Central Melanocortin Pathway Research Articles

Obesity Characteristics Are Poor Predictors of Genetic Mutations Associated with Obesity.

The genetic contribution to obesity is substantial and may underpin the altered pathophysiology. One such pathway involves melanocortin signaling in the hypothalamus. Genetic variants can cause dysregulation in the central melanocortin pathway that can result in early onset of hyperphagia and obesity. Clinically identifying patients who are at risk of known genetic mutations is challenging. The main purpose of this study was to identify associations between the clinico-demographical characteristics and the presence of a genetic mutation associated with obesity. We tested samples from 238 adult patients with class III obesity between October 2021 to February 2023 using next-generation sequencing (NGS) (Illumina, NovaSeq 6000 Sequencing System). The results were classified as "no variant identified" or "variant identified". 107 patients (45%) had one or more gene mutation in the leptin-melanocortin pathway. All variants were heterozygous. The patients with a gene mutation had a BMI of 48.4 ± 0.8 kg/m2 (mean ± SEM), and those without a gene mutation had a BMI of 49.4 ± 0.7 kg/m2 (p = 0.4). The mean age of onset of obesity in patients with a gene mutation was 13.9 ± 1.3 years and for those without gene mutations was 11.5 ± 0.9 years (p = 0.1). The incidence of hyperphagia as a child was also not predictive (p = 0.4). Gene mutations associated with obesity in patients with a BMI > 40 kg/m2 are common. However, a patient's BMI, age of onset of obesity, or age of onset of hyperphagia did not help to differentiate which patients may be more likely to have genetic mutations associated with obesity.

The promise of new anti-obesity therapies arising from knowledge of genetic obesity traits.

Obesity is a multifactorial and complex disease that often manifests in early childhood with a lifelong burden. Polygenic and monogenic obesity are driven by the interaction between genetic predisposition and environmental factors. Polygenic variants are frequent and confer small effect sizes. Rare monogenic obesity syndromes are caused by defined pathogenic variants in single genes with large effect sizes. Most of these genes are involved in the central nervous regulation of body weight; for example, genes of the leptin–melanocortin pathway. Clinically, patients with monogenic obesity present with impaired satiety, hyperphagia and pronounced food-seeking behaviour in early childhood, which leads to severe early-onset obesity. With the advent of novel pharmacological treatment options emerging for monogenic obesity syndromes that target the central melanocortin pathway, genetic testing is recommended for patients with rapid weight gain in infancy and additional clinical suggestive features. Likewise, patients with obesity associated with hypothalamic damage or other forms of syndromic obesity involving energy regulatory circuits could benefit from these novel pharmacological treatment options. Early identification of patients affected by syndromic obesity will lead to appropriate treatment, thereby preventing the development of obesity sequelae, avoiding failure of conservative treatment approaches and alleviating stigmatization of patients and their families.

MC3R links nutritional state to childhood growth and the timing of puberty.

The state of somatic energy stores in metazoans is communicated to the brain, which regulates key aspects of behaviour, growth, nutrient partitioning and development1. The central melanocortin system acts through melanocortin 4 receptor (MC4R) to control appetite, food intake and energy expenditure2. Here we present evidence that MC3R regulates the timing of sexual maturation, the rate of linear growth and the accrual of lean mass, which are all energy-sensitive processes. We found that humans who carry loss-of-function mutations in MC3R, including a rare homozygote individual, have a later onset of puberty. Consistent with previous findings in mice, they also had reduced linear growth, lean mass and circulatinglevels of IGF1. Mice lacking Mc3r had delayed sexual maturation and an insensitivity of reproductive cycle length to nutritional perturbation. The expression of Mc3r is enriched in hypothalamic neurons that control reproduction and growth, and expression increases during postnatal development in a manner that is consistent with a role in theregulation of sexual maturation. These findings suggest a bifurcating model of nutrient sensing by the central melanocortin pathway with signalling through MC4R controlling the acquisition and retention of calories, whereas signalling through MC3R primarily regulates the dispositionof calories into growth, lean mass and the timing of sexual maturation.

