. Consistently, Angptl4-null mice displayed increased body weight and hypothalamic AMPK activity but reduced energy expenditure. Food intake following a fast was significantly greater in Angptl4-null mice, which was normalized by centrally administered Angptl4. Moreover, anorectic responses to leptin, insulin, and glucose were diminished in Angptl4-null mice. In contrast, Angptl4-null mice were resistant to diet-induced obesity, indicating obesity-promoting effects of Angptl4 under the condition of fat-enriched diet.CONCLUSIONSWe have demonstrated that hypothalamic Angptl4 is regulated by physiological appetite regulators and mediates their anorexigenic effects via inhibition of hypothalamic AMPK activity. Therefore, Angptl4 appears to have an important role in central regulation of energy metabolism.

Hormone Interactions Regulating Energy Balance During Pregnancy

Appetite and food intake are increased during pregnancy, comprising an adaptive response that facilitates energy storage in preparation for the high metabolic demands of pregnancy and subsequent lactation. To maintain the increased energy intake in the face of increased adiposity and rising leptin levels, pregnant females become resistant to the central anorectic actions of leptin. In rats, pregnancy-induced leptin resistance is characterised by elevated neuropeptide Y and reduced pro-opiomelanocortin expression in the arcuate nucleus, reduced leptin receptor mRNA levels and suppression of leptin-induced phosphorylated signal transducer and activator of transcription-3 protein in the ventromedial hypothalamic nucleus, as well as a loss of anorectic responses to both leptin and alpha-melantocyte-stimulating hormone. Our recent data suggest that this leptin-resistance may also cause central insulin resistance and an altered peripheral glucose homeostasis. The specific hormone changes during pregnancy that might mediate these effects on leptin signalling are a current focus of investigation. In pseudopregnant rats, chronic i.c.v. infusion of ovine prolactin to mimic patterns of placental lactogen secretion that occur during pregnancy completely blocked the ability of leptin to suppress food intake. These data suggest that placental lactogen secretion may mediate the hormone-induced loss of response to leptin during pregnancy. This action of prolactin/placental lactogen appears to be mediated downstream of the primary leptin-responsive neurones in the mediobasal hypothalamus, possibly in the paraventricular nucleus. Our studies show complex hormone-induced adaptations in the normal hypothalamic pathways regulating body weight homeostasis during pregnancy.

Vaspin and amylin are expressed in human and rat placenta and regulated by nutritional status.

Amylin (islet amyloid polypeptide) and vaspin (visceral adipose tissue specific serpin) are gut and adipocyte hormones involved in the regulation of body weight homeostasis. The aim of this study was to examine whether amylin and vaspin are expressed in human and rat placenta, as well as their regulation by nutritional status. Our results demonstrate that amylin and vaspin are localized in both human and rat placenta. In the rat term placenta vaspin was demonstrated in the trophoblast of the fetal villi, the labyrinth. Vaspin immunostaining in human placenta was localized in cytotrophoblast and syncytiotrophoblast in the first trimester placentas while in the third trimester vaspin was localized in the syncytiotrophoblast. Regarding amylin, rat placenta of 16 days of gestational age showed an intense immunostaining, mainly localized in the labyrinth. On the other hand, in the human third trimester placenta amylin immunoreactivity was intense in the syncytiotrophoblast of the chorionic villi and in decidual cells. Furthermore, placental amylin and vaspin showed an opposite pattern of expression during pregnancy, with vaspin showing the highest expression level at the end and amylin at the beginning of pregnancy. Finally, food restriction also has contrary effects on their expression, increasing vaspin but decreasing amylin placental mRNA and protein levels. Taken together, our results demonstrate that vaspin and amylin are modulated by energy status in the placenta, which suggests that these proteins may be involved in the regulation of placental metabolic functions.

Neuromedin S and U

The physiological and endocrine homeostatic systems that regulate body weight are complex. Several peripheral systems need to be coordinated with central nervous system processes for proper energy balance regulation. Systems for energy storage (white adipose tissue), energy expenditure (skeletal muscle and brown adipose tissue), and energy absorption (gut) (1) inform the brain how much fuel is available short- and long-term. These systems coordinate with expected fuel demand, which is impacted by environment, temperature, season, reproduction and offspring care, food availability, and predation pressure. Whereas a handful of mainstream peptides receive ample of attention from investigators, other important signals are less recognized. A recent study by Peier et al. (2) highlights the importance of neuromedins U (NMU) and S (NMS) acting centrally on the NMU receptor 2 (NMUR2) in the regulation of body weight homeostasis.

