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Rare variants in melanocortin 4 receptor gene (MC4R) result in a severe form of early-onset obesity; however, it is unclear how these variants may affect abdominal fat distribution, intrahepatic fat accumulation, and related metabolic sequelae. Eight hundred seventy-seven youth (6-21 years) with overweight/obesity, recruited from the Yale Pediatric Obesity Clinic in New Haven, CT, underwent genetic analysis to screen for functionally damaging, rare variants (MAF < 0.01) in MC4R. Participants were assigned to a Pathogenic Variant or No Pathogenic Variant group and completed a 10-timepoint 180-min oral glucose tolerance test (OGTT) and abdominal MRI. Compared to the No Pathogenic Variant group, the Pathogenic Variant group demonstrated significantly greater glucose concentrations (AUC Pathogenic variants in MC4R are associated with increased VAT, HFF%, and insulin resistance, independent from the degree of obesity in youth. Show less

E3 ubiquitin ligases play a crucial role in modulating receptor stability and signaling at the cell surface, yet the mechanisms governing their substrate specificity remain incompletely understood. Mahogunin Ring Finger 1 (MGRN1) is a membrane-tethered E3 ligase that fine-tunes signaling sensitivity by targeting surface receptors for ubiquitination and degradation. Unlike cytosolic E3 ligases, membrane-tethered E3s require transmembrane adapters to selectively recognize and regulate surface receptors, yet few such ligases have been studied in detail. While MGRN1 is known to regulate the receptor Smoothened (SMO) within the Hedgehog pathway through its interaction with the transmembrane adapter Multiple Epidermal Growth Factor-like 8 (MEGF8), the broader scope of its regulatory network has been speculative. Here, we identify Attractin (ATRN) and Attractin-like 1 (ATRNL1) as additional transmembrane adapters that recruit MGRN1 and regulate cell surface receptor turnover. Through co-immunoprecipitation, we show that ATRN and ATRNL1 likely interact with the RING domain of MGRN1. Functional assays reveal that MGRN1 requires these transmembrane adapters to ubiquitinate and degrade the melanocortin receptors MC1R and MC4R, in a process analogous to its regulation of SMO. Loss of MGRN1 leads to increased surface and ciliary localization of MC4R in fibroblasts and elevated MC1R levels in melanocytes, with the latter resulting in enhanced eumelanin production. These findings expand the repertoire of MGRN1-regulated receptors and provide new insight into a shared mechanism by which membrane-tethered E3 ligases utilize transmembrane adapters to dictate substrate receptor specificity. By elucidating how MGRN1 selectively engages with surface receptors, this work establishes a broader framework for understanding how this unique class of E3 ligases fine-tunes receptor homeostasis and signaling output. Show less

This study investigates the relationships between melanocortin-4 receptor (MC4R) rs17782313 gene polymorphisms, low-fat diet, aerobic exercise, and the reduction in blood lipid levels in individuals with obesity. A total of 240 adults living with obesity were enrolled to take part in a 12-week program that combined exercises with dietary interventions. Measurements taken included body weight, body mass index (BMI), plasma lipids, fasting insulin (FIN), and insulin resistance (Homeostasis Model Assessment, HOMA-IR). All participants underwent exercise intervention and genotyping. Our findings revealed significant interactions between genotype, sex, and diet in modulating lipid metabolism. Specifically, after the exercise intervention, the mean reduction in BMI in was: CC+CT with low-fat diet: -2.56 ± 1.98 kg/m The CC+CT genotype group, particularly males on a low-fat diet, showed robust improvements in TG, LDL-C, and insulin resistance markers. However, HDL-C responses were inconsistent across subgroups. Notably, males with the CC+CT allele exhibited the most pronounced benefits in LDL-C reduction and HOMA-IR improvement with a low-fat diet. Show less

The internal milieu of the body is controlled by a system of interoceptors coupled to motor outflows that drive compensatory adaptive responses. These include the arterial chemoreceptors, best known for sensing arterial oxygen. In cardiometabolic diseases, such as essential hypertension, the carotid bodies (CB) exhibit heightened reflex sensitivity and tonic activity without an apparent stimulus. The mechanisms behind CB sensitization in these conditions are not well understood. Guided by functional genomics, a range of functional assays is used to interrogate downstream intracellular and interorgan signaling pathways involved in arterial chemosensory function. Here, we report the presence of the MC4R (melanocortin 4 receptor) in the mammalian CB and show its elevated expression in experimental hypertension. We demonstrate that melanocortin agonists activate arterial chemosensory cells, modulating CB chemosensory afferent drive to influence chemoreflex-evoked sympathetic and ventilatory activity. Transcriptional analysis of hypertensive CB implicates the activation of the Mash1 (mammalian achaete-scute homolog 1; Collectively, our data indicate a primarily pathophysiological role of melanocortin signaling in arterial chemosensation, contributing to excess sympathetic activity in cardiometabolic disease. Show less

Obesity is a global health challenge marked by substantial inter-individual differences in responses to dietary and lifestyle interventions. Traditional weight loss strategies often overlook critical biological variations in genetics, metabolic profiles, and gut microbiota composition, contributing to poor adherence and variable outcomes. Our primary aim is to identify key biological and behavioral effectors relevant to precision medicine for weight control, with a particular focus on nutrition, while also discussing their current and potential integration into digital health platforms. Thus, this review aligns more closely with the identification of influential factors within precision medicine (e.g., genetic, metabolic, and microbiome factors) but also explores how these factors are currently integrated into digital health tools. We synthesize recent advances in nutrigenomics, nutritional metabolomics, and microbiome-informed nutrition, highlighting how tailored dietary strategies-such as high-protein, low-glycemic, polyphenol-enriched, and fiber-based diets-can be aligned with specific genetic variants (e.g., FTO and MC4R), metabolic phenotypes (e.g., insulin resistance), and gut microbiota profiles (e.g., Show less

Bardet-Biedl syndrome (BBS) is a rare, genetically heterogeneous, and highly pleiotropic autosomal recessive ciliopathy. Patients typically present with early loss of vision, hyperphagia, severe obesity, learning difficulties, and renal dysfunction. In patients with BBS, dysfunction of the immotile primary cilia in the hypothalamic melanocortin-4 receptor (MC4R) pathway responsible for controlling energy balance, hunger, and satiety results in severe hyperphagia manifesting in food-seeking behaviors that drive the development of obesity early in childhood. These behaviors have negative impacts on many areas of the lives of patients with BBS and their families/caregivers, including sleep, mood, school/work, and social/family relationships. Additionally, many patients feel stigmatized due to their hyperphagia-associated food-seeking behaviors and the resulting obesity, which exacerbates the impacts of hyperphagia on quality of life. Early identification and management of hyperphagia in patients with BBS is key: mitigating food-seeking and weight gain can improve quality of life and reduce the risk of metabolic and cardiovascular diseases that is increased in patients with BBS. Until recently, the only treatment strategies available were lifestyle and diet modifications. However, targeted treatment with the novel MC4R agonist setmelanotide now offers an effective management option to reduce hyperphagia and weight in patients with BBS, improving overall health and quality of life. Show less

Food addiction (FA) has gained more scientific attention but needs deeper understanding. Data indicates that the central melanocortin (MC) system through the MC4 receptor (MC4R) and its polymorphisms play a crucial role in the regulation of eating behaviour and in the motivation for the rewarding properties of food potentially leading to obesity. This may also contribute to the emergence of altered reward-related behaviors such as FA. The study aims to evaluate the genetic contribution of rs17782313, rs12970134, rs10871777, rs6567160, rs17700144 MC4R polymorphisms to the development of FA and to assess the association between these MC4R variations and clinical features. Eating (EDE-Q, BES, NEQ, GQ) and general psychopathology (BDI-II, STAI-S, DERS) were evaluated in patients with obesity with and without FA. Y-FAS 2.0 was used to assess FA. A blood sample was collected from all patients for the genotyping of MC4R polymorphisms. All the polymorphisms were equally distributed between groups except for rs17782313. A direct association between rs17782313 with FA was evident. Patients with FA and with C allele showed higher risk of FA compared to group without FA. There was a significant effect of rs17782313 on psychopathological variables in patients with FA. Allele C carriers exhibited higher anxiety and depression than T carriers. The rs17782313 of the MC4R showed an association with FA. A significant direct influence of C allele on anxiety and depression emerged in the group with FA but not in patients without FA. Show less

Adipokines regulate body weight and metabolism by targeting the hypothalamus, influencing feeding, energy expenditure (EE) and insulin sensitivity. Angiopoietin-like 2 (Angptl2) is a pro-inflammatory adipokine linking obesity to insulin resistance. Both Angptl2 and its receptor are expressed in the central nervous system. Yet, the contribution of Angptl2 to the regulation of energy metabolism and relevant hypothalamic neuropeptides in male and female mice is unknown. We aim at determining the impact of Angptl2 knockdown (KD) on energy balance, nutrient partitioning and hypothalamic responses to a standard (STD) or high-fat diet (HFD) in mice. Three-month-old male and female Angptl2-KD mice and wildtype (WT) littermates were fed 16 weeks either a STD or a HFD. Body weight, food consumption and insulin sensitivity were assessed along with measurements of EE, respiratory exchange ratio (RER) and locomotor activity. We quantified the expression of Angptl2 and its receptors itga5, mag and pirb in the medio-basal hypothalamus (MBH) of WT mice, and MBH neuropeptide Y (NPY), agouti-related neuropeptide (AgRP) and proopiomelanocortin (POMC) gene expression in both KD and control fasting mice. Lack of Angptl2 reduced food intake in males on both diets, and in females on HFD. In KD males, this anorexigenic effect was associated with lower body weight, increased EE, improved insulin sensitivity and lower hypothalamic orexigenic NPY expression compared to controls. Female Angptl2-KD mice however, exhibited unaltered body weight, EE and insulin sensitivity, and elevated NPY, AgRP and MC4R expression compared to controls. Fasting caused an increase in the MBH of mag expression in males and females but Angptl2 expression only in female mice. Angptl2 KD improved diet-induced obesity and associated metabolic dysfunction in male mice. The lack of similar changes in female mice and divergent MBH neuropeptide profile suggest that sex-dependent mechanisms underly the anabolic effects of this proinflammatory adipokine. Show less

Obesity is a multifactorial disease caused by an interaction between genetic, environmental and behavioral factors. Polymorphisms of the two genes Circadian Locomotor Output Cycles Kaput (CLOCK) rs1801260 and Melanocortin-4-receptor (MC4R) rs17782313, are associated with obesity. Knowledge is limited on the interaction between CLOCK, MC4R and obesity. The aim was to explore the interactions between the CLOCK and MC4R gene variants on markers related to obesity. There were 423 subjects with information on two genetic variants of two genes (CLOCK and MC4R). Their interaction was evaluated with: chronotype, sleeping duration, emotional eating, food timing, stress, dietary intake, appetite, physical activity (assessed by questionnaires), anthropometric measures of obesity (assessed by physical measurements), and also hormonal factors (assessed by ELISA). Generalized Linear Models were applied. Our results revealed that significant differences were observed between the genotypes of CLOCK rs1801260 for weight, Body Mass Index (BMI), Glucagon-like peptide-1 (GLP-1), cortisol, energy, fat, sleep duration, chronotype, appetite, depression, stress, emotional eating, physical activity, breakfast, lunch, and dinner time (p˂0.05). Also, significant differences were observed between the genotypes of MC4R rs17782313 for weight, BMI, Waist Circumference (WC), Waist to Hip Ratio (WHR), ghrelin, energy, carbohydrate, fat, appetite, depression, stress, breakfast time, and emotional eating (p˂0.05). Our findings also showed significant interactions between the CLOCK (CC)∗MC4R (CT) genotypes for higher appetite, stress and CLOCK (CT)∗ MC4R (CC) genotypes for higher fat and energy intake and CLOCK (CC)∗MC4R (CC) genotypes for higher weight, BMI, energy and fat intake, appetite, emotional eating, stress, ghrelin, cortisol and lower sleep duration and GLP-1 (p˂ 0.05). Due to the non-significance of the interaction in CLOCK (CT)∗ MC4R (CT) genotypes, it seems that the presence of a healthy arm in the CLOCK and MC4R polymorphism is necessary for the proper function of the genes. Thus, these results highlight that gene variants and their interaction should be considered in obesity assessment. Show less

Estrogens can modulate energy balance by regulating food intake and energy expenditure. Hayashi et al. revealed that hypothalamic neuroestrogens, especially E2 from aromatase Cyp19a1, regulate appetite and body weight. In ovariectomized mice, elevated hypothalamic Cyp19a1 and Mc4r expression coincided with reduced food intake and weight loss. Pharmacological or genetic disruption of aromatase in mice lowered Mc4r expression and increased food intake, whereas neuronal Cyp19a1 overexpression enhanced Mc4r expression and suppressed appetite, independent of leptin. Therefore, neuroestrogens critically maintain metabolic equilibrium, positioning aromatase-derived E2 as a promising anti-obesity target. Show less

Obesity and its associated intestinal inflammatory responses represent a significant global challenge. (IF) is a dietary intervention demonstrating various health benefits, including weight loss, enhanced metabolic health, and increased longevity. However, its effect on the intestinal inflammation induced by high-fat diet (HFD) is still not fully comprehended. Thirty-four male Sprague-Dawley rats were randomized into three groups: Control (fed standard chow diet for 24 weeks); the HFD group (fed HFD for 24 weeks); and the HFD + IF group (fed HFD for 12 weeks, followed by an alternate day regimen of fasting and HFD for 12 weeks). The results revealed that IF significantly reduced body weight, food intake, and blood glucose levels compared to the HFD group. Furthermore, rats undergoing the intermittent fasting regimen exhibited a significant reduction in resting time, along with increased durations of grooming and exploration when compared to those on HFD. IF significantly reduced HFD-induced intestinal oxidative stress by lowering malondialdehyde levels and substantially increasing intestinal total antioxidant capacity, consistent with histopathological findings of gastric and intestinal tissues. The investigation of the underlying mechanisms revealed that IF significantly increased the intestinal expression of Farnesoid X receptor (FXR), glucagon-like peptide 1 (GLP-1), and melanocortin-4 receptors (MC4R), with a significant decrease in gastrointestinal peroxisome proliferator-activated receptor-γ (PPAR-γ) compared to the HFD group. The findings indicate that IF can mitigate HFD-induced intestinal inflammation via the FXR/GLP-1/MC4R/ PPAR-γ pathway. This highlights the need for further research to elucidate these mechanisms. Show less

Leptin, a key adipokine regulating energy homeostasis, has been extensively studied for its potential in the management of obesity. However, its therapeutic efficacy is often limited due to leptin resistance. This review synthesizes animal and clinical evidence on leptin's role in obesity, focusing on models such as genetically deficient mice (e.g., ob/ob, db/db), diet-induced obesity mice, and clinical conditions such as congenital leptin deficiency (CLD), leptin receptor deficiency (LRD), lipodystrophy, and common obesity. The mechanisms underlying leptin resistance are summarized, including hyperleptinemia, impaired JAK2-STAT3 signaling, reduced blood-brain barrier permeability, defective autophagy, endoplasmic reticulum stress, inflammation, decreased leptin receptor expression, leptin signaling pathway dysfunction, increased mTOR activity, and peripheral leptin resistance. Due to these leptin receptor and/or post-receptor signaling pathway defects, leptin or its analogs usually fail to produce the expected weight-loss effect in individuals with overweight or obesity, although they remain highly effective in individuals with CLD and lipodystrophy, as well as in ob/ob mice. Alternative strategies, such as melanocortin-4 receptor (MC4R) agonists (e.g., setmelanotide) for LRD treatment, are very promising. Future directions include enhancing leptin sensitization, combining leptin with other drugs, and exploring partial leptin reduction to mitigate compensatory responses during weight loss. The review emphasizes the complexity of leptin resistance and the necessity of targeted approaches in obesity therapy. Show less

Metabolic diseases, like type 2 diabetes mellitus and obesity, show a growing public health concern in Sri Lanka. Genetic predisposition and diet contribute to metabolic disease risk, but there are limited investigations into the impact of gene-diet interactions on metabolic disease risk in the Sri Lankan population. In this study, we examined whether a metabolic genetic risk score (GRS), constructed from 10 single nucleotide polymorphisms (SNPs), interacts with dietary factors to influence metabolic health indicators in Sri Lankan adults. This cross-sectional study included 105 generally healthy adults aged 25-50 years from the GOOD (Genetics of Obesity and Diabetes) study. Anthropometric, biochemical, and dietary data using food frequency questionnaires were collected using validated methods. Genotyping was performed using the KASP A statistically significant interaction was identified between the 10-SNP metabolic GRS and polyunsaturated fatty acid (PUFA) intake on waist circumference (P This study provides novel insights to understand gene-diet interactions affecting metabolic traits in Sri Lankans. The findings suggest that higher PUFA intake may mitigate genetic susceptibility to central obesity, highlighting the importance of personalized dietary recommendations for metabolic disease prevention. Further studies in larger cohorts are warranted to confirm this finding. Show less

Obesity stands out as the most common multifactorial nutritional problem affecting domestic cats. According to studies, the prevalence of overweight or obese cats varies between 11.5% and 63%. Various factors such as breed, age, gender, reproductive status, owner-pet relationship, diet type, and environmental factors have been identified as potential risk factors for the development of obesity in cats. Among the genes involved in regulating energy balance, one of the prominent genes is melanocortin-4 receptor gene (MC4R). A specific missense variant in the feline MC4R gene (c.92 C > T) has been associated with overweight in diabetic domestic shorthaired cats. In this study, it was aimed to determine the polymorphisms in MC4R gene in random bred cats and cats belonging to a registered breed in Turkey and to investigate their relationship with obesity. Blood samples from 30 obese and 20 non-obese cats were collected into sterile vacuum EDTA tubes. Exon 1 of the MC4R was amplified and sequenced. As a result of DNA sequence analysis, we identified a total of six SNPs in the feline MC4R gene, four of which were found for the first time in this study. As a result of comparing allele frequencies in obese and non-obese cats, a significant relationship was found between SNP rs783632116 and obesity. The results of regression analyses evaluating the effects of SNP genotypes, sex and infertility status on feline Body Mass Index (fBMI) indicated that non-synonymous SNPs rs783632116, ss11356259660 and ss11356259661 were significantly associated with fBMI. Show less

Osteoarthritis (OA) is a common progressive joint disorder marked by synovial inflammation, cartilage degeneration, the formation of osteophytes, though its underlying molecular mechanisms remain unclear. This study integrated bioinformatics and experimental validation to identify key genes in OA synovium and their association with immune infiltration. Analysis of the GSE82107 dataset (10 OA, 7 controls) revealed 909 differentially expressed genes (525 upregulated, 384 downregulated). WGCNA identified the "midnightblue" module, and its intersection with DEGs yielded 122 genes enriched in cytokine-cytokine receptor interaction, JAK-STAT signaling, and autophagy pathways. Protein-protein interaction analysis highlighted FLT3LG, MC4R, CXCL10, CARTPT, and LHX2 as core genes (AUC 0.743-0.871). Immune infiltration analysis showed elevated M0 macrophages in OA, with CXCL10 showing a strong positive correlation with M1 macrophage infiltration (r = 0.74), and MC4R correlating with the presence of follicular helper T cells (r = 0.85). In vitro, OA-derived fibroblast-like synoviocytes exhibited CXCL10 upregulation, MC4R downregulation, and increased IL-6, IL-8, and TNF-α secretion, which were markedly reduced by CXCL10 knockdown or MC4R overexpression. Synovial tissue assays confirmed these expression patterns. CXCL10 and MC4R may represent promising diagnostic markers and therapeutic targets, offering new insights into OA immunopathogenesis and precision intervention. Show less

We aimed to investigate whether genetic variants in the leptin-melanocortin system involved in anorexigenic signaling influence personality dimensions and psychopathological symptoms in eating disorders (ED) patients. The population consisted of 309 ED patients [221 with anorexia nervosa (AN) and 88 with bulimia nervosa (BN)] and 396 healthy controls. Patients underwent psychometric assessment using the Eating Disorders Inventory Test-2 (EDI-2) and the Symptom Checklist 90 Revised (SCL-90R) questionnaires. Fourteen tag-SNPs in the LEP, POMC, and MC4R genes, were determined. Drive for thinness (DT) was significantly affected by genetic variability. After correction for multiple testing, regression models showed that AN patients carrying the LEP rs11761556 CC variant genotype scored higher in this scale than AA/CA carriers did [mean difference = 4.43 (2.18-6.68), p < 0.001], although the significance was restrained to the restrictive subtype [4.92 (2.00-7.83), p = 0.001]. BN patients with the LEP rs10954173 AA genotype displayed lower scores [-8.7 (-12.31--3.91); p < 0.001]. Finally, gene-gene interaction analyses revealed two SNP pairs associated with body-mass index in AN patients (LEPrs3828942-POMCrs1009388, p < 0.001 and LEP rs11763517-POMCrs1009388, p = 0.002). Regarding DT scores, the POMCrs6545975-LEP11763517 SNP pair showed the strongest effect (p < 0.001) in AN. Genetic variants in the leptin-melanocortin system, may interact to influence personality dimensions in ED patients, which highlights the importance of considering genetic factors in the pathophysiology of these disorders. Show less

Maternal consumption of monosaccharides during pregnancy and lactation can program long-term metabolic and neurobehavioral outcomes in offspring. The melanocortin-4 receptor (MC4R) is a key regulator of metabolism and behavior. However, the impact of maternal monosaccharide diets on MC4R signaling within mesocorticolimbic regions remains unclear. In this study, we investigated the effects of maternal glucose (GLU) and fructose (FRU) diets on metabolic, molecular, and neurochemical outcomes in offspring. Adolescent and young adult male and female Wistar rat offspring, following maternal GLU and FRU exposure during pregnancy and lactation, underwent sucrose preference testing, intraperitoneal glucose tolerance tests, and serum lipid profiling. In addition, the gene expression of The maternal GLU diet reduced total calorie intake during lactation, while the FRU diet increased the dams’ caloric intake from sugar during both pregnancy and lactation. In the offspring, a maternal FRU diet increased sucrose consumption in young adult males and dysregulated glucose homeostasis in both adolescent and young adult males. Maternal monosaccharide diets also influenced serum lipid profiles and increased the body weights of their offspring. At the molecular level, region-, sex-, and age-specific changes in gene expression were observed, particularly the upregulation of These findings suggest that maