The melanocortin system as a potential target for treating alcohol use disorders: A review of pre-clinical data.

The melanocortin (MC) system consists of neuropeptides that are cleaved from the polypeptide precursor proopiomelanocortin (POMC). In the brain, MC neuropeptides signal primarily through the MC-3 and MC-4 receptors, which are widely expressed throughout the brain. While the MC system has been largely studied for its role in food intake and body weight regulation, converging evidence has emerged over approximately the last 20-years showing that alcohol (ethanol), and other drugs of abuse influence the central MC system, and that manipulating MC receptor signalling modulates ethanol intake. Although there is divergent evidence, the wealth of data appears to suggest that activating MC signalling, primarily through the MC-4 receptor, is protective against excessive ethanol consumption. In the present review, we first describe the MC system and then detail how ethanol exposure and consumption alters central MC and MC-receptor expression and levels. This is followed by a review of the data, from pharmacological and genetic studies, which show that manipulations of MC receptor activity alter ethanol intake. We then briefly highlight studies implicating a role for the MC system in modulating neurobiological responses and intake of other drugs of abuse, including amphetamine, cocaine and opioids. Finally, we introduce relatively new observations that the drug, bupropion (BUP), a drug that activates central MC activity, significantly reduces ethanol intake in rodent models when administered alone and in combination with the non-selective opioid receptor antagonist, naltrexone. Phase II clinical trials are currently underway to assess the efficacy of BUP as a treatment for alcohol use disorders.

The melanocortin signaling cAMP axis accelerates repair and reduces mutagenesis of platinum-induced DNA damage.

Using primary melanocytes and HEK293 cells, we found that cAMP signaling accelerates repair of bi- and mono-functional platinum-induced DNA damage. Elevating cAMP signaling either by the agonistic MC1R ligand melanocyte stimulating hormone (MSH) or by pharmacologic cAMP induction by forskolin enhanced clearance of intrastrand cisplatin-adducts in melanocytes or MC1R-transfected HEK293 cells. MC1R antagonists human beta-defensin 3 and agouti signaling protein blocked MSH- but not forskolin-mediated enhancement of platinum-induced DNA damage. cAMP-enhanced repair of cisplatin-induced DNA damage was dependent on PKA-mediated phosphorylation of ATR on S435 which promoted ATR's interaction with the key NER factor xeroderma pigmentosum A (XPA) and facilitated recruitment of an XPA-ATR-pS435 complex to sites of cisplatin DNA damage. Moreover, we developed an oligonucleotide retrieval immunoprecipitation (ORiP) assay using a novel platinated-DNA substrate to establish kinetics of ATR-pS435 and XPA's associations with cisplatin-damaged DNA. Expression of a non-phosphorylatable ATR-S435A construct or deletion of A kinase-anchoring protein 12 (AKAP12) impeded platinum adduct clearance and prevented cAMP-mediated enhancement of ATR and XPA's associations with cisplatin-damaged DNA, indicating that ATR phosphorylation at S435 is necessary for cAMP-enhanced repair of platinum-induced damage and protection against cisplatin-induced mutagenesis. These data implicate cAMP signaling as a critical regulator of genomic stability against platinum-induced mutagenesis.

Fuel homeostasis and locomotor behavior: role of leptin and melanocortin pathways.

BACKGROUND: While it is now accepted that genes and their products affect food intake, the concept that locomotor behavior or the propensity for physical activity is controlled by neuro hum oral regulators is frequently underappreciated. In mammals, complex interactions have developed to allow the cross-talk between fuel homeostasis and physical activity. AIM: The aim of this review is to provide a synopsis of the influence of the leptin-melanocortin pathway, a well-studied pivotal player in body weight regulation, on locomotor behaviors. CONCLUSIONS: In rodents, reductions in leptin levels that physiologically occur following acute food deprivation or a reduction of the fat mass consequent to prolonged caloric restrictions are associated with a decrease in total locomotor activity and simultaneous increase in food-anticipatory activity, a locomotor behavior which reflects a foraging attitude. These actions can be prevented by leptin administration and are at least partially mediated by the neurons of the melanocortin pathway. In humans, twin studies have attributed to genetic factors approximately 50% of the variance of physical activity. An elevated number of the genes or loci which may affect physical activity are involved in body weight homeostasis. Polymorphisms of the melanocortin-4 and leptin receptors have repeatedly been associated with the level of physical activity. Unraveling the complexity of the regulation of locomotor behavior and the interconnections with the pathways involved in energy homeostasis may help explain the substantial individual variability in physical activities in humans and disentangle the harmful effects of sedentary lifestyle, which may be distinct from the detrimental effects of obesity.

Protective effects of the melanocortin analog NDP-α-MSH in rats undergoing cardiac arrest.

We previously reported that melanocortins afford cardioprotection in conditions of experimental myocardial ischemia/reperfusion, with involvement of the janus kinases (JAK), extracellular signal-regulated kinases (ERK) and signal transducers and activators of transcription (STAT) signalings. We investigated the influence of the melanocortin analog [Nle(4), D-Phe(7)]α-melanocyte-stimulating hormone (NDP-α-MSH) on short-term detrimental responses to cardiac arrest (CA) induced in rats by intravenous (i.v.) administration of potassium chloride, followed by cardiopulmonary resuscitation (CPR) plus epinephrine treatment. In CA/CPR rats i.v. treated with epinephrine (0.1 mg/kg) and returned to spontaneous circulation (48%) we recorded low values of mean arterial pressure (MAP) and heart rate (HR), alteration of hemogasanalysis parameters, left ventricle low expression of the cardioprotective transcription factors pJAK2 and pTyr-STAT3 (JAK-dependent), increased oxidative stress, up-regulation of the inflammatory mediators tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and down-regulation of the anti-inflammatory cytokine IL-10, as assessed at 1h and 3h after CPR. On the other hand, i.v. treatment during CPR with epinephrine plus NDP-α-MSH (340 µg/kg) almost completely restored the basal conditions of MAP and HR, reversed metabolic acidosis, induced left ventricle up-regulation of pJAK2, pTyr-STAT3 and IL-10, attenuated oxidative stress, down-regulated TNF-α and IL-6 levels, and improved survival rate by 81%. CA/CPR plus epinephrine alone or in combination with NDP-α-MSH did not affect left ventricle pSer-STAT3 (ERK1/2-dependent) and pERK1/2 levels. These results indicate that melanocortins improve return to spontaneous circulation, reverse metabolic acidosis, and inhibit heart oxidative stress and inflammatory cascade triggered by CA/CPR, likely via activation of the JAK/STAT signaling pathway.

[Monogenic human obesity: role of the leptin-melanocortin system in the regulation of food intake and body weight in humans]. / Obesidad monogénica humana: papel del sistema leptina-melanocortina en la regulación de la ingesta de alimentos y el peso corporal en humanos.

Human obesity is a disorder of multifactorial origin in which genetic and environmental factors are involved. To understand the mechanisms regulating energy intake and fat accumulation in the body, it is important to study the genetic alterations causing monogenic obesity. Most of the genes involved in monogenic obesity are associated with the leptin-melanocortin system; hence the importance of studying this system by analysing natural mutations in mice. Previous studies have described mutations in leptin and its receptor, proopiomelanocortin and prohormone convertase 1 associated with human obesity of monogenic origin. The aim of this study is to provide an updated review of the main characteristics and functioning of the leptin-melanocortin system, and its implications and potentialities in regulating food intake and body weight.

Characterization of murine melanocortin receptors mediating adipocyte lipolysis and examination of signalling pathways involved.

The melanocortin receptors (MCRs) belong to the G-protein coupled receptors (family A). So far, 5 different subtypes have been described (MC1R-MC5R) and of these MC2R and MC5R have been proposed to act directly in adipocytes and regulate lipolysis in rodents. Using ACTH and α-melanocyte stimulating hormone (α-MSH) generated from proopiomelanocortin (POMC), as well as synthetic MSH analogues to stimulate lipolysis in murine 3T3-L1 adipocytes it is shown that MC2R and MC5R are lipolytic mediators in differentiated 3T3-L1 adipocytes. Involvement of cAMP, phosphorylated extracellular signal-regulated kinase (ERK) 1/2, protein kinase B (PKB), adenosine 5' monophosphate activated protein kinase (AMPK) and Jun-amino-terminal kinase (JNK) in MCR mediated lipolysis were studied. Interestingly, results obtained in 3T3-L1 cells suggest that lipolysis stimulated by α-MSH, NDP-α-MSH, MT-II, SHU9119 and PG-901 is mediated through MC5R in a cAMP independent manner. Finally, we identify essential differences in MCR mediated lipolysis when using 3T3-L1 cells compared to primary adipocytes.

mu-Opioid receptor stimulation in the nucleus accumbens elevates fatty tastant intake by increasing palatability and suppressing satiety signals.

Infusion of a µ-opioid receptor (MOR) agonist into the nucleus accumbens (NAcc) drives voracious food intake, an effect hypothesized to occur through increased tastant palatability. While intake of many palatable foods is elevated by MOR stimulation, this manipulation has a preferential effect on fatty food ingestion. Consumption of high-fat foods is increased by NAcc MOR stimulation even in rats that prefer a carbohydrate-rich alternative under baseline conditions. This suggests that NAcc MOR stimulation may not simply potentiate palatability signals and raises the possibility that mechanisms mediating fat intake may be distinct from those underlying intake of other tastants. The present study was conducted to investigate the physiological mechanisms underlying the effects of NAcc MOR stimulation on fatty food intake. In experiment 1, we analyzed lick microstructure in rats ingesting Intralipid to identify the changes underlying feeding induced by infusion of a MOR-specific agonist into the NAcc. MOR stimulation in the NAcc core, but not shell, increased burst duration and first-minute licks, while simultaneously increasing the rate and duration of Intralipid ingestion. These results suggest that MOR activation in the core increases Intralipid palatability and attenuates inhibitory postingestive feedback. In experiment 2, we measured the effects of MOR stimulation in the NAcc core on consumption of nonnutritive olestra. A MOR-specific agonist dose dependently increased olestra intake, demonstrating that caloric signaling is not required for hyperphagia induced by NAcc MOR stimulation. Feeding induced by drug infusion in both experiments 1 and 2 was blocked by a MOR antagonist. In experiment 3, we determined whether MOR activation in the NAcc core could attenuate satiety-related signaling caused by infusion of the melanocortin agonist MTII into the third ventricle. Suppression of intake caused by MTII was reversed by MOR stimulation. Together, our results suggest that MOR stimulation in the NAcc core elevates fatty food intake through palatability mechanisms dependent on orosensory cues and suppression of satiety signals inhibiting food intake.

Ghrelin-induced adiposity is independent of orexigenic effects.

Ghrelin is a hormone produced predominantly by the stomach that targets a number of specific areas in the central nervous system to promote a positive energy balance by increasing food intake and energy storage. In that respect, similarities exist with the effects of consuming a high-fat diet (HFD), which also increases caloric intake and the amount of stored calories. We determined whether the effects of ghrelin on feeding and adiposity are influenced by the exposure to an HFD. Chronic intracerebroventricular ghrelin (2.5 nmol/d) increased feeding in lean rats fed a low-fat control diet (CD) [192 ± 5 g (ghrelin+CD) vs. 152 ± 5 g (control i.c.v. saline+CD), P<0.001], but the combination of ghrelin plus HFD did not result in significantly greater hyperphagia [150 ± 7 g (ghrelin+HFD) vs. 136 ± 4 g (saline+HFD)]. Despite failing to increase food intake in rats fed the HFD, ghrelin nonetheless increased adiposity [fat mass increase of 14 ± 2 g (ghrelin+HFD) vs. 1 ± 1 g (saline+HFD), P<0.001] up-regulating the gene expression of lipogenic enzymes in white adipose tissue. Our findings demonstrate that factors associated with high-fat feeding functionally interact with pathways regulating the effect of ghrelin on food intake. We conclude that ghrelin's central effects on nutrient intake and nutrient partitioning can be separated and suggest an opportunity to identify respective independent neuronal pathways.