Functional Dissection of PVN MC4R Neural Pathway in Autonomic and Cardiovascular Functions

Central melanocortin pathways, mainly via acting on melanocortin-4 receptor (MC4R), play an important role in both energy homeostasis and sympathetic control of cardiovascular function. The paraventricular nucleus of hypothalamus (PVN) is one of hypothalamic nuclei with highest MC4R expression and is well known for its role in metabolic and autonomic regulations; however, the role of PVN-MC4R neural pathways in this regard remains incompletely understood. In this study, we first tested whether chemogenetic activation of PVN-MC4R neurons affects cardiovascular function. Adeno-associated virus (AAV) expressing excitatory (hM3Dq) Designer Receptors Exclusively Activated by Designer Drugs (DREADD) receptors were directly injected into the PVN of MC4R-Cre knock-in mice that are implanted with radio-telemetry for chronic monitoring of blood pressure. DREADD activation of PVN-MC4R neurons significantly elevated mean arterial pressure and heart rate. Next, we prepared a separate group of mice and subjected them to a battery of tests to gain insight into the role of these neurons in other behavioral and physiological regulations. Whole-body infrared thermal imaging upon DREADD activation of PVN-MC4R neurons revealed significant increase of temperature in near neck region, lower back, and tail. Behavioral monitoring in PhenoTyper cage further showed that DREADD activation of PVN-MC4R neurons leads to hypoactivity, suppressed feeding, and trend toward increased drinking behavior. In order to gain further insight into the neuroanatomical organization of PVN-MC4R neurons, we comprehensively mapped afferent projections of PVN-MC4R neurons by stereotaxically delivering Cre-dependent AAV driving expression of eYFP into the PVN of MC4R-Cre mice, which revealed a broad innervation of PVN-MC4R neurons to the brain regions that are known to be important for metabolic homeostasis and autonomic-cardiovascular control, including but not limited to parabrachial nucleus, nucleus of solitary tract, ventrolateral medulla, and spinal cord. Additionally, using a combination of sophisticated viral tools, we also mapped the brain regions where neurons provide monosynaptic inputs to PVN-MC4R neurons. In addition to the brain regions in which neurons are known to send monosynaptic inputs to PVN-MC4R neurons, such as arcuate nucleus, few discreate presynaptic neurons were also observed in organum vasculosum of the lamina terminalis, bed nucleus of the stria terminalis, supraoptic nucleus (SON) and ventral subiculum (vSub). These results provide an important insight into the neuroanatomical organization and multifaceted role of PVN-MC4R neural pathways in behavioral and physiological regulations.

The Role of PVN MC4R Neural Pathway in Autonomic Control of Metabolic Homeostasis and Cardiovascular Function

Central melanocortin pathways, mainly via acting on melanocortin‐4 receptor (MC4R), play an important role in both energy balance and sympathetic traffics affecting cardiovascular function. MC4R deficiency in both humans and rodents causes obesity, insulin resistance and diabetes while maintaining low to normal sympathetic tone and blood pressure, suggesting a critical role of MC4R signaling in metabolic homeostasis and obesity‐associated sympathetic overdrive and hypertension. MC4R is widely expressed in the brain including hypothalamic paraventricular nucleus (PVN) which functions as an integrative center for energy metabolism and autonomic regulation. However, whether and how PVNMC4R pathways contribute to the sympathetic control of cardiovascular function and metabolic homeostasis remain incompletely understood. In present study, we first comprehensively mapped afferent projections of PVNMC4R neurons by stereotaxically delivering Cre‐dependent AAV driving expression of eYFP into the PVN of MC4R‐Cre knock‐in mice, which allow targeted anterograde tract‐tracing of PVNMC4R neurons throughout the brain. In addition to known brain region for feeding behavior (i.e. parabrachial nucleus), we found broad innervations of PVNMC4R neurons to various brain regions important for autonomic‐cardiovascular control and energy metabolism, including but not limited to nucleus of solitary tractus , dorsal motor nucleus of vagus, rostral ventrolateral medulla (RVLM) and spinal cord. Using a combination of sophisticated viral tools, we further reveal that thoracic spinal cord‐projecting PVNMC4R neurons are exclusively located in the posterolateral PVN and send collateral projections to RVLM. Functionally, microinjection of synthetic MC4R agonist (MTII) into the PVN evokes renal sympathetic nerve activity in anesthetized mice and chemogenetic activation of PVNMC4R neurons elevates blood pressure and decreases food intake in freely moving animals. Additionally, genetic ablation of PVNMC4R neurons in adult mice using Cre‐dependent AAV expressing Casp3 causes hyperphagia and massive weight gain (over 80% increase within 6 weeks). These results provide an important insight into the role of PVNMCR neural circuits in regulating metabolic homeostasis and cardiovascular function. Optogenetic and chemogenetic studies are ongoing to functionally dissect the neural circuits downstream of PVNMC4R neurons.Support or Funding InformationNational Institute of Health (R01), AHA Postdoctoral Grant Award (19POST34450083)