5-HT2CRs Expressed by Pro-Opiomelanocortin Neurons Regulate Energy Homeostasis

SummaryDrugs activating 5-hydroxytryptamine 2C receptors (5-HT2CRs) potently suppress appetite, but the underlying mechanisms for these effects are not fully understood. To tackle this issue, we generated mice with global 5-HT2CR deficiency (2C null) and mice with 5-HT2CRs re-expression only in pro-opiomelanocortin (POMC) neurons (2C/POMC mice). We show that 2C null mice predictably developed hyperphagia, hyperactivity, and obesity and showed attenuated responses to anorexigenic 5-HT drugs. Remarkably, all these deficiencies were normalized in 2C/POMC mice. These results demonstrate that 5-HT2CR expression solely in POMC neurons is sufficient to mediate effects of serotoninergic compounds on food intake. The findings also highlight the physiological relevance of the 5-HT2CR-melanocortin circuitry in the long-term regulation of energy balance.

691 Switching of Leptin Effects On Peripheral Vagal Afferent Mechanosensitivity with Feeding and Fasting

Background: Leptin is an important peptide involved in regulation of body weight homeostasis. In addition to secretion from adipose tissue it is also synthesized and secreted from gastric epithelial cells (Bado et al., Nature 1998; 394: 790-3). Leptin receptor is expressed in rat vagal afferents and expression of the receptor is regulated by feeding (Buyse et al., Eur. J. Neurosci. 2001; 14: 64-72). Whether this translates to a functional effect of leptin on vagal afferents is unknown. Aims: 1) To determine the effect of leptin on the response of tension and mucosal receptors to mechanical stimulation in tissue from mice fed ad libitum and mice fasted for 18 hours. 2) To determine the expression of leptin receptor in fed and fastedmice. Methods: Single fiber recordings of gastroesophageal vagal mechanoreceptors were made in mouse (J Neurophysiol, 2002: 87; 2095). mRNA from nodose ganglia was quantified by real-time RT-PCR. Results: In fasted mice, leptin (0.1-10nM) reduced by >50% the response of mouse tension receptors to circumferential stretch (0.5-5g, p<0.01, n=6). Leptin had no effect on mucosal receptor responses to mucosal stroking with calibrated von Frey hairs (10-1000mg). In fed mice, leptin (0.1-10nM) more than doubled mucosal receptor mechanosensory responses (p<0.01, n=5), but had no effect on tension receptors (n=5). There was six-fold greater expression of leptin receptor mRNA in the fed mouse nodose ganglia than those from fasted mice (p<0.001). Conclusion: Leptin has a substantial effect on the mechanosensitivity of gastroesophageal vagal afferents. This changes dramatically from fasting to feeding, to the extent that there is a switch from inhibition to potentiation. The mechanisms of these changes remain to be found, but they are consistent with a role of leptin as a regulator of food intake via vagal pathways. Supported by University of Adelaide and NHMRC Australia

Adipose-Specific Disruption of Signal Transducer and Activator of Transcription 3 Increases Body Weight and Adiposity

To determine the role of STAT3 in adipose tissue, we used Cre-loxP DNA recombination to create mice with an adipocyte-specific disruption of the STAT3 gene (ASKO mice). aP2-Cre-driven disappearance of STAT3 expression occurred on d 6 of adipogenesis, a time point when preadipocytes have already undergone conversion to adipocytes. Thus, this knockout model examined the role of STAT3 in mature but not differentiating adipocytes. Beginning at 9 wk of age, ASKO mice weighed more than their littermate controls and had increased adipose tissue mass, associated with adipocyte hypertrophy, but not adipocyte hyperplasia, hyperphagia, or reduced energy expenditure. Leptin-induced, but not isoproterenol-induced, lipolysis was impaired in ASKO adipocytes, which may partially explain the increased cell size. Despite reduced adiponectin and increased liver triacylglycerol, ASKO mice displayed normal glucose tolerance. Overall, these findings demonstrate that adipocyte STAT3 regulates body weight homeostasis in part through direct effects of leptin on adipocytes.