Brown fat biology and thermogenesis.

Brown fat (brown adipose tissue, BAT) primary function is to produce heat. There is now compelling evidence to indicate that brown fat cells in some BAT depots share their predecessor cells with myocytes. Brown adipocyte (trans)differentiation depends on various receptors / transcription factors that include peroxisome proliferator-activated receptor g (PPARgamma), PPARgamma-coactivator-1alpha (PGC1alpha), PRD1-BF1-RIZ1 homologous domain-containing 16 (PRDM16), CCAAT/enhancer-binding protein beta (C/EBP-beta) and bone morphogenetic protein 7 (BMP7). Such mediators also help BAT to acquire its thermogenic phenotype, which is essentially conferred by uncoupling protein 1 (UCP1). UCP1 uncouples adenosine-5'-triphosphate (ATP) synthesis from substrate oxidation in brown adipocytes. Its activity depends on the availability of fatty acids delivered upon BAT's beta)-adrenergic activation, which, physiologically, ensues from the sympathetic nervous system (SNS) activation of the tissue. SNS-mediated thermogenesis is largely controlled by the hypothalamus and brainstem. Recently, positron emission tomography / computed tomography (PET/CT) scanning investigations have revealed the presence in adult humans of important neck and shoulder BAT depots. That finding has contributed to reinstate a strong interest for brown adipocyte biology and thermogenesis. This review aims at the unique biology of BAT with the emphasis put on the recent discoveries regarding the brown adipocyte development and function.

Thermoregulation, energy balance, regulatory peptides: recent developments.

Energy balance of the body is determined mainly by the function of various hypothalamic and brainstem nuclei, according to a complex interaction between the regulation of body temperature (actual metabolic rate vs. heat loss) and regulation of body weight (metabolic rate vs. food intake). The direct effect of central anabolic neuropeptides (neuropeptide Y, orexins, melanin concentrating hormone, etc.) is to enhance food intake and suppress metabolic rate with a tendency to cause hypothermia, while central catabolic neuropeptides (melanocortins, corticotropin releasing factor, cocaine-amphetamine regulated peptide, etc.) suppress food intake and enhance energy expenditure with a tendency to induce hyperthermia. Many other neuropeptides are neither clearly anabolic, nor clearly catabolic, but still influence these complex hypothalamic/brainstem functions. Some peripheral peptides (e.g. leptin, insulin, ghrelin) acting at either peripheral or cerebral sites also contribute to the regulation of energy balance. The prevailing thermoregulatory status, the substances or neural signals representing actual feeding vs. established nutritional states, and the aging process may modify the expression and/or activity of peripheral and central peptides and peptide receptors.

Genetic and pharmacologic blockade of central melanocortin signaling attenuates cardiac cachexia in rodent models of heart failure.