Tracing the effect of the melanocortin-4 receptor pathway in obesity: study design and methodology of the TEMPO registry.

Purpose: The hypothalamic melanocortin-4 receptor (MC4R) pathway, a component of the central melanocortin pathway, regulates energy balance and satiety. Rare genetic disorders of obesity may be characterized by impaired MC4R pathway signaling, which results in early-onset severe obesity and insatiable hunger (hyperphagia). The TEMPO registry (NCT03479437) is a voluntary, prospective, open-ended registry of individuals with rare genetic disorders of obesity due to mutations in genes within the MC4R pathway who have early-onset severe obesity. The objective of the TEMPO registry is to evaluate the burden of rare genetic disorders of obesity on individuals, their parents/caregivers, health care providers, and the health care system.Patients and methods: Individuals with rare genetic disorders of obesity (adults aged ≥18 years and children and adolescents aged from 2 to 17 years) will be referred by their health care providers or by a genetic screening study. Individuals must meet age- and sex-specific body mass index values that define the clinical criteria for severe obesity and carry selected variants in MC4R or in one of several genes upstream or downstream of the MC4R. Online surveys will be completed by the individual, parent/caregiver, and health care provider at baseline and annually thereafter and will collect data on demographics, results of genetic testing, medical/family history, disease characteristics, resource utilization, eating habits/hunger episodes, social and emotional impacts, and interest in future clinical trial participation.Conclusions: The TEMPO registry will provide insights into the overall course and disease burden for individuals with rare genetic disorders of obesity. Health care providers may use this resource to improve the identification, diagnosis, and treatment of individuals with rare forms of genetic obesity.

POMC Neurons: Feeding, Energy Metabolism, and Beyond.

The central melanocortin system is a well-established neuronal pathway involved in regulating energy metabolism. Pro-opiomelanocortin (POMC) neurons, agouti gene-related protein (AgRP) neurons, and their downstream cells expressing the melanocortin-3 (MC3R) and melanocortin-4 receptors (MC4R) are three key components of the central melanocortin pathway. This chapter focuses on the Pomc gene and the POMC neural system. First, I summarize the established role of this system in inhibiting food intake. Second, in light of new cutting-edge techniques, our understanding of how POMC neurons function to regulate energy homeostasis has been refined during the last few years. I describe some recent advances and discuss bidirectional effects of POMC neurons on feeding. Finally, the physiological significance beyond energy metabolism, in particular for reward and sex, is also discussed.

The thermogenic effect of nesfatin-1 requires recruitment of the melanocortin system.