Genetic Dissection of Neuronal Pathways Controlling Energy Homeostasis

Recent research has identified a number of genes playing critical roles in the central regulation of energy homeostasis. Subsequently, models of the neurocircuitry regulating energy balance have been suggested, although their physiological relevance remains mostly untested. Using the Cre/loxP system, we can now genetically dissect these neurocircuits and establish the specific roles of these genes in small neuronal subpopulations. Here we focus on two receptors shown to be critical in the central regulation of energy homeostasis: leptin (LepR) and melanocortin-4 receptors (MC4R). Mice and humans deficient in either leptin or melanocortin signaling are severely obese. A prominent model of leptin action places the arcuate nucleus of the hypothalamus, and in particular arcuate proopiomelanocortin (POMC) neurons, at the center stage of energy balance regulation. By deleting LepR specifically from POMC neurons in mice, we showed that LepR on POMC neurons are required but not solely responsible for leptin's regulation of body weight homeostasis. Thus, LepR on other neurons must also be critically important in leptin-mediated regulation of body weight homeostasis. Data from MC4R-deficient mice have shown that MC4Rs regulate both sides of the energy intake/energy expenditure balance. Our recent experiments used MC4R-deficient mice with restored MC4R expression only in the paraventricular hypothalamus and a subpopulation of amygdala neurons. We showed that MC4Rs in the paraventricular hypothalamus and/or amygdala are sufficient to control food intake but that MC4Rs elsewhere control energy expenditure, thereby discovering the novel concept of functional and anatomical divergence of MC4Rs.

Microarray profiling of human white adipose tissue after exogenous leptin injection

Leptin is a secreted adipocyte hormone that plays a key role in the regulation of body weight homeostasis. The leptin effect on human white adipose tissue (WAT) is still debated. The aim of this study was to assess whether the administration of polyethylene glycol-leptin (PEG-OB) in a single supraphysiological dose has transcriptional effects on genes of WAT and to identify its target genes and functional pathways in WAT. Blood samples and WAT biopsies were obtained from 10 healthy nonobese men before treatment and 72 h after the PEG-OB injection, leading to an approximate 809-fold increase in circulating leptin. The WAT gene expression profile before and after the PEG-OB injection was compared using pangenomic microarrays. Functional gene annotations based on the gene ontology of the PEG-OB regulated genes were performed using both an 'in house' automated procedure and GenMAPP (Gene Microarray Pathway Profiler), designed for viewing and analyzing gene expression data in the context of biological pathways. Statistical analysis of microarray data revealed that PEG-OB had a major down-regulated effect on WAT gene expression, as we obtained 1,822 and 100 down- and up-regulated genes, respectively. Microarray data were validated using reverse transcription quantitative PCR. Functional gene annotations of PEG-OB regulated genes revealed that the functional class related to immunity and inflammation was among the most mobilized PEG-OB pathway in WAT. These genes are mainly expressed in the cell of the stroma vascular fraction in comparison with adipocytes. Our observations support the hypothesis that leptin could act on WAT, particularly on genes related to inflammation and immunity, which may suggest a novel leptin target pathway in human WAT.

Identifying hypothalamic pathways controlling food intake, body weight, and glucose homeostasis

The past decade has greatly increased our understanding and appreciation of the ability of the central nervous system (CNS) to regulate food intake and body weight. This was spearheaded by the discovery of key molecules regulating body weight homeostasis. It is now also apparent that the CNS, especially the hypothalamus, plays a primary role in directly regulating glucose homeostasis, independently of effects on body weight. These discoveries are important given the increasing incidences of obesity and type II diabetes in Western societies. In this article, we will highlight recent data from genetically modified mice. These data and other models have helped to dissect the CNS pathways regulating body weight and glucose homeostasis. Finally, although these studies have been illustrative, they also underscore our relative lack of knowledge and highlight the need for more definitive approaches to unravel the functional significance of these pathways.

Leptin Receptor Signaling in POMC Neurons Is Required for Normal Body Weight Homeostasis

Neuroanatomical and electrophysiological studies have shown that hypothalamic POMC neurons are targets of the adipostatic hormone leptin. However, the physiological relevance of leptin signaling in these neurons has not yet been directly tested. Here, using the Cre/loxP system, we critically test the functional importance of leptin action on POMC neurons by deleting leptin receptors specifically from these cells in mice. Mice lacking leptin signaling in POMC neurons are mildly obese, hyperleptinemic, and have altered expression of hypothalamic neuropeptides. In summary, leptin receptors on POMC neurons are required but not solely responsible for leptin's regulation of body weight homeostasis.