The central melanocortin system plays a key role in the regulation of food intake and energy homeostasis. We investigated whether genetic or pharmacologic blockade of central melanocortin signaling attenuates cardiac cachexia in mice and rats with heart failure. Permanent ligation of the left coronary artery (myocardial infarction (MI)) or sham operation was performed in wild-type (WT) or melanocortin-4 receptor (MC4R) knockout mice. Eight weeks after surgery, WT-Sham mice had significant increases in lean body mass (LBM; P<0.05) and fat mass (P<0.05), whereas WT-MI did not gain significant amounts of LBM or fat mass. Resting basal metabolic rate (BMR) was significantly lower in WT-Sham mice compared to WT-MI mice (P<0.001). In contrast, both MC4-Sham and MC4-MI mice gained significant amounts of LBM (P<0.05) and fat mass (P<0.05) over the study period. There was no significant difference in the BMR between MC4-Sham and MC4-MI mice. In the second experiment, rats received aortic bands or sham operations, and after recovery received i.c.v. injections of either artificial cerebrospinal fluid (aCSF) or the melanocortin antagonist agouti-related protein (AGRP) for 2 weeks. Banded rats receiving AGRP gained significant amount of LBM (P<0.05) and fat mass (P<0.05) over the treatment period, whereas banded rats receiving aCSF did not gain significant amounts of LBM or fat mass. These results demonstrated that genetic and pharmacologic blockade of melanocortin signaling attenuated the metabolic manifestations of cardiac cachexia in murine and rat models of heart failure.

Update on melanocortin interventions for cachexia: progress toward clinical application.

Cachexia is a devastating syndrome of body wasting that is associated with multiple common chronic diseases including cancer, chronic kidney disease, and chronic heart failure. These underlying diseases are associated with increased levels of inflammatory cytokines and result in anorexia, increased resting energy expenditure, and loss of fat and lean body mass. Prior experiments have implicated the central melanocortin system in the hypothalamus with the propagation of these symptoms of cachexia. Pharmacologic blockade of this system using melanocortin antagonists causes attenuation of the signs of cachexia in laboratory models. Recent advances in our knowledge of this disease process have involved further elucidation of the pathophysiology of melanocortin activation and demonstration of the efficacy of melanocortin antagonists in new models of cachexia, including cardiac cachexia. In addition, small molecule antagonists of the melanocortin-4 receptor continue to be introduced, including ones with oral bioavailability. These developments generate optimism that melanocortin antagonism will be used to treat humans with disease-associated cachexia. However, to date, human application has remained elusive and it is unclear when we will know whether humans with cachexia would benefit from treatment with these compounds.

Sistema leptina-melanocortinas en la regulación de la ingesta y el peso corporal / Leptin-melanocortin system, body weight regulation and obesity

Obesity is a multifactorial disease that is rarely associated to single gene defects. However, due to their direct cause-effect relationships, those genetic defects that cause some forms of monogenic obesity are relevant in the study of mechanisms that contribute to increased energy intake and body fat accumulation. Most of the genes that have been shown to cause monogenic obesity are related to the leptin-melanocortin system. The functionality of this system has been elucidated through natural mutations (Agouti, ob and db) in mice and knock-out models. Mutations related to human monogenic obesity have been described in leptin, leptin receptor, proopiomelanocortin, prohormone convertase 1 or melanocortin receptor 4 genes. Therapy with human recombinant leptin in patients with genetic deficiency of the hormone is an effective medical treatment of obesity, although only applicable to very few families. The use of leptin-melanocortin agonists, drugs to avoid leptin resistance or combinations of treatments with leptin and other satiating peptides are currently being investigated for multifacotiral human obesity (Rev Méd Chile 2009; 137:1225-34).

A functional melanocortin system may be required for chronic CNS-mediated antidiabetic and cardiovascular actions of leptin.