Nesfatin-1 is a bioactive polypeptide expressed both in the brain and peripheral tissues and involved in the control of energy balance by reducing food intake. Central administration of nesfatin-1 significantly increases energy expenditure, as demonstrated by a higher dry heat loss; yet, the mechanisms underlying the thermogenic effect of central nesfatin-1 remain unknown. Therefore, in this study, we sought to investigate whether the increase in energy expenditure induced by nesfatin-1 is mediated by the central melanocortin pathway, which was previously reported to mediate central nesfatin-1´s effects on feeding and numerous other physiological functions. With the application of direct calorimetry, we found that intracerebroventricular nesfatin-1 (25 pmol) treatment increased dry heat loss and that this effect was fully blocked by simultaneous administration of an equimolar dose of the melanocortin 3/4 receptor antagonist, SHU9119. Interestingly, the nesfatin-1-induced increase in dry heat loss was positively correlated with body weight loss. In addition, as assessed with thermal imaging, intracerebroventricular nesfatin-1 (100 pmol) increased interscapular brown adipose tissue (iBAT) as well as tail temperature, suggesting increased heat production in the iBAT and heat dissipation over the tail surface. Finally, nesfatin-1 upregulated pro-opiomelanocortin and melanocortin 3 receptor mRNA expression in the hypothalamus, accompanied by a significant increase in iodothyronine deiodinase 2 and by a nonsignificant increase in uncoupling protein 1 and peroxisome proliferator-activated receptor gamma coactivator-1 alpha mRNA in the iBAT. Overall, we clearly demonstrate that nesfatin-1 requires the activation of the central melanocortin system to increase iBAT thermogenesis and, in turn, overall energy expenditure.

Characterization of the melanocortin-4 receptor gene from Spinibarbus hollandi and the association between its polymorphisms and S. hollandi growth traits

The melanocortin-4 receptor gene (MC4R) is a member of the central melanocortin pathway, which influences development, growth, metabolism, and appetite. In this study, MC4R was cloned and characterized in Spinibarbus hollandi. MC4R DNA is composed of 3068 nucleotides with a 978 nucleotide open reading frame encoding a protein of 326 amino acids. Quantitative real-time polymerase chain reaction (PCR) analysis revealed that MC4R messenger RNA was ubiquitously expressed in tissues, with the most transcriptional abundance in brain and gonad, and that the expression level of MC4R was significantly higher in the lightest group than in the heaviest group of S. hollandi. A primary assessment of sequence variability revealed six single nucleotide polymorphisms (SNPs), among which, four were in the promoter (−698A>G, −679C>T, −326C>T, and −202A>G) and two were in the exon (36A>G and 234C>T). Three SNPs, −698A>G, −679C>T, and 234C>T, were significantly associated with growth traits, two of which, −698A>G and −679C>T, were in complete linkage. The other three SNPs showed no significant associations with any of the growth traits. Our data indicated a significant association between genetic variations in the S. hollandi MC4R and growth traits. Accordingly, the SNPs identified in the MC4R could be used as potential genetic markers in future breeding programs for S. hollandi and other fish.

Nesfatin-1 employs the central melanocortin pathway to stimulate non-shivering thermogenesis in brown adipose tissue (BAT)

Nesfatin-1 is a bioactive polypeptide involved in the regulation of food-intake and insulin secretion. Recently, our group has demonstrated that nesfatin-1 also increases energy expenditure; however, the underlying mechanism is still to be identified. Therefore, in this study, we sought to investigate whether this increase is mediated by the central melanocortin (MC) pathway, which had previously been reported to underlie the anorexigenic effect of nesfatin-1. Male Wistar rats (˜300 g) were stereotaxically implanted with intracerebroventricular cannula to receive central injections. With the application of direct calorimetry, we show that nesfatin-1 (25 pmol/rat) elicits a substantial increase in dry heat loss (p < 0.01; peak effect at 5h) over the 8h time-course, and that this effect is completely precluded by the co-administration with equimolar dose of SHU9119, a potent MC3/4 receptor antagonist (p < 0.01). The increased dry heat loss induced by nesfatin-1 correlates positively with body weight loss (r = 0.879, p < 0.001), which does not occur after the co-administration with SHU9119. Moreover, with the use of thermography, we report that nesfatin-1 (100 pmol/rat) specifically increases interscapular BAT (iBAT) (p < 0.01; peak effect at 5h), as well as inner ear temperature (p < 0.05, peak effect at 5h). The RT-PCR analysis reveals that centrally administered nesfatin-1 promotes POMC and MC3 receptor mRNA expression (p < 0.05, respectively) in the hypothalamus, accompanied with a trend of increase in UCP1 and PGC-1α in the iBAT. Overall, we herein demonstrate that the increase in dry heat loss induced by nesfatin-1 is a neuroendocrine process mediated via the central melanocortin system that elicits activity in the iBAT.

