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The melanocortin 4 receptor (MC4R) plays a central role in appetite regulation, and agonistic activity at this receptor promotes satiety. Results from two randomized controlled clinical trials examine the effects of bremelanotide's agonism at MC4R on caloric intake and body weight.Premenopausal women with a body mass index30 kg/mIn Study A, 27 of 30 bremelanotide subjects (90.0%) completed the trial and exhibited a significantly greater reduction in body weight after 16 days versus placebo [least squares mean difference (95% CI), -1.3 (-1.9 to -0.8) kg; p .0001]. Mean caloric intake in bremelanotide subjects was decreased versus placebo, with a magnitude of reduction of approximately 400 kcal/day throughout Study A (p .01). In Study B, 15 of 27 subjects (55.6%) completed all three phases. Significantly greater reduction of mean body weight occurred in twice-daily bremelanotide subjects versus placebo (1.7 vs. 0.9 kg, respectively, p .001). Total caloric intake reduction was significantly greater in the bremelanotide groups versus placebo (mean difference range: 398-469 kcal; p .0001).Agonist activity at the MC4R may aid in reducing caloric intake and weight loss in obese women.

Introduction: Obesity is a strong promoter of cardiometabolic risk factors and is associated with several chronic comorbidities. Recently, the role of α-melanocyte stimulating hormone (α-MSH) and agouti related peptide (Ag-RP) in regulation of energy balance has attracted much attention. In current study, we evaluated the association between α-MSH and Ag-RP with cardiometabolic factors among obese individuals with different adherence to Diet Quality Index-International (DQI-I) values. Methods: In this research, 188 obese adults aged between 20 and 50 years old and body mass index (BMI) between 30 and 40 kg/m2 were recruited. Dietary intakes of participants and DQI-I calculation was performed using a semi-quantitative food frequency questionnaire (FFQ) with 132 food items. Serum glucose, lipids, insulin, and plasma α-MSH and Ag-RP levels were measured using ELISA kits. Homeostasis model assessment for insulin resistance index (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI) were also calculated. Results: Among those with the lowest adherence to DQI-I, Ag-RP was positively associated with systolic blood pressure (SBP) (P = 0.03) among males, which was associated with waist circumference (WC) (P = 0.01) and diastolic blood pressure (DBP) (P = 0.01). Moreover, among males with low and moderate adherence to DQI-I, α-MSH was positively associated with insulin (P = 0.04), weight (P = 0.03), WC (P < 0.01), SDP (P = 0.02) and DBP (P = 0.01). Also, Ag-RP showed a positive association with BMI values (R2 = 0.03; P = 0.03). Conclusion: According to our findings, in obese subjects with poor to moderate adherence to DQI-I, Ag-RP and α-MSH were in positive correlation with cardiometabolic risk factors. These findings further clarify the clinical importance of these parameters as prognostic factors of cardiometabolic abnormalities.

Work in recent decades has established that metabolic hormones released by endocrine cells and diverse other cell types serve to regulate nutrient intake and energy homeostasis. Tsukushi (TSK) is a leucine-rich repeat-containing protein secreted primarily by the liver that exerts an inhibitory effect on brown fat sympathetic innervation and thermogenesis. Despite this, physiological regulation of TSK and the mechanisms underlying its effects on energy balance remain poorly understood. Here we show that hepatic expression and plasma concentrations of TSK are induced by feeding and regulated by melanocortin-4 receptor (MC4R) signaling. We generated TSK and MC4R–double-knockout mice to elucidate the nature of cross talk between TSK and the central regulatory circuit of energy balance. Remarkably, TSK inactivation restores energy balance, ameliorates hyperphagia, and improves metabolic health in MC4R-deficient mice. TSK ablation enhances thermogenic gene expression in brown fat, dampens obesity-association inflammation in the liver and adipose tissue, and protects MC4R-null mice from diet-induced nonalcoholic steatohepatitis. At the cellular level, TSK deficiency augments feeding-induced c-Fos expression in the paraventricular nucleus of the hypothalamus. These results illustrate physiological cross talk between TSK and the central regulatory circuit in maintaining energy balance and metabolic homeostasis.

Hypoactive sexual desire disorder (HSDD) is a common female sexual dysfunction and is estimated to affect approximately 10% of women in the United States. It has been suggested that HSDD is associated with an imbalance of hormone and neurotransmitter levels in the brain, resulting in decreased excitation, increased inhibition, or a combination of both. Evidence suggests neurotransmitters, including dopamine (DA), norepinephrine, and serotonin, as well as hormones such as estradiol and testosterone, contribute to female sexual desire and response. Current treatments for HSDD include psychotherapy, and two US Food and Drug Administration-approved medications for premenopausal women: flibanserin, a serotonin mixed agonist and antagonist, and bremelanotide, a melanocortin receptor (MCR) agonist. Melanocortins are endogenous neuropeptides associated with the excitatory pathway of the female sexual response system. MCRs are found throughout the body, including the brain. Bremelanotide is an MCR agonist that nonselectively activates several of the receptor subtypes, of which subtype 4 (MC4R) is the most relevant at therapeutic doses. MC4R is predominantly expressed in the medial preoptic area (mPOA) of the hypothalamus in the brain, and is important for female sexual function. Animal studies suggest that bremelanotide may affect female sexual desire by activating presynaptic MC4Rs on neurons in the mPOA of the hypothalamus, leading to increased release of DA, an excitatory neurotransmitter that increases sexual desire. This review presents what is known about the mechanism of action of bremelanotide in the context of treating HSDD.

New findings What is the central question of this study? Can chronic treatment of pituitary adenylate cyclase-activating polypeptide (PACAP) deficient mice with the melanocortin agonist melanotan II during cold acclimation rescue the impaired thermogenic capacity previously observed in PACAP deficient mice? What is the main finding and its importance? Using a genetic model of PACAP deficiency, this study provides evidence that PACAP acts upstream of the melanocortin system in regulating sympathetic nerve activity to brown adipose tissue in mice. Abstract Impaired adipose tissue function in obesity, including reduced thermogenic potential, has detrimental consequences for metabolic health. Hormonal regulation of adaptive thermogenesis is being explored as a potential therapeutic target for human obesity. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide expressed in nuclei of the hypothalamus known to regulate energy expenditure, and functional studies reveal a role for PACAP in the central regulation of thermogenesis, although mechanisms are not well understood. We hypothesized that PACAP acts upstream of the melanocortin system to regulate sympathetic nerve activity to stimulate thermogenesis. To assess this, female PACAP-/- and PACAP+/+ mice were given daily peripheral injections of a melanocortin receptor agonist, melanotan II (MTII), for 3 weeks during cold acclimation, and the effect of MTII on thermogenic capacity and adipose tissue remodelling was examined by physiological and histological analyses. MTII partially rescued the impaired thermogenic capacity in PACAP-/- mice as compared to PACAP+/+ mice as determined by measuring noradrenaline-induced metabolic rate. In addition, MTII treatment during cold acclimation corrected the previously identified deficit in lipid utilization in response to adrenergic stimulation in PACAP-/- null mice, suggesting impaired lipid mobilization may contribute to the impaired thermogenic capacity of PACAP-/- mice. Results presented here provide physiological evidence to suggest that PACAP acts upstream of melanocortin receptors to facilitate sympathetically induced mechanisms of adaptive thermogenesis in response to cold acclimation.

Leptin-melanocortin pathway plays an essential role in the body weight regulation. Enhanced melanocortin signaling in the hypothalamus results in both decreased food intake and increased energy expenditure. The discovery of monogenic obesities with dysfunction of melanocortin-4 receptor (MC4R) greatly contributed to understanding of energy balance regulation. This review presents phenotypical characterization and prevalence of the MC4R gene mutations. Genome-wide association studies revealed that MC4R gene is significantly related not only to monogenic obesities but also to common obesity. An interaction of variants in the MC4R gene with fat mass and obesity associated (FTO) gene significantly increases the risk for obesity, particularly in adolescence. On the other hand, about 15 % of the MC4R gene variants result in a gain of function that protects against obesity and is associated with favorable metabolic profile. Long-term attempts to activate the MC4R have recently been finalized by a discovery of setmelanotide, a novel specific MC4R agonist that is devoid of untoward cardiovascular side-effects. The employment of specific MC4R agonists may open new horizons not only in the treatment of rare monogenic obesities but also in some common obesities where stimulation of MC4R could be achieved.

Background Erythropoietic protoporphyria (EPP) is an ultra-rare genetic disorder (prevalence 1:150`000) characterized by instant painful phototoxic burn reactions in skin exposed to visible light. Afamelanotide is the first clinically tested therapy effectively increasing the time EPP patients can spend in direct sunlight without developing symptoms and reducing the number and severity of phototoxic reactions. Objectives We report our data on real-world effectiveness of afamelanotide treatment in EPP and its phototoxic burn protection factor (PBPF). Methods We analysed clinical data collected between 2016 and 2018 in the Swiss EPP cohort (n = 39) on maximum phototoxic burn tolerance time (PBTT), i.e., maximum time spent in sunlight without phototoxic reaction, severity of phototoxic reactions as assessed by an 11-point Likert-type visual analogue scale (VAS), with 0 being no pain and 10 being the worst possible pain, and Quality of Life (QoL), as assessed with an EPP-specific instrument. Results Before treatment, the PBTT was median 10 min (IQR 5–20). Under treatment, PBTT increased to median 180 min (IQR 120–240). Individual PBPF increased 1.8- to 180-fold (full range, median 15). The pain severity of the worst phototoxic reaction before treatment was median 10 and under treatment median 6 (IQR 3–7). QoL at the end of the observation period in 2018 (with all the assessed patients under treatment) was 81.4% (IQR 69.4–93.4, n = 34). A 97.4% treatment adherence rate was observed. Conclusion Treatment of EPP patients with afamelanotide is highly effective under real-world conditions. We suggest PBTT as a clinical meaningful endpoint in further clinical trials.

Aim To report an analysis of ~1 year of setmelanotide treatment for obesity and hunger, as well as metabolic and cardiac outcomes, in individuals with Bardet‐Biedl syndrome (BBS). Materials and methods Individuals aged 12 years and older with BBS received once‐daily setmelanotide. The dose was titrated every 2 weeks to establish the individual therapeutic dose (≤3 mg); treatment continued for an additional 10 weeks. Participants who lost 5 kg or more (or ≥5% of body weight if

BACKGROUND AND OBJECTIVES In this secondary analysis of a pilot clinical trial with individuals with alcohol and nicotine use disorders, we investigate the relationship between serum concentrations of oxytocin, β-endorphin, melatonin, α-melanocyte-stimulating hormone, substance P, and orexin, with objective biomarkers (salivary cotinine and serum γ-glutamyl transferase [GGT]) as well as with self-reported smoking and alcohol drinking. METHODS Biomarkers for a total of N = 19 participants were analyzed using multiplexed, competitive format immune-assay (peptides) and enzyme competitive immunoassay (saliva). A regression analysis using Pearson's correlation coefficient was utilized to determine correlations. We controlled for multiple comparisons, checked for collinearities, and ran two-sided statistical tests. RESULTS We found significant positive correlations for cotinine and oxytocin (P = .002), β-endorphin (P = .008), and orexin (P

The clinical effectiveness of adrenocorticotropin in inducing remission of steroid-resistant nephrotic syndrome points to a steroidogenic-independent anti-proteinuric activity of melanocortins. However, which melanocortin receptors (MCR) convey this beneficial effect and if systemic or podocyte-specific mechanisms are involved remain uncertain. In vivo, wild-type (WT) mice developed heavy proteinuria and kidney dysfunction following Adriamycin insult, concomitant with focal segmental glomerulosclerosis (FSGS) and podocytopathy, marked by loss of podocin and synaptopodin, podocytopenia and extensive foot process effacement on electron microscopy. All these pathologic findings were prominently attenuated by NDP-MSH, a potent non-steroidogenic pan-MCR agonist. Surprisingly, MC1R deficiency in MC1R-null mice barely affected the severity of Adriamycin-elicited injury. Moreover, the beneficial effect of NDP-MSH was completely preserved in MC1R-null mice, suggesting that MC1R is likely non-essential for the protective action. A direct podocyte effect seems to contribute to the beneficial effect of NDP-MSH, because Adriamycin-inflicted cytopathic signs in primary podocytes prepared from WT mice were all mitigated by NDP-MSH, including apoptosis, loss of podocyte markers, de novo expression of the podocyte injury marker desmin, actin cytoskeleton derangement and podocyte hypermotility. Consistent with in vivo findings, the podoprotective activity of NDP-MSH was fully preserved in MC1R-null podocytes. Mechanistically, MC1R expression was predominantly distributed to glomerular endothelial cells in glomeruli but negligibly noted in podocytes in vivo and in vitro, suggesting that MC1R signaling is unlikely involved in direct podocyte protection. Ergo, melanocortin therapy protects against podocyte injury and ameliorates proteinuria and glomerulopathy in experimental FSGS, at least in part, via a podocyte-specific non-MC1R-mediated melanocortinergic signaling.

Background: High ethanol intake induces a neuroinflammatory response resulting in the subsequent maintenance of chronic alcohol consumption. The melanocortin system plays a pivotal role in the modulation of alcohol consumption. Interestingly, it has been shown that the activation of melanocortin-4 receptor (MC4R) in the brain decreases the neuroinflammatory response in models of brain damage other than alcohol consumption, such as LPS-induced neuroinflammation, cerebral ischemia, glutamate excitotoxicity, and spinal cord injury. Objectives: In this work, we aimed to study whether MC4R activation by a synthetic MC4R-agonist peptide prevents ethanol-induced neuroinflammation, and if alcohol consumption produces changes in MC4R expression in the hippocampus and hypothalamus. Methods: Ethanol-preferring Sprague Dawley rats were selected offering access to 20% ethanol on alternate days for 4 weeks (intermittent access protocol). After this time, animals were i.p. administered an MC4R agonist peptide in the last 2 days of the protocol. Then, the expression of the proinflammatory cytokines interleukin 6 (IL-6), interleukin 1-beta (IL-1β), and tumor necrosis factor-alpha (TNF-α) were measured in the hippocampus, hypothalamus and prefrontal cortex. It was also evaluated if ethanol intake produces alterations in the expression of MC4R in the hippocampus and the hypothalamus. Results: Alcohol consumption increased the expression of MC4R in the hippocampus and the hypothalamus. The administration of the MC4R agonist reduced IL-6, IL-1β and TNF-α levels in hippocampus, hypothalamus and prefrontal cortex, to those observed in control rats that did not drink alcohol. Conclusion: High ethanol consumption produces an increase in the expression of MC4R in the hippocampus and hypothalamus. The administration of a synthetic MC4R-agonist peptide prevents neuroinflammation induced by alcohol consumption in the hippocampus, hypothalamus, and prefrontal cortex. These results could explain the effect of α-MSH and other synthetic MC4R agonists in decreasing alcohol intake through the reduction of the ethanol-induced inflammatory response in the brain.

The distribution pattern of chemokine CXCL14-immunoreactive cells was examined by immunohistochemistry in the pituitary of the gecko Hemidactylus platyurus. Immunoreactive cells were observed in the pars intermedia and pars distalis of the pituitary, but not in the pars nervosa. All α-melanocyte-stimulating hormone (αMSH)-producing cells were immunoreactive for CXCL14 in the pars intermedia. The CXCL14-immunoreactive cells corresponded to prolactin (PRL)-producing cells but not to other adenohypophyseal-hormone-producing cells in the pars distalis. CXCL14 secreted from αMSH-producing cells and PRL-producing cells may regulate insulin release from β cells in the pancreatic islets as well as glucose uptake in the muscle cells together with αMSH and/or PRL. In addition, secreted CXCL14 with αMSH and/or PRL may act as a bioactive factor regulating hormone release in the adenohypophyseal cells of the reptilian pars distalis.

IMPORTANCE: The effectiveness of afamelanotide treatment in patients with erythropoietic protoporphyria (EPP) in clinical practice who experience pain after light exposure that substantially impairs quality of life is unknown. OBJECTIVE: To evaluate the association of afamelanotide treatment with outcomes in patients with EPP in regular practice during longer-term follow-up. DESIGN, SETTING, AND PARTICIPANTS: This single-center, prospective postauthorization safety and efficacy cohort study was directed and approved by the European Medicines Agency. Data were collected from patients with EPP treated with afamelanotide at Erasmus MC between June 2016 and September 2018. Analysis began October 2018. MAIN OUTCOMES AND MEASURES: Time spent outside during treatment, number of phototoxic reactions, disease-specific quality of life, usage of protective clothing, and adverse events. RESULTS: A total of 117 patients with EPP (59 women [50.4%]; mean [SD] age, 43.0 [15.5] years) were treated with afamelanotide. Nearly all patients continued treatment (115 [98%]) with a median (interquartile range) follow-up of 2.0 (1.3-2.1) years. Compared with baseline, mean time spent outside during treatment increased significantly by an added 6.1 hours per week (95% CI, 3.62-8.67; P

The melanocortin-4 receptor (MC4R) has been critically investigated for the past two decades, and novel findings regarding MC4R signalling and its potential exploitation in weight loss therapy have lately been emphasized. An association between MC4R and obesity is well established, with disease-causing mutations affecting 1% to 6% of obese patients. More than 200 MC4R variants have been reported, although conflicting results as to their effects have been found in different cohorts. Most notably, some MC4R gain-of-function variants seem to rescue obesity and related complications via specific pathways such as beta-arrestin (ß-arrestin) recruitment. Broadly speaking, however, dysfunctional MC4R dysregulates satiety and induces hyperphagia. The picture at the mechanistic level is complicated as, in addition to the canonical G stimulatory pathway, the ß-arrestin signalling pathway and ions (particularly calcium) seem to interact with MC4R signalling to contribute to or alleviate obesity pathogenesis. Thus, the overall complexity of the MC4R signalling spectra has broadened considerably, indicating there is great potential for the development of new drugs to manage obesity and its related complications. Alpha-melanocyte-stimulating hormone is the major endogenous MC4R agonist, but structure-based ligand discovery studies have identified possible superior and selective agonists that can improve MC4R function. However, some of these agonists characterized in vitro and in vivo confer adverse effects in patients, as demonstrated in clinical trials. In this review, we provide a comprehensive insight into the genetics, function and regulation of MC4R and its contribution to obesity. We also outline new approaches in drug development and emerging drug candidates to treat obesity.

Inflammation, hyaluronan production, and adipogenesis are the main pathological events leading to thyroid eye disease (TED). α-Melanocytemelanocyte-stimulating hormone (α-MSH) is a well-known tridecapeptidetreatment for several inflammatory disorders including sepsis syndrome, acute respiratory distress syndrome, rheumatoid arthritis, and encephalitis. Here, we investigated the effect of α-MSH treatment on TED. The 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Lactate Dehydrogenase (LDH) assays were performed to analyze the effect of α-MSH on cell viability and it’s toxicity. Using primary cultures of orbital fibroblasts from TED patients and non-TED as control, we examined the effects of α-MSH on proinflammatory cytokine production induced by interleukin (IL)-1β, further analyzed by real-time reverse transcription-polymerase chain reaction (qPCR) and western blotting. Immunofluorescence staining assay and qPCR were performed to examine proopiomelanocortin (POMC) expression, the upstream neuropeptide of α-MSH in TED patients and non-TED control. Treatment with non-cytotoxic concentrations of α-MSH resulted in the dose-dependent inhibition of mRNA and protein levels (p&lt, 0.05) for IL-1β-induced inflammatory cytokines: IL-6, IL-8, MCP-1, ICAM-1, and COX-2. The expression of POMC mRNA and protein were significantly higher in TED patients compared to non-TED control (p&lt, 0.05). Our data show significant inhibitory effects of α-MSH on inflammation, POMC production in orbital fibroblasts. At present, this is the first in vitro preclinical evidence of α-MSH therapeutic effect on TED. These findings indicate that POMC and α-MSH may play a role in the immune regulation of TED and can be a potential therapeutic target.

The molecular sensors underlying nutrient-stimulated GLP-1 secretion are currently being investigated. Peripheral administration of melanocortin-4 receptor (MC4R) agonists have been reported to increase GLP-1 plasma concentrations in mice and humans but it is unknown whether this effect results from a direct effect on the GLP-1 secreting L-cells in the intestine, from other effects in the intestine or from extra-intestinal effects. We investigated L-cell expression of MC4R in mouse and human L-cells by reanalyzing publicly available RNA sequencing databases (mouse and human) and by RT-qPCR (mouse), and assessed whether administration of MC4R agonists to a physiologically relevant gut model, isolated perfused mouse and rat small intestine, would stimulate GLP-1 secretion or potentiate glucose-stimulated secretion. L-cell MC4R expression was low in mouse duodenum and hardly detectable in the ileum and MC4R expression was hardly detectable in human L-cells. In isolated perfused mouse and rat intestine, neither intra-luminal nor intra-arterial administration of NDP-alpha-MSH, a potent MC4R agonist, had any effect on GLP-1 secretion (P ≥0.98, n = 5–6) from the upper or lower-half of the small intestine in mice or in the lower half in rats. Furthermore, HS014—an often used MC4R antagonist, which we found to be a partial agonist—did not affect the glucose-induced GLP-1 response in the rat, P = 0.62, n = 6). Studies on transfected COS7-cells confirmed bioactivity of the used compounds and that concentrations employed were well within in the effective range. Our combined data therefore suggest that MC4R-activated GLP-1 secretion in rodents either exclusively occurs in the colon or involves extra-intestinal signaling.

Background Over the past 20 years, insights from human and mouse genetics have illuminated the central role of the brain leptin-melanocortin pathway in the control of mammalian food intake, with genetic disruption resulting in extreme obesity, and more subtle polymorphic variation influencing the population distribution of body-weight. At the end of 2020, the Food & Drug Administration (FDA) approved setmelanotide, a melanocortin 4 receptor agonist, for use in individuals with severe obesity due to either pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1) or leptin receptor (LEPR) deficiency. Scope of review Here, we will chart the history of the melanocortin pathway, explore its pharmacology, genetics and physiology, and tell the story of how a neuropeptidergic circuit managed to find its way to becoming an important druggable obesity target. Conclusions Unravelling the genetics of the subset of severe obesity has revealed the importance of the melanocortin pathway in appetitive control; coupling this with studying the molecular pharmacology of compounds that bind the melanocortin receptors has brought a new drug to the market for obesity. This process provides a template of drug discovery for complex disorders, which in the case of setmelanotide took 25 years to go from a single gene to an approved drug.

Background Responder analyses are used to determine whether changes that occur during a clinical trial are clinically meaningful; for subjective endpoints such as those based on patient-reported outcomes (PROs), responder analyses are particularly useful. Aim To identify the minimal clinically important difference (MCID) for selected scores on questionnaires assessing female sexual functioning and to use these differences to analyze the response in a large, controlled, phase 2b, dose-finding study of bremelanotide in premenopausal women with hypoactive sexual desire disorder (HSDD) and mixed HSDD/female sexual arousal disorder (FSAD). Methods The responder analyses were performed for the change from baseline to end of study for a total of 7 endpoints. Each PRO endpoint was assessed using at least 1 of 4 types of responder analyses: a planned analysis anchored to MCIDs based on expert estimates (historical anchors); post hoc analyses based on self-reported global benefit; receiver operating characteristic (ROC) curves; and cumulative distribution function. The prespecified analysis groups were all female sexual dysfunction (FSD)-based diagnoses (all study participants), those with HSDD alone, and a combined group of those with FSAD alone plus those with mixed HSDD/FSAD. Post hoc analyses were also performed for subjects with mixed HSDD/FSAD with a primary diagnosis of HSDD. Outcomes MCIDs based on the ROC curves for changes in Female Sexual Function Index–desire domain, Female Sexual Distress Scale–Desire/Arousal/Orgasm (FSDS-DAO) total score, FSDS-DAO item 13 and 14 scores, and number of satisfying sexual events. Results Outcomes matched those based on input from clinical experts. For all 7 endpoints, responder rates at the 1.75 mg dose in the overall modified intention-to-treat population achieved statistical significance compared with placebo (P ≤ .03). Clinical Implications These responder definitions were subsequently used in the bremelanotide phase 3 registration studies (RECONNECT) that evaluated the safety and efficacy of the bremelanotide 1.75 mg subcutaneous dose in premenopausal women with HSDD. Strengths & Limitations MCIDs for this study were based on changes from a single-blind phase to account for changes due to the placebo effect. These analyses were restricted to a study population composed only of premenopausal women with a clinical diagnosis of HSDD and/or FSAD and were based on data from the same clinical trial. Conclusion Bremelanotide was safe and well tolerated and demonstrated significant improvement in efficacy vs placebo in the phase 2b trial. The multiple responder analyses offer a valuable approach for determining clinically important effects of bremelanotide for HSDD and FSAD.

We examined the distribution of the orexin-like peptides in the pituitary and median eminence of the flat-tailed house gecko (Hemidactylus platyurus) using immunohistochemistry. Orexin-B-like, but not orexin-A-like, immunoreactivity was detected in the pituitary, specifically in the pars intermedia, and these cells corresponded to alpha-melanocyte-stimulating hormone (αMSH)-producing cells. Orexin-B and αMSH secreted from pars intermedia may modulate secretion of adenohypophyseal cells in the pars distalis. In the median eminence, orexin-B-immunoreactive puncta and fibres were observed, and these structures corresponded to gonadotropin-releasing hormone (GnRH)-immunoreactive puncta and fibres. Orexin-B secreted from GnRH-containing neurons in the hypothalamus may affect thyrotropin-releasing hormone-containing neurons resulting in modulation of αMSH secretion of melanotrophs in the pars intermedia.

The initial discovery that ob/ob mice become obese because of a recessive mutation of the leptin gene has been crucial to discover the melanocortin pathway to control appetite. In the melanocortin pathway, the fed state is signaled by abundance of circulating hormones such as leptin and insulin, which bind to receptors expressed at the surface of pro-opiomelanocortin (POMC) neurons to promote processing of POMC to the mature hormone α-melanocyte-stimulating hormone (α-MSH). The α-MSH released by POMC neurons then signals to decrease energy intake by binding to melanocortin-4 receptor (MC4R) expressed by MC4R neurons to the paraventricular nucleus (PVN). Conversely, in the ‘starved state’ activity of agouti-related neuropeptide (AgRP) and of neuropeptide Y (NPY)-expressing neurons is increased by decreased levels of circulating leptin and insulin and by the orexigenic hormone ghrelin to promote food intake. This initial understanding of the melanocortin pathway has recently been implemented by the description of the complex neuronal circuit that controls the activity of POMC, AgRP/NPY and MC4R neurons and downstream signaling by these neurons. This review summarizes the progress done on the melanocortin pathway and describes how obesity alters this pathway to disrupt energy homeostasis. We also describe progress on how leptin and insulin receptors signal in POMC neurons, how MC4R signals and how altered expression and traffic of MC4R change the acute signaling and desensitization properties of the receptor. We also describe how the discovery of the melanocortin pathway has led to the use of melanocortin agonists to treat obesity derived from genetic disorders.

Loss of appetite affects one-third of patients with CKD and is the leading cause of malnutrition in this population. Orexigenic Agouti-related peptide (AgRP) with neuropeptide-Y (NPY) and anorexigenic melanocyte-stimulating hormone-alpha (MSH-alpha) with cocaine- and amphetamine-regulated transcript (CART) are known to regulate appetite. In this study, we aimed to evaluate the levels of these peptides in CKD patients compared to healthy subjects and demonstrate the effects of dialysis treatment and erythropoiesis-stimulating agent (ESA) therapy. The cross-sectional study is composed of consecutive inclusion of 20 healthy individuals, 20 predialysis CKD patients, 20 HD, and 20 peritoneal dialysis (PD) patients. Exclusion criteria were an active infection, history of malignancy, hypo- or hyperthyroidism, and diabetes. Patients on dialysis had targeted Kt/Vs. Demographic features and BMIs of the four groups were similar. Levels of AgRP, NPY, AMSH, and CART were significantly different between groups. Nondialysis CKD patients had significantly lower hypothalamic hormones compared to healthy individuals, HD and PD patients (P = 0.02, P = 0.03, and P = 0.07 for AgRP; P = 0.02, P = 0.01, and P = 0.09 for NPY; P = 0.02, P = 0.02, and P = 0.03 for AMSH; P = 0.02, P = 0.005, and P = 0.030 for CART). Dialysis patients with or without ESA treatment had similar hormone levels (P = 0.13 for AgRP; P = 0.11 for NPY; P = 0.23 for AMSH, and P = 019 for CART). Predialysis CKD patients have lower orexigenic and presumably indirectly lower anorexigenic peptides compared to healthy subjects and dialysis patients. ESA treatment does not affect these hypothalamic peptides in dialysis patients.

Mice with a targeted mutation in the pro-opiomelanocortin (Pomc) gene (Pomctm1/tm1 mice) are unable to synthesize desacetyl-α-MSH and α-MSH and they develop obesity when fed chow diet. In this study, we hypothesized that a chronic high-fat (HF) diet exacerbates Pomctm1/tm1 mouse obesity. Male and female Pomcwt/wt and Pomctm1/tm1 mice were fed low-fat (LF) (10 kcal percent fat) or HF (45 kcal percent fat) diets from weaning for 23 weeks. We show that Pomctm1/tm1 mouse obesity is sexually dimorphic and exacerbated by an HF diet. Male Pomctm1/tm1 mice develop obesity because they are hyperphagic compared with Pomcwt/wt mice when fed an LF or HF diet. Female Pomctm1/tm1 mice develop obesity when feeding on an LF or HF diet because they exhibit signs of reduced energy expenditure (no change in feed efficiency; body weight gained exceeding energy intake) compared with Pomcwt/wt mice. A chronic HF diet exacerbates male Pomctm1/tm1 and Pomcwt/wt mouse obesity, and the increased energy intake fully accounts for increased weight gain. In contrast, female Pomcwt/wt mice are protected from chronic HF diet–induced obesity because they reduce the amount of HF diet eaten, and they appear to increase their energy expenditure (no change in feed efficiency but energy intake exceeding body weight gained). A chronic HF diet exacerbates female Pomctm1/tm1 mouse obesity due to impaired ability to reduce the amount of HF diet eaten and apparent impaired HF diet–induced adaptive thermogenesis. Our data show that desacetyl-α-MSH and α-MSH are required for sexually dimorphic HF diet–induced C57BL/6J obesity. In conclusion, desacetyl-α-MSH and α-MSH play salutary roles in sexually dimorphic melanocortin obesity and sexually dimorphic HF diet–induced C57BL/6J obesity.

This review evaluates published studies regarding alpha-melanocyte stimulating hormone (α-MSH) in ghrelin-elicited feeding and gut motility. We have sought to integrate all available evidences to provide a complete review on the properties of melanocortin receptors (MCR) and the potential clinical treatment of α-MSH after ghrelin-elicited feeding and gut motility. The available studies were grouped into four categories: food intake, gastric emptying, small intestinal transit, and colonic transit. As we describe, the literature provides evidence of the ability of ghrelin to increase food intake, gastric emptying, small intestinal transit, and colonic transit. α-MSH, which displays high affinity for the MC3 and MC4 receptors, can competitively activate MCRs with agouti-related protein stimulated by ghrelin, and partly attenuates the effect of acyl ghrelin on food intake. Central ghrelin-induced acceleration of gastric emptying is not mediated by MCRs, but the acceleration of the small intestinal transit is at least partly mediated via MCRs in the brain. Similar to fecal pellets and total fecal weight, distal colonic motility and secretion are partly mediated by MCRs in the brain. The interplay between acyl ghrelin and MCRs may provide a new therapeutic avenue to ameliorate anorexia and constipation.

Li et al. develop a new mouse model that recapitulates risperidone-induced metabolic syndrome. Using a combination of transcriptomic, genetic, and electrophysiological approaches, they show that risperidone targets hypothalamic MC4Rs to cause weight gain and that setmelanotide, an MC4R agonist, mitigates its metabolic side effects., Atypical antipsychotics such as risperidone cause drug-induced metabolic syndrome. However, the underlying mechanisms remain largely unknown. Here, we report a new mouse model that reliably reproduces risperidone-induced weight gain, adiposity, and glucose intolerance. We found that risperidone treatment acutely altered energy balance in C57BL/6 mice and that hyperphagia accounted for most of the weight gain. Transcriptomic analyses in the hypothalamus of risperidone-fed mice revealed that risperidone treatment reduced the expression of Mc4r. Furthermore, Mc4r in Sim1 neurons was necessary for risperidone-induced hyperphagia and weight gain. Moreover, we found that the same pathway underlies the obesogenic effect of olanzapine—another commonly prescribed antipsychotic drug. Remarkably, whole-cell patch-clamp recording demonstrated that risperidone acutely inhibited the activity of hypothalamic Mc4r neurons via the opening of a postsynaptic potassium conductance. Finally, we showed that treatment with setmelanotide, an MC4R-specific agonist, mitigated hyperphagia and obesity in both risperidone- and olanzapine-fed mice., Graphical Abstract

Persons with type 1 diabetes have an increased risk of stroke compared with the general population. α-Melanocyte-stimulating hormone (α-MSH) is a neuropeptide that has protective effects against ischemia/reperfusion (I/R) induced organ damages. In this study, we aimed to investigate the neuroprotective role of this peptide on I/R induced brain damage after experimental stroke associated with hyperglycemia using C57BL/6J Ins2Akita/+ mice. Experimental stroke was induced by blocking the right middle cerebral artery for 2 h with reperfusion for 2 and 22 h, respectively using the intraluminal method. Animals were treated intraperitoneally with or without α-MSH at 1 h after ischemia and 1 h after reperfusion. Significantly higher survival rate and lower neurological scores were recorded in animals injected with α-MSH. Similarly, neuron death, glial cells activation as well as oxidative and nitrosative stress were significantly decreased in α-MSH treated group. Relative intensities of matrix metallopeptidases 9, cyclooxygenase 2 and nuclear factor-κB were significantly decreased while intensities of Akt, heme oxygenase (HO) 1, HO-2 and B-cell lymphoma 2 were significantly increased after α-MSH treatment. In addition, gene expressions of monocarboxylate transporter (MCT) 1, MCT-2 and activity-regulated cytoskeleton-associated protein were significantly higher in brain samples treated with α-MSH, suggesting this peptide may have role in neuron survival by an involvement of lactate metabolism. In conclusion, α-MSH is neuroprotective under hyperglycemic condition against I/R induced brain damage by its anti-inflammatory, anti-oxidative and anti-apoptotic properties. The use of α-MSH analogues may be potential therapeutic agents for diabetic stroke.

Alpha-melanocyte-stimulating hormone (α-MSH), a peptide derived from proopiomelanocortin (POMC), and melanin-concentrating hormone (MCH), act as neuromodulators and regulate food intake in vertebrates. In teleosts, these peptides are also involved competitively in body color regulation; α-MSH induces a dark body color, while MCH induces a pale body color. Similarly, members of the growth hormone (GH) family, somatolactin (SL) and prolactin (PRL), which are involved in the regulation of energy metabolism, are also associated with body color regulation in teleosts. Since these hormones are involved in both body color regulation and energy metabolism, it is possible that feeding status can affect body color. Here, we examined the effects of fasting on the response of goldfish body coloration to changes in background color. Goldfish were acclimated for one week in tanks with a white or black background under conditions of periodic feeding or fasting. The results showed that body color and expression levels of pmch1 and pomc were affected by background color, irrespective of feeding status. Expression levels of sla were higher in fish maintained in tanks with a black background than in tanks with a white background, and higher in the fasted fish compared to the fed fish. However, the pattern of slb expression was almost the opposite of that observed in sla expression. The expression levels of gh and prl in the pituitary, and pmch2a and pmch2b in the brain, were not affected by background color. These results suggest that MCH, α-MSH, SLα, and SLβ might be involved in body color regulation and that they are affected by background color in goldfish. The results also suggest that feeding status may affect body color regulation via SLα and SLβ, although these effects might be limited compared to the effect of background color.

Setmelanotide (IMCIVREE™, Rhythm Pharmaceuticals) is a melanocortin-4 (MC4) receptor agonist developed for the treatment of obesity arising from proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency. The drug has received its first approval in the USA for chronic weight management in patients 6 years and older with obesity caused by POMC, PCSK1 and LEPR deficiency and has been granted PRIority MEdicines (PRIME) designation by the European Medicines Agency for the treatment of obesity and the control of hunger associated with deficiency disorders of the MC4 receptor pathway. Setmelanotide is also being developed in other rare genetic disorders associated with obesity including Bardet-Biedl Syndrome, Alstrom Syndrome, POMC and other MC4R pathway heterozygous deficiency obesities, and POMC epigenetic disorders. This article summarizes the milestones in the development of setmelanotide leading to this first approval for obesity caused by POMC, PCSK1 and LEPR deficiency.

The central nervous system is involved in regulation of defaecation. It is generally considered that supraspinal regions control the spinal defaecation centre. However, signal transmission from supraspinal regions to the spinal defaecation centre is still unclear. In this study, we investigated the regulatory role of an anorexigenic neuropeptide, α-MSH, in the spinal defaecation centre in rats. Intrathecal administration of α-MSH to the L6-S1 spinal cord enhanced colorectal motility. The prokinetic effect of α-MSH was abolished by severing the pelvic nerves. In contrast, severing the colonic nerves or thoracic cord transection at the T4 level had no impact on the effect of α-MSH. RT-PCR analysis revealed MC1R mRNA and MC4R mRNA expression in the L6-S1 spinal cord. Intrathecally administered MC1R agonists, BMS470539 and SHU9119, mimicked the α-MSH effect, but a MC4R agonist, THIQ, had no effect. These results demonstrate that α-MSH binds to MC1R in the spinal defaecation centre and activates pelvic nerves, leading to enhancement of colorectal motility. This is, to our knowledge, the first report showing the functional role of α-MSH in the spinal cord. In conclusion, our findings suggest that α-MSH is a candidate for a neurotransmitter from supraspinal regions to the spinal defaecation centre.

Objective: Hypothalamic melanocortin 4 receptors (MC4R) are a key regulator of energy homeostasis. Brain-penetrant MC4R agonists have failed, as concentrations required to suppress food intake also increase blood pressure. However, peripherally located MC4R may also mediate metabolic benefits of MC4R activation. Mc4r transcript is enriched in mouse enteroendocrine L cells and peripheral administration of the endogenous MC4R agonist, α-melanocyte stimulating hormone (α-MSH), triggers the release of the anorectic hormones Glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) in mice. This study aimed to determine whether pathways linking MC4R and L-cell secretion exist in humans. Design: GLP-1 and PYY levels were assessed in body mass index–matched individuals with or without loss-of-function MC4R mutations following an oral glucose tolerance test. Immunohistochemistry was performed on human intestinal sections to characterize the mucosal MC4R system. Static incubations with MC4R agonists were carried out on human intestinal epithelia, GLP-1 and PYY contents of secretion supernatants were assayed. Results: Fasting PYY levels and oral glucose-induced GLP-1 secretion were reduced in humans carrying a total loss-of-function MC4R mutation. MC4R was localized to L cells and regulates GLP-1 and PYY secretion from ex vivo human intestine. α-MSH immunoreactivity in the human intestinal epithelia was predominantly localized to L cells. Glucose-sensitive mucosal pro-opiomelanocortin cells provide a local source of α-MSH that is essential for glucose-induced GLP-1 secretion in small intestine. Conclusion: Our findings describe a previously unidentified signaling nexus in the human gastrointestinal tract involving α-MSH release and MC4R activation on L cells in an autocrine and paracrine fashion. Outcomes from this study have direct implications for targeting mucosal MC4R to treat human metabolic disorders. Refereed/Peer-reviewed

Purpose: Alpha-melanocyte-stimulating hormone (alpha-MSH) has proven cardiovascular effects and plays a significant role as an endogenous countermeasure to ischemia-reperfusion injury. The aim of the current study was to examine the response of alpha-MSH during exercise in patients diagnosed with coronary artery disease (CAD) and evaluate its value in the assessment of severity and prognosis. Methods: Forty subjects with documented CAD (i.e., lesions on coronary angiography ≥ 50%) were included. Cardiopulmonary exercise testing (CPET) on a treadmill (TM) and recumbent ergometer (RE) were performed on two visits, 2–4 days apart, during 2 months of coronary angiography; subsequently, the subjects were followed up for 32 ± 10 months. At rest, at peak CPET, and after 3 min of recovery, plasma levels of alpha-MSH were measured by enzyme-linked immunosorbent assay technique. Results: Mean ejection fraction was 56.7 ± 9.6%. Alpha-MSH similarly increased from rest to peak CPET on both modalities. There were no significant differences in alpha-MSH values during testing in patients with 1,2- and 3-vesel CAD, nor in patients with a SYNTAX score 0.05). Among CPET and hormonal parameters, ∆alpha-MSH recovery/peak during RE CPET was the best predictor of cardiac event occurrence (chi-square 6.67, HR = 0.51, CI = 0.25–1.02, p = 0.010). Conclusion: ∆alpha-MSH recovery/peak during RE CPET has predictive value for CAD prognosis, demonstrating involvement of alpha-MSH in CAD and a link between stress hormones and cardiac events.

Objective Amylin was found to regulate glucose and lipid metabolism by acting on the arcuate nucleus of the hypothalamus (ARC). Maternal high-fat diet (HFD) induces sex-specific metabolic diseases mediated by the ARC in offspring. This study was performed to explore 1) the effect of maternal HFD-induced alterations in amylin on the differentiation of hypothalamic neurons and metabolic disorders in male offspring and 2) the specific molecular mechanism underlying the regulation of amylin and its receptor in response to maternal HFD. Methods Maternal HFD and gestational hyper-amylin mice models were established to explore the role of hypothalamic amylin and receptor activity-modifying protein 3 (Ramp3) in regulating offspring metabolism. RNA pull-down, mass spectrometry, RNA immunoprecipitation, and RNA decay assays were performed to investigate the mechanism underlying the influence of maternal HFD on Ramp3 deficiency in the fetal hypothalamus. Results Male offspring with maternal HFD grew heavier and developed metabolic disorders, whereas female offspring with maternal HFD showed a slight increase in body weight and did not develop metabolic disorders compared to those exposed to maternal normal chow diet (NCD). Male offspring exposed to a maternal HFD had hyperamylinemia from birth until adulthood, which was inconsistent with offspring exposed to maternal NCD. Hyperamylinemia in the maternal HFD-exposed male offspring might be attributed to amylin accumulation following Ramp3 deficiency in the fetal hypothalamus. After Ramp3 knockdown in hypothalamic neural stem cells (htNSCs), amylin was found to fail to promote the differentiation of anorexigenic alpha-melanocyte-stimulating hormone-proopiomelanocortin (α-MSH-POMC) neurons but not orexigenic agouti-related protein-neuropeptide Y (AgRP-Npy) neurons. An investigation of the mechanism involved showed that IGF2BP1 could specifically bind to Ramp3 in htNSCs and maintain its mRNA stability. Downregulation of IGF2BP1 in htNSCs in the HFD group could decrease Ramp3 expression and lead to an impairment of α-MSH-POMC neuron differentiation. Conclusions These findings suggest that gestational exposure to HFD decreases the expression of IGF2BP1 in the hypothalami of male offspring and destabilizes Ramp3 mRNA, which leads to amylin resistance. The subsequent impairment of POMC neuron differentiation induces sex-specific metabolic disorders in adulthood., Graphical abstract Image 1, Highlights • Maternal HFD leads to Ramp3 deficiency in fetal hypothalami of male offspring. • IGF2BP1 binds to Ramp3 in htNSCs specifically and maintains its mRNA stability. • Maternal HFD decreases Ramp3 in htNSCs via downregulating IGF2BP1. • Ramp3 deficiency induced by maternal HFD results in amylin resistance in htNSCs. • Amylin resistance induced by Ramp3 deficiency impairs POMC neuron differentiation.

The melanocortin peptides have an important role in regulating body weight and appetite. Mice that lack the desacetyl-α-MSH and α-MSH peptides (Pomctm1/tm1) develop obesity. This effect is exacerbated by a high fat diet (HFD). However, development of obesity in female Pomctm1/tm1 mice during chronic HFD conditions is not fully accounted for by the increased energy intake. We hypothesized that the protection against chronic HFD-induced obesity imparted by MSH peptides in females is mediated by sex-specific alterations in the gut structure and gut microbiota. We determined that female WT mice had reduced jejunum villus length and increased crypt depth in response to chronic HFD. WT males and Pomctm1/tm1 mice lacked this adaptation to a chronic HFD. Both Pomctm1/tm1 genotype and chronic HFD were significantly associated with gut microbiota composition. Sex-specific associations between Pomctm1/tm1 genotype and gut microbiota were observed in the presence of a chronic HFD. Pomctm1/tm1 females had significantly reduced fecal acetate and propionate concentrations when compared to WT females. We conclude that MSH peptides influence jejunum villus length, crypt depth and the structure of the gut microbiota. These effects favor reduced nutrient absorption and occur in addition to the recognized roles of desacetyl-α-MSH and α-MSH peptides in appetite control.

White adipose tissue (WAT) browning is a potent mechanism to dissipate energy as heat and, thus, its activation constitutes a promise therapeutic approach to obesity. We previously reported the melanocortin α-melanocyte stimulating hormone (α-MSH) ability to increase the number of beige cells in subcutaneous inguinal WAT (ingWAT) in high fat diet (HFD)-fed mice. The current study examined the browning effect of intraperitoneally administered α-MSH on diverse fat depots from mice fed with HFD or standard rodent diet (SD). For this, mRNA expression of browning hallmark genes was quantified concomitantly with histological examination of the adipose tissue samples (epidydimal (eWAT), mesenteric (mWAT), retroperitoneal (rpWAT) or ingWAT). As well, α-MSH impact on body weight, serum profile, WAT mass and lipolytic rates were evaluated. In the visceral depots mWAT, eWAT and rpWAT from HFD-fed mice, α-MSH was not able to induce a browning mechanism. Surprisingly, in SD-fed mice, α-MSH decreased the expression of several beige-specific genes in rpWAT and promoted an increase of the size of lipid droplets. No browning effect was observed in ingWAT from SD-fed mice. We also verified that HFD ingestion per se stimulated the browning mechanisms in rpWAT, but not in mWAT and eWAT. In conclusion, the fat depots from diverse anatomical locations respond differently to α-MSH treatment when exposed to different diets.

OBJECTIVE The purpose of this study was to investigate the peripheral concentrations of leptin and neuropeptides taking part in the melanocortin pathway in hypothalamic obesity (HO) associated with craniopharyngioma (CP) and to find a peripheral marker for diagnosis. METHODS Thirty-one patients (52% girls; median age 16 years) with CP were enrolled in the study group. They were grouped as CP with obesity (CPobesity , n = 17) and CP without obesity (CPnonobesity , n = 14). Two control groups without CP consisted of 27 children with obesity (OC) (55% girls; median age 13.8 years) and 25 children without obesity (normal control [NC]) (72% girls; median age 14.5 years). Obesity was defined as BMI percentile ≥ 95%. Fasting serum concentrations of leptin, brain-derived neurotrophic factor (BDNF), and alpha-melanocyte-stimulating hormone (α-MSH) were measured in the groups. RESULTS Leptin and BDNF concentrations were correlated with BMI SD score (SDS) in controls (OC + NC) and CP. However, there was no correlation between α-MSH and BMI-SDS in CP or control groups. After adjusting for age, sex, and BMI-SDS, α-MSH was found to be significantly higher in CPobesity than in other groups, whereas leptin and BDNF were comparable among the four groups. CONCLUSIONS Serum BDNF, just like leptin, increased with BMI, regardless of hypothalamic damage. On the contrary, α-MSH concentration was significantly high in HO, designating a potential biomarker for HO in CP.

Feeding-regulatory peptides such as thyrotropin-releasing hormone (TRH), α-melanocyte-stimulating hormone (α-MSH) and their receptors are expressed in brain regions involved in the homeostatic and hedonic control of food intake, such as the hypothalamus and the mesolimbic system, respectively. The nucleus accumbens (NAc) is part of the latter, a brain circuit involved in processing reward stimuli and the appetitive motivation of feeding. When TRH or α-MSH are administered in the NAc, both decrease food intake, through activating their respective receptors, TRH-R1 and MC4R. The actions of α-MSH as a homeostatic feeding-regulator involves the increase of hypothalamic TRH expression, thus, we aimed to identify whether TRH signaling in the NAc was also participating in α-MSH-induced reduction of food intake. α-MSH administration in the NAc of 48 h fasted rats reduced their food intake during the 2-h period of refeeding, increased accumbal TRH mRNA expression and decreased that of MC4R. Such downregulated MC4R mRNA levels implied a compensatory decrease of α-MSH actions in the NAc after the previous pathway stimulation. The co-administration of α-MSH along with an antisense oligonucleotide directed against pro-TRH mRNA in the NAc impaired the α-MSH-induced feeding reduction, supporting that the accumbal TRHergic pathway is downstream of α-MSH actions to inhibit feeding. Our results suggested that TRH in the NAc mediates some effects of α-MSH on inhibition of food intake; this supports the role of TRH not only as a homeostatic regulator but also as modulating the motivational aspects of feeding.

Amylin, a pancreatic hormone and neuropeptide, acts principally in the hindbrain to decrease food intake and has recently been shown to act as a neurotrophic factor to control the development of area postrema → nucleus of the solitary tract and arcuate hypothalamic nucleus → paraventricular nucleus axonal fiber outgrowth. Amylin is also able to activate ERK signaling specifically in POMC neurons independently of leptin. For investigation of the physiological role of amylin signaling in POMC neurons, the core component of the amylin receptor, calcitonin receptor (CTR), was depleted from POMC neurons using an inducible mouse model. The loss of CTR in POMC neurons leads to increased body weight gain, increased adiposity, and glucose intolerance in male knockout mice, characterized by decreased energy expenditure (EE) and decreased expression of uncoupling protein 1 (UCP1) in brown adipose tissue. Furthermore, a decreased spontaneous locomotor activity and absent thermogenic reaction to the application of the amylin receptor agonist were observed in male and female mice. Together, these results show a significant physiological impact of amylin/calcitonin signaling in CTR-POMC neurons on energy metabolism and demonstrate the need for sex-specific approaches in obesity research and potentially treatment.

Objective To investigate the features of neuropeptide Y (NPY), α-melanocyte stimulating hormone (α-MSH), and agouti-related protein (AgRP) in type 2 diabetes mellitus (T2DM) patients with hypertension. Methods Patients with T2DM (n = 384) and healthy volunteers (n = 80) were enrolled into this study. Serum NPY, α-MSH, and AgRP levels were detected using ELISA. Results Significantly higher NPY and lower α-MSH and AgRP levels were observed in patients with diabetes compared with those without diabetes, and the mean NPY levels increased, while α-MSH and AgRP levels decreased, with the development of hypertension compared with diabetic patients without hypertension. α-MSH and AgRP levels decreased with an increase in blood pressure in hypertension compared with the non-hypertension patients. Multiple stepwise linear regression analysis showed that NPY, α-MSH, and AgRP levels were closely associated with blood pressure and glucose control. Receiver operating characteristic (ROC) curve analyses indicated that α-MSH may be a better marker compared with NPY and AgRP for regulating glucose and blood pressure and to distinguish between T2DM patients with and without hypertension. Conclusion NPY, α-MSH, and AgRP might play different roles and be closely related to the occurrence and development of diabetes and hypertension.

International audience; Obesity, defined by an excess of body fat impacting on health, is a complex disease resulting from the interaction between many genetic/epigenetic factors and environmental triggers. For some clinical situations with severe obesity, it has been possible to classify these obesity forms according to the molecular alterations. These include: (i) syndromic obesity, which associates severe early-onset obesity with neurodevelopmental disorders and/or polymalformative syndrome and (ii) non-syndromic monogenic obesity, due to gene variants most often located in the leptin-melanocortin pathway. In addition to severe obesity, patients affected by these diseases display complex somatic conditions, eventually including obesity comorbidities, neuropsychological and psychiatric disorders. These conditions render the clinical management of these patients particularly challenging. Patients' early diagnosis is critical to allow specialized and multidisciplinary care, with a necessary interaction between the health and social sectors. Up to now, the management of genetic obesity was only based, above all, on controlling the patient's environment, which involves limiting access to food, ensuring a reassuring daily eating environment that limits impulsiveness, and the practice of adapted, supported, and supervised physical activity. Bariatric surgery has also been undertaken in genetic obesity cases with uncertain outcomes. The context is rapidly changing, as new innovative therapies are currently being tested both for syndromic and monogenic forms of obesity. This review focuses on care management and new therapeutic opportunities in genetic obesity, including the use of the melanocortin 4 agonist, setmelanotide. The results from ongoing trials will hopefully pave the way to a future precision medicine approach for genetic obesity.

Exposure to high ambient temperatures (HAT) is associated with increased mortality, weight loss, immunosuppression, and metabolic malfunction in birds, all of which are likely downstream effects of reduced food intake. While the mechanisms mediating the physiological responses to HAT are documented, the neural mechanisms mediating behavioral responses are poorly understood. The aim of the present study was thus to investigate the hypothalamic mechanisms mediating heat-induced anorexia in four-day old broiler chicks. In Experiment 1, chicks exposed to HAT reduced food intake for the duration of exposure compared to controls in a thermoneutral environment (TN). In Experiment 2, HAT chicks that were administered an intracerebroventricular (ICV) injection of neuropeptide Y (NPY) increased food intake for 60 min post-injection, while TN chicks that received NPY increased food intake for 180 min post-injection. In Experiment 3, chicks in both the TN and HAT groups that received ICV injections of corticotropin-releasing factor (CRF) reduced food intake for up to 180 min post-injection. In Experiment 4, chicks that were exposed to HAT and received an ICV injection of astressin ate the same as controls in the TN group. In Experiment 5, chicks exposed to HAT that received an ICV injection of α-melanocyte stimulating hormone reduced food intake at both a high and low dose, with the low dose not reducing food intake in TN chicks. In Experiment 6, there was increased c-Fos expression in the hypothalamic paraventricular nucleus (PVN), lateral hypothalamic area (LHA), and the nucleus of the hippocampal commissure (NHpC). In Experiment 7, exposure to HAT was associated with decreased CRF mRNA in the NHpC, increased CRF mRNA in the PVN, and decreased NPY mRNA in the arcuate nucleus (ARC). In sum, these results demonstrate that exposure to HAT causes a reduction in food intake that is likely mediated via downregulation of NPY via the CRF system.

Proopiomelanocortin (POMC) is a neuropeptide precursor produced in the anterior and intermediate pituitary lobes, the hypothalamic arcuate nucleus (ARC), and solitary tract nucleus. Alpha-melanocyte-stimulating hormone (α-MSH) is a cell type specific POMC derivative that is essential for regulating feeding, and energy homeostasis. However, the molecular mechanism underlying POMC/α-MSH secretion remains unclear. Ca2+-dependent activator protein for secretion 2 (CAPS2) is a regulatory protein involved in the exocytosis of dense-core vesicles containing neuropeptides. We previously reported CAPS2 localization in the intermediate pituitary lobe and reduced body weights in Caps2-knockout (Caps2-KO) mice, compared to control mice. Here, we aimed to investigate CAPS2 expression in POMC-expressing neurons and the effects of CAPS2 deficiency on the secretion of POMC-related peptides and feeding behavior phenotype. CAPS2 was localized in the POMC-expressing neurons of the intermediate pituitary lobe, hypothalamic ARC, and the paraventricular nucleus, which is innervated by hypothalamic neurons. POMC protein levels in the intermediate pituitary lobe of Caps2-KO mice were significantly higher than that in the control mice, suggesting a possible accumulation of POMC-derived peptides in the intermediate pituitary lobe of Caps2-KO mice. Moreover, administration of low-dose melanotan-2, an α-MSH receptor (MC4R) agonist, decreased food intake per body weight in Caps2-KO mice; no such effect was observed in the wildtype mice. Collectively, these results suggest that CAPS2 is involved in regulating the secretion of POMC-derived peptides, including α-MSH, is partially associated with feeding, and affects energy metabolism.

The aim of this study was to investigate the association between the magnitude of weight loss (WL) and serum concentrations of the main adipocytokines and appetite-regulating hormones in adolescents with obesity.After completion of informed consent,108 adolescents with obesity (14-19 y of age; postpubertal) were submitted to clinical, nutritional, psychological, physical exercise, and physiotherapy support for 1 y. Body composition (BC) and plasma levels of neuropeptides (neuropeptide Y [NPY], agouti-related peptide [AgRP], and α-melanocyte-stimulating hormone [α-MSH]) and leptin were measured at baseline and post-intervention.After therapy, adolescents who lost10% body weight and10% body weight (were compared. Both groups presented improvements in BC and reduced leptin. The Δα-MSH, Δα-MSH/AgRP ratio, and Δα-MSH/NPY ratio were lower and AgRP and NPY variations were higher in the low weight loss group. The leptin concentration was close to normal in the high weight loss only. The ΔWeight, Δα-MSH and Δleptin were associated with body fat loss by multiple linear regressions for all samples.Weight loss10% seems to reverse obesity-induced hyperleptinemia while stabilizing the neuropeptides that control appetite in adolescents with obesity. We were able to produce a prognostic mathematical model to predict body fat loss using weight, leptin, and α-MSH variations.

Adverse energy states exert a potent suppressive influence on the reproductive axis by inhibiting the pulsatile release of gonadotrophin-releasing hormone and luteinising hormone. One potential mechanism underlying this involves the metabolic-sensing pro-opiomelanocortin and agouti-related peptide/neuropeptide Y (AgRP/NPY) neuronal populations directly controlling the activity of the arcuate nucleus kisspeptin neurones comprising the gonadotrophin-releasing hormone pulse generator. Using acute brain slice electrophysiology and calcium imaging approaches in Kiss1-GFP and Kiss1-GCaMP6 mice, we investigated whether NPY and α-melanocyte-stimulating hormone provide a direct modulatory influence on the activity of arcuate kisspeptin neurones in the adult mouse. NPY was found to exert a potent suppressive influence upon the neurokinin B-evoked firing of approximately one-half of arcuate kisspeptin neurones in both sexes. This effect was blocked partially by the NPY1R antagonist BIBO 3304, whereas the NPY5R antagonist L152,804 was ineffective. NPY also suppressed the neurokinin B-evoked increase in intracellular calcium levels in the presence of tetrodotoxin and amino acid receptor antagonists, indicating that the inhibitory effects of NPY are direct on kisspeptin neurones. By contrast, no effects of α-melanocyte-stimulating hormone were found on the excitability of arcuate kisspeptin neurones. These studies provide further evidence supporting the hypothesis that AgRP/NPY neurones link energy status and luteinising hormone pulsatility by demonstrating that NPY has a direct suppressive influence upon the activity of a subpopulation of arcuate kisspeptin neurones.

Background Although the Melanocortin-4 Receptor (MC4R) gene rs17782313 C/T has been consistently related to obesity risk, the interaction between MC4R polymorphism and diet quality indices on cardio-metabolic risk factors has not yet investigated. Therefore we aimed to test this hypothesis. Methods This cross-sectional study recruited 188 (96 males and 92 females) healthy obese adults aged 20–50 years. Diet quality indices including Healthy Eating Index-2015 (HEI-2015) and Diet Quality Index-International (DQI-I) were constructed using data from a validated food frequency questionnaire. MC4R s17782313 were genotyped by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). The interaction between MC4R polymorphism and diet quality indices was tested by Analysis of covariance (ANCOVA) multivariate interaction model. Results There were significant gene-diet interactions between rs17782313 and HEI-2015 (P Interaction P Interaction Conclusion Our study showed that MC4R rs17782313 interacts with adherence to the dietary quality indices (HEI and DQI-I) to influence several cardio-metabolic risk factors in obese male and females. Further large prospective studies are warranted to confirm our findings.

The steady increase in the prevalence of obesity and associated type II diabetes mellitus is a major health concern, particularly among children. Maternal obesity represents a risk factor that contributes to metabolic perturbations in the offspring. Endoplasmic reticulum (ER) stress has emerged as a critical mechanism involved in leptin resistance and type 2 diabetes in adult individuals. Here, we used a mouse model of maternal obesity to investigate the importance of early life ER stress in the nutritional programming of this metabolic disease. Offspring of obese dams developed glucose intolerance and displayed increased body weight, adiposity, and food intake. Moreover, maternal obesity disrupted the development of melanocortin circuits associated with neonatal hyperleptinemia and leptin resistance. ER stress-related genes were up-regulated in the hypothalamus of neonates born to obese mothers. Neonatal treatment with the ER stress-relieving drug tauroursodeoxycholic acid improved metabolic and neurodevelopmental deficits and reversed leptin resistance in the offspring of obese dams., Maternal obesity predisposes offspring to develop obesity and type 2 diabetes in later life, but the mechanisms are unclear. This study shows that the metabolic and hypothalamic defects associated with maternal obesity involve high levels of endoplasmic reticulum stress during critical periods of growth and development.

The use of hypnosis can generate hallucinatory phenomena, which ranged from vivid/auditory imagery to fully developed “hallucinations” in selected people. The aim of this pilot trial was investigating the acute effects of a hypnosis-induced hallucinated breakfast (HB) compared to those of a real breakfast (RB) on subjective appetite and appetite-regulating hormones in highly hypnotizable individuals. Eight healthy post-menopausal women were recruited to consume two meals: the HB and the RB in a randomized crossover design. Participants underwent appetite sensations measurements (before meal and each 30-min until 270-min) and blood sample collection (at 0, 20, 60, 90, 180-min). A 3-day food-record was filled after each meal. The adjusted repeated measures ANCOVA did not show any meal×time interactions on subjective appetite postprandially. As expected, significantly higher glucose (p < 0.001), insulin (p < 0.001), and lower free fatty acid (p < 0.001) concentrations were found after the RB, but not following HB. Furthermore, RB significantly increased postprandial levels of glucagon-like-peptide-1 and peptide-YY at 20, 60, 90 and 180-min, whereas acylated-ghrelin and leptin levels did not differ. Postprandial neuropeptide-Y and orexin-A values significantly increased at different time-points after RB, but not following HB, while α-melanocyte-stimulating hormone levels enhanced after HB only. Energy intakes were significantly lower after HB on the test-day only (HB = 1146.6 ± 343.8 vs RB = 1634.7 ± 274.2 kcal/d; p = 0.003). Appetite sensation might be modulated by fully developed meal “hallucination” induced by hypnosis, likely affecting brain-peptides implicated in the appetite regulation. However, further studies are needed to verify these results obtained in a highly selected group of individuals. NCT03934580.

Objective Hair greying (i.e., canities) is a component of chronological ageing and occurs regardless of gender or ethnicity. Canities is directly linked to the loss of melanin and increase in oxidative stress in the hair follicle and shaft. To promote hair pigmentation and reduce the hair greying process, an agonist of α-melanocyte-stimulating hormone (α-MSH), a biomimetic peptide (palmitoyl tetrapeptide-20; PTP20) was developed. The aim of this study was to describe the effects of the designed peptide on hair greying. Methods Effect of the PTP20 on the enzymatic activity of catalase and the production of H2 O2 by Human Follicle Dermal Papilla Cells (HFDPC) was evaluated. Influence of PTP20 on the expression of melanocortin receptor-1 (MC1-R) and the production of melanin were investigated. Enzymatic activity of sirtuin 1 (SIRT1) after treatment with PTP20 was also determined. Ex vivo studies using human micro-dissected hairs allowed to visualize the effect of PTP20 on the expression in hair follicle of catalase, TRP-1, TRP-2, Melan-A, ASIP, and MC1-R. These investigations were completed by a clinical study on 15 human male volunteers suffering from premature canities. Results The in vitro and ex vivo studies revealed the capacity of the examined PTP20 peptide to enhance the expression of catalase and to decrease (30%) the intracellular level of H2 O2 . Moreover, PTP20 was shown to activate in vitro and ex vivo the melanogenesis process. In fact, an increase in the production of melanin was shown to be correlated with elevated expression of MC1-R, TRP-1, and Melan-A, and with the reduction in ASIP expression. A modulation on TRP-2 was also observed. The pivotal role of MC1-R was confirmed on protein expression analysed on volunteer's plucked hairs after 3 months of the daily application of lotion containing 10 ppm of PTP20 peptide. Conclusion The current findings demonstrate the ability of the biomimetic PTP20 peptide to preserve the function of follicular melanocytes. The present results suggest potential cosmetic application of this newly designed agonist of α-MSH to promote hair pigmentation and thus, reduce the hair greying process.

Intraperitoneal administration of the melanocortin agonist melanotan II (MTII) to mice causes a profound, transient hypometabolism/hypothermia. It is preserved in mice lacking any one of melanocortin receptors 1, 3, 4, or 5, suggesting a mechanism independent of the canonical melanocortin receptors. Here we show that MTII-induced hypothermia was abolished in KitW-sh/W-sh mice, which lack mast cells, demonstrating that mast cells are required. MRGPRB2 is a receptor that detects many cationic molecules and activates mast cells in an antigen-independent manner. In vitro, MTII stimulated mast cells by both MRGPRB2-dependent and -independent mechanisms, and MTII-induced hypothermia was intact in MRGPRB2-null mice. Confirming that MTII activated mast cells, MTII treatment increased plasma histamine levels in both wild-type and MRGPRB2-null, but not in KitW-sh/W-sh, mice. The released histamine produced hypothermia via histamine H1 receptors because either a selective antagonist, pyrilamine, or ablation of H1 receptors greatly diminished the hypothermia. Other drugs, including compound 48/80, a commonly used mast cell activator, also produced hypothermia by both mast cell-dependent and -independent mechanisms. These results suggest that mast cell activation should be considered when investigating the mechanism of drug-induced hypothermia in mice.