OBJECTIVE: We recently showed that leptin has powerful central nervous system (CNS)-mediated antidiabetic and cardiovascular actions. This study tested whether the CNS melanocortin system mediates these actions of leptin in diabetic rats. RESEARCH DESIGN AND METHODS: A cannula was placed in the lateral ventricle of Sprague-Dawley rats for intracerebroventricular infusions, and arterial and venous catheters were implanted to measure mean arterial pressure (MAP) and heart rate 24 h/day and for intravenous infusions. After recovery from surgery for 8 days, rats were injected with streptozotocin (STZ), and 5 days later, either saline or the melanocortin 3 and 4 receptor (MC3/4R) antagonist SHU-9119 (1 nmol/h) was infused intracerebroventricularly for 17 days. Seven days after starting the antagonist, leptin (0.62 microg/h) was added to the intracerebroventricular infusion for 10 days. Another group of diabetic rats was infused with the MC3/4R agonist MTII (10 ng/h i.c.v.) for 12 days, followed by 7 days at 50 ng/h. RESULTS: Induction of diabetes caused hyperphagia, hyperglycemia, and decreases in heart rate (-76 bpm) and MAP (-7 mmHg). Leptin restored appetite, blood glucose, heart rate, and MAP back to pre-diabetic values in vehicle-treated rats, whereas it had no effect in SHU-9119-treated rats. MTII infusions transiently reduced blood glucose and raised heart rate and MAP, which returned to diabetic values 5-7 days after starting the infusion. CONCLUSIONS: Although a functional melanocortin system is necessary for the CNS-mediated antidiabetic and cardiovascular actions of leptin, chronic MC3/4R activation is apparently not sufficient to mimic these actions of leptin that may involve interactions of multiple pathways.

Neural control of the anorexia-cachexia syndrome.

The anorexia-cachexia syndrome is a debilitating clinical condition characterizing the course of chronic diseases, which heavily impacts on patients' morbidity and quality of life, ultimately accelerating death. The pathogenesis is multifactorial and reflects the complexity and redundancy of the mechanisms controlling energy homeostasis under physiological conditions. Accumulating evidence indicates that, during disease, disturbances of the hypothalamic pathways controlling energy homeostasis occur, leading to profound metabolic changes in peripheral tissues. In particular, the hypothalamic melanocortin system does not respond appropriately to peripheral inputs, and its activity is diverted largely toward the promotion of catabolic stimuli (i.e., reduced energy intake, increased energy expenditure, possibly increased muscle proteolysis, and adipose tissue loss). Hypothalamic proinflammatory cytokines and serotonin, among other factors, are key in triggering hypothalamic resistance. These catabolic effects represent the central response to peripheral challenges (i.e., growing tumor, renal, cardiac failure, disrupted hepatic metabolism) that are likely sensed by the brain through the vagus nerve. Also, disease-induced changes in fatty acid oxidation within hypothalamic neurons may contribute to the dysfunction of the hypothalamic melanocortin system. Ultimately, sympathetic outflow mediates, at least in part, the metabolic changes in peripheral tissues. Other factors are likely involved in the pathogenesis of the anorexia-cachexia syndrome, and their role is currently being elucidated. However, available evidence shows that the constellation of symptoms characterizing this syndrome should be considered, at least in part, as different phenotypes of common neurochemical/metabolic alterations in the presence of a chronic inflammatory state.

Cross-talk between estrogen and leptin signaling in the hypothalamus.

Obesity, characterized by enhanced food intake (hyperphagia) and reduced energy expenditure that results in the accumulation of body fat, is a major risk factor for various diseases, including diabetes, cardiovascular disease, and cancer. In the United States, more than half of adults are overweight, and this number continues to increase. The adipocyte-secreted hormone leptin and its downstream signaling mediators play crucial roles in the regulation of energy balance. Leptin decreases feeding while increasing energy expenditure and permitting energy-intensive neuroendocrine processes, such as reproduction. Thus, leptin also modulates the neuroendocrine reproductive axis. The gonadal steroid hormone estrogen plays a central role in the regulation of reproduction and also contributes to the regulation of energy balance. Estrogen deficiency promotes feeding and weight gain, and estrogen facilitates, and to some extent mimics, some actions of leptin. In this review, we examine the functions of estrogen and leptin in the brain, with a focus on mechanisms by which leptin and estrogen cooperate in the regulation of energy homeostasis.

Effects of pro-opiomelanocortin (POMC) on food intake and body weight: mechanisms and therapeutic potential?

POMC (pro-opiomelanocortin) is a complex polypeptide precursor which is cleaved into smaller biologically active peptides such as the melanocortins, alpha-, beta- and gamma-melanocyte-stimulating hormone. Data from human genetic and murine studies convincingly show that an intact central melanocortin signalling pathway is critical for normal energy homoeostasis. Not only does a loss of normal melanocortin signalling lead to obesity, but there are also data implicating increased melanocortin activity in the pathogenesis of cachexia. The study of POMC biology has lead to some fundamental insights into the mechanisms controlling food intake and body weight. This increased understanding of the physiological roles of the melanocortin system has opened up the potential for the design and development of rational therapies to treat perturbations in energy homoeostasis.

Melanocortin interventions in cachexia: how soon from bench to bedside?

PURPOSE OF REVIEW: Cachexia is a condition of anorexia and wasting that accompanies many diseases including cancer, heart failure, and renal failure. One key center that is probably involved in the propagation of symptoms of cachexia is the melanocortin system in the hypothalamus and brainstem. This review focuses on cachexia treatment interventions that act via melanocortin antagonism, by direct or indirect means. RECENT FINDINGS: Recent reports include a description of the physiology of the melanocortin system and its responsiveness to inflammatory cytokines. Regarding treatment potential, multiple reports describe the effectiveness of small molecule antagonists of the melanocortin-4 receptor in animal models of cachexia. These melanocortin antagonists, given by peripheral injection, improve food intake and lean body mass retention in the setting of cancer and renal failure. Additional reports provide evidence of melanocortin antagonism following treatment of cachexia using ghrelin and eicosonoic acid. SUMMARY: Cachexia is a serious condition that accompanies various disease states and currently does not have effective treatments. The melanocortin system may play a direct role in producing symptoms of cachexia, making antagonism of this system a logical objective for ameliorating these symptoms. Thus far, however, no data on human application have been published.

Regulation of central melanocortin signaling by interleukin-1 beta.

Anorexia and involuntary weight loss are common and debilitating complications of a number of chronic diseases and inflammatory states. Proinflammatory cytokines, including IL-1 beta, are hypothesized to mediate these responses through direct actions on the central nervous system. However, the neural circuits through which proinflammatory cytokines regulate food intake and energy balance remain to be characterized. Here we report that IL-1 beta activates the central melanocortin system, a key neuronal circuit in the regulation of energy homeostasis. Proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARC) were found to express the type I IL-1 receptor. Intracerebroventricular injection of IL-1 beta induced the expression of Fos protein in ARC POMC neurons but not in POMC neurons in the commissural nucleus of the tractus solitarius. We further show that IL-1 beta increases the frequency of action potentials of ARC POMC neurons and stimulates the release of alpha-MSH from hypothalamic explants in a dose-dependent fashion. Collectively, our data support a model in which IL-1 beta increases central melanocortin signaling by activating a subpopulation of hypothalamic POMC neurons and stimulating their release of alpha-MSH.

Hormonal regulation of the arcuate nucleus melanocortin system.

Over the past century, the hypothalamus has emerged as one of the critical sites involved in energy homeostasis. Degeneration studies in rats performed some six decades ago, first led to identifying hypothalamic subregions controlling food intake and body weight. The idea that the central nervous system (CNS), and the hypothalamus in particular, are key in metabolism regulation was reinforced by the discovery of leptin in 1994. Since the identification of leptin, enormous progress has been made in the understanding of the regulation of hypothalamic and extrahypothalamic brain regions that control food intake and energy expenditure by peripheral signals such as hormones. An important challenge is to decipher these complicated interactions between peripheral signals and neuronal circuits to better understand the etiology of metabolic disorders and to identify opportunities to intervene with pharmacological treatment. In this review, we focus on the hormonal regulation of the neuronal circuits of the arcuate nucleus of the hypothalamus: the melanocortin system.