Participation of the central melanocortin system in metabolic regulation and energy homeostasis.

Obesity and metabolic disorders, such as type 2 diabetes and hypertension, have attracted considerable attention as life-threatening diseases not only in developed countries but also worldwide. Additionally, the rate of obesity in young people all over the world is rapidly increasing. Accumulated evidence suggests that the central nervous system may participate in the development of and/or protection from obesity. For example, in the brain, the hypothalamic melanocortin system senses and integrates central and peripheral metabolic signals and controls the degree of energy expenditure and feeding behavior, in concert with metabolic status, to regulate whole-body energy homeostasis. Currently, researchers are studying the mechanisms by which peripheral metabolic molecules control feeding behavior and energy balance through the central melanocortin system. Accordingly, recent studies have revealed that some inflammatory molecules and transcription factors participate in feeding behavior and energy balance by controlling the central melanocortin pathway, and have thus become new candidates as therapeutic targets to fight metabolic diseases such as obesity and diabetes.

An intrinsic gut leptin-melanocortin pathway modulates intestinal microsomal triglyceride transfer protein and lipid absorption

Fat is delivered to tissues by apoB-containing lipoproteins synthesized in the liver and intestine with the help of an intracellular chaperone, microsomal triglyceride transfer protein (MTP). Leptin, a hormone secreted by adipose tissue, acts in the brain and on peripheral tissues to regulate fat storage and metabolism. Our aim was to identify the role of leptin signaling in MTP regulation and lipid absorption using several mouse models deficient in leptin receptor (LEPR) signaling and downstream effectors. Mice with spontaneous LEPR B mutations or targeted ablation of LEPR B in proopiomelanocortin (POMC) or agouti gene related peptide (AGRP) expressing cells had increased triglyceride in plasma, liver, and intestine. Furthermore, melanocortin 4 receptor (MC4R) knockout mice expressed a similar triglyceride phenotype, suggesting that leptin might regulate intestinal MTP expression through the melanocortin pathway. Mechanistic studies revealed that the accumulation of triglyceride in the intestine might be secondary to decreased expression of MTP and lipid absorption in these mice. Surgical and chemical blockade of vagal efferent outflow to the intestine in wild-type mice failed to alter the triglyceride phenotype, demonstrating that central neural control mechanisms were likely not involved in the observed regulation of intestinal MTP. Instead, we found that enterocytes express LEPR, POMC, AGRP, and MC4R. We propose that a peripheral, local gut signaling mechanism involving LEPR B and MC4R regulates intestinal MTP and controls intestinal lipid absorption.

Mouse models for the central melanocortin system

Obesity is characterized by an excess storage of body fat and promotes the risk for complex disease traits such as diabetes mellitus and cardiovascular diseases. The obesity prevalence in Europe is rising and meanwhile ranges from 10 to 20% in men and 15-25% in women. Body fat accumulation occurs in states of positive energy balance and is favored by interactions among environmental, psychosocial and genetic factors. Energy balance is regulated by a complex neuronal network of anorexigenic and orexigenic neurons which integrates peripheral and central hormonal and neuronal signals relaying information on the metabolic status of organs and tissues in the body. A key component of this network is the central melanocortin pathway in the hypothalamus that elicits metabolic and behavioral adaptations for the maintenance of energy homeostasis. Genetic defects in this system cause obesity in mice and humans. In this review we emphasize mouse models with spontaneous natural mutations as well as targeted mutations that contributed to our understanding of the central melanocortin system function in the control of energy balance.

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.