Leptin Modulates Behavioral Responses to Sweet Substances by Influencing Peripheral Taste Structures

Leptin is a hormone that regulates body weight homeostasis mainly via the hypothalamic functional leptin receptor Ob-Rb. Recently, we proposed that the taste organ is a new peripheral target for leptin. Leptin selectively inhibits mouse taste cell responses to sweet substances and thereby may act as a sweet taste modulator. The present study further investigated leptin action on the taste system by examining expression of Ob-Rb in taste cells and behavioral responses to sweet substances in leptin-deficient ob/ob, and Ob-Rb-deficient db/db mice and their normal litter mates. RT-PCR analysis showed that Ob-Rb was expressed in taste cells in all strains tested. The db/db mice, however, had a RT-PCR product containing an abnormal db insertion that leads to an impaired shorter intracellular domain. In situ hybridization analysis showed that the hybridization signals for normal Ob-Rb mRNA were detected in taste cells in lean and ob/ob mice but not in db/db mice. Two different behavioral tests, one using sweet-bitter mixtures as taste stimuli and the other a conditioned taste aversion paradigm, demonstrated that responses to sucrose and saccharin were significantly decreased after ip injection of leptin in ob/ob and normal littermates, but not in db/db mice. These results suggest that leptin suppresses behavioral responses to sweet substances through its action on Ob-Rb in taste cells. Such taste modulation by leptin may be involved in regulation for food intake.

Agouti Expression in Human Adipose Tissue

It is well recognized that the agouti/melanocortin system is an important regulator of body weight homeostasis. Given that agouti is expressed in human adipose tissue and that the ectopic expression of agouti in adipose tissue results in moderately obese mice, the link between agouti expression in human adipose tissue and obesity/type 2 diabetes was investigated. Although there was no apparent relationship between agouti mRNA levels and BMI, agouti mRNA levels were significantly elevated in subjects with type 2 diabetes. The regulation of agouti in cultured human adipocytes revealed that insulin did not regulate agouti mRNA, whereas dexamethasone treatment potently increased the levels of agouti mRNA. Experiments with cultured human preadipocytes and with cells obtained from transgenic mice that overexpress agouti demonstrated that melanocortin receptor (MCR) signaling in adipose tissue can regulate both preadipocyte proliferation and differentiation. Taken together, these results reveal that agouti can regulate adipogenesis at several levels and suggest that there are functional consequences of elevated agouti levels in human adipose tissue. The influence of MCR signaling on adipogenesis combined with the well-established role of MCR signaling in the hypothalamus suggest that adipogenesis is coordinately regulated with food intake and energy expenditure.

Altered glucose homeostasis in proopiomelanocortin-null mouse mutants lacking central and peripheral melanocortin.

Prolonged obesity frequently leads to insulin resistance and, eventually, to diabetes. This relationship reflects the integration of fat stores and carbohydrate metabolism and the coordination of central nervous system functions, e.g. appetite, and peripheral metabolism. Recent work suggests that the melanocortin system is involved in this integration; specifically, central administration of melanocyte-stimulating hormone (MSH) decreases, whereas lack of central MSH signaling increases, peripheral insulin resistance. Here we asked whether MSH acting in the periphery has a complementary role in insulin resistance. We tested this in a mouse model where the proopiomelanocortin (POMC) gene encoding all of the melanocortins has been genetically deleted. The homozygous POMC-null mouse lacks central as well as peripheral MSH signaling; in addition, it lacks adrenal glands and thus is devoid of corticosterone and epinephrine. Here we report that homozygous POMC mutants have normal serum levels of insulin, normal fasting levels of glucose, and normal clearance of glucose in glucose tolerance tests. Thus, insulin production and sensitivity and glucose uptake in peripheral tissues are functioning normally. However, we found a striking inability of the homozygous POMC mutants to recover from insulin-induced hypoglycemia. This defect was in the glucagon-mediated counterregulatory response. Both peripheral administration of an MSH analog and supplementation with corticosterone alleviated the hypoglycemia after insulin challenge, but did not make the obese POMC mutant mice diabetic. We conclude that, similar to the regulation of body weight homeostasis, the regulation of glucose homeostasis requires the integration of both central and peripheral melanocortin signaling systems.