Melanocortin signaling via the MC4 receptor regulates T cell function

The central melanocortin pathway is critical for regulating food intake and energy expenditure. However, precise role of melanocortins and MC4 receptor in regulation of thymic function remains to be elucidated. Here we demonstrate that MC4R are highly expressed in thymus and lymphoid organs. Compared to wild type control mice, genetic deletion of MC4R led to reduced cellularity and loss of cortico‐medullary junctions suggesting increased thymic involution. Interestingly, the absence of MC4R mediated signals caused a marked increase in lipid bearing thymic fibroblasts and reduction in medullary thymic epithelial cells with reduced thymic output. Analysis of lymphoid progenitors revealed significant reduction in LSK cells in bone marrow and ETP cells in thymus. Using complementarity determining region 3 (CDR3) length polymorphism analysis we next demonstrated that absence of MC4R causes a severe contraction of peripheral T cell receptor diversity suggesting reduced immune‐surveillance. Collectively, these data demonstrates a novel role of melanocortin ‐MC4R pathway in coupling metabolic and immune system. In addition, our findings suggest that specific Mc4R agonists may serve as an important target for rejuvenating thymic function.

The leptin melanocortin pathway and the control of body weight: lessons from human and murine genetics

The recent rapid increase in the prevalence of obesity across the world is undoubtedly due to changes in diet and lifestyle. However, it is also indisputable that different people react differently to this change in environment and this variation in response is likely to be genetically determined. While for the majority of people this effect is presumed to be polygenic in origin, there is now strong evidence for a small number of genes having a large effect in some families with severe obesity. Studies of these families, coupled with parallel studies in murine models, have provided novel insights into the molecules involved in the regulation of appetite, energy expenditure and nutrient partitioning. We review here the lessons we have learnt from mouse models of obesity, both naturally occurring and artificially generated through targeted gene deletions, and more importantly from human monogenic syndromes of obesity. These have illuminated the critical role in which the central leptin melanocortin pathway plays in the control of mammalian food intake and body weight.

Hyperphagia Alters Expression of Hypothalamic 5-HT2C and 5-HT1B Receptor Genes and Plasma Des-Acyl Ghrelin Levels in AyMice

The central melanocortin (MC) pathway is suggested to mediate satiety signaling downstream of serotonin (5-HT)2C receptors. 5-HT2C receptor mutant mice consume more food, which leads to late-onset obesity and impaired glucose tolerance. Ay mice with ectopic expression of the agouti peptide, which leads to a perturbation of the central MC pathway, develop obesity and diabetes, associated with low levels of plasma total ghrelin. Here, we report that 5-wk-old Ay mice consumed more food in association with decreases in levels of plasma des-acyl ghrelin, but not active ghrelin, and increases in hypothalamic 5-HT2C and 5-HT1B receptor gene expression compared with wild-type mice matched for age and body weight. These alterations were also observed in 8-wk-old obese Ay mice. Restricted feeding significantly decreased hypothalamic 5-HT2C and 5-HT1B receptor gene expression in association with a reversal of the decreases in plasma des-acyl ghrelin levels in 5-wk-old Ay mice. Moreover, restricted feeding reduced body weight, hyperinsulinemia, and hyperglycemia in association with increases in plasma des-acyl ghrelin levels in 8-wk-old obese Ay mice. Administration of m-chlorophenylpiperazine and fenfluramine, both of which induce anorexic effects via 5-HT2C receptors and/or 5-HT1B receptors, suppressed food intake in 5- and 8-wk-old Ay mice, whereas the anorexic effects were attenuated in food-restricted Ay mice. These findings suggest that the agouti peptide down-regulates hypothalamic 5-HT2C and 5-HT1B receptor gene expression under restricted feeding conditions, whereas chronic hyperphagia increases the expression of these genes and decreases plasma des-acyl ghrelin levels in Ay mice.

Adipose Tissue as an Endocrine Organ

Adipose tissue plays a critical role in energy homeostasis, not only in storing triglycerides, but also responding to nutrient, neural, and hormonal signals and secreting adipokines that control feeding, thermogenesis, immunity, and neuroendocrine function. A rise in leptin signals satiety to the brain through receptors in hypothalamic and brainstem neurons. Leptin activates tyrosine kinase, Janus kinase 2, and signal transducer and activator of transcription 3, leading to increased levels of anorexigenic peptides, e.g., alpha-melanocyte stimulating hormone and cocaine- and amphetamine-regulated transcript, and inhibition of orexigenic peptides, e.g., neuropeptide Y and agouti-related peptide. Obesity is characterized by hyperleptinemia and hypothalamic leptin resistance, partly caused by induction of suppressor of cytokine signaling-3. Leptin falls rapidly during fasting and potently stimulates appetite, reduces thermogenesis, and mediates the inhibition of thyroid and reproductive hormones and activation of the hypothalamic-pituitary-adrenal axis. These actions are integrated by the paraventicular hypothalamic nucleus. Leptin also decreases glucose and stimulates lipolysis through central and peripheral pathways involving AMP-activated protein kinase (AMPK). Adiponectin is secreted exclusively by adipocytes and has been linked to glucose, lipid, and cardiovascular regulation. Obesity, diabetes, and atherosclerosis have been associated with reduced adiponectin levels, whereas adiponectin treatment reverses these abnormalities partly through activation of AMPK in liver and muscle. Administration of adiponectin in the brain recapitulates the peripheral actions to increase fatty acid oxidation and insulin sensitivity and reduce glucose. Although putative adiponectin receptors are widespread in peripheral organs and brain, it is uncertain whether adiponectin acts exclusively through these targets. As with leptin, adiponectin requires the central melanocortin pathway. Furthermore, adiponectin stimulates fatty acid oxidation and reduces glucose and lipids, at least in part, by activating AMPK in muscle and liver.

Melanotan-II: Investigation of the inducer and facilitator effects on penile erection in anaesthetized rat

The effects of melanotan-II, a non-specific agonist of melanocortin receptors, on erection and its possible sites of action were investigated in anesthetized rats. Delivered i.v. (0.1, 0.3 and 1mg/kg) or within the paraventricular nucleus of the hypothalamus (0.1 and 1μg), melanotan-II exerted a dose-dependent inducer activity on erection by eliciting erectile events and shortening latency of the first erectile event to occur. Erectile events were of higher amplitude in rats treated with melanotan-II i.t. (0.2μg) delivered at the L6–S1 level than in animals treated with the vehicle i.t. delivered. Erectile responses elicited by cavernous nerve stimulation were increased after i.v. melanotan-II (1mg/kg), thereby exerting facilitator effect on erection. In contrast, melanotan-II injected within the corpus cavernosum (1μg) did not display any facilitator activity. To investigate the neural pathways involved in the facilitator effect of melanotan-II, we performed acute spinalization (T8 level) and differential selective nerve transections. Neither spinalization nor bilateral transection of pelvic nerves or dorsal penile nerves impaired facilitator activity of i.v. melanotan-II (1mg/kg). Conversely, the facilitator effect of melanotan-II was abolished after acute removal of the lumbar paravertebral sympathetic chain. These results lead to the conclusion that central and peripheral melanocortin pathways are recruited by melanotan-II, depending on its route of delivery, to exert both inducer and facilitator activities on erection.

Melanocortin receptors and energy homeostasis

Purpose of review This article highlights new information regarding the physiology of the central melanocortin system and how defects in it contribute to human metabolic disease. Recent findings Selective abolition of leptin action on pro-opiomelanocortin neurons causes an obese phenotype, demonstrating that leptin signaling through pro-opiomelanocortin neurons is essential for normal energy homeostasis. Novel roles of leptin are also becoming apparent with evidence that acetylation of α-melanocyte-stimulating hormone into its more biologically activity form is leptin dependent. Leptin can also regulate hepatic glucose fluxes through a central melanocortin-dependent pathway. We review evidence that the brain stem melanocortin system mediates the effects of cholecystokinin, suggesting that the melanocortin system integrates short-term satiety signals as well as long-term adipostatic signals like leptin. The downstream targets of MC4-R are now becoming apparent with melanin-concentrating hormone and brain-derived neurotrophic factor implicated as key ‘second order’ mediators. Evidence from different ethnic groups shows MC4-R mutations to be the most common single gene disorder causing obesity. The functional properties of naturally occurring human mutants suggest the N-terminal domain of the MC4-R may function as a tethered intramolecular ligand, maintaining constitutive receptor activity. Summary Recent studies have reiterated the critical role the central melanocortin pathway plays in the control of energy balance. Given the public health challenge that obesity presents, the potential attractiveness of the melanocortin system as a therapeutic target only grows as knowledge of its molecular physiology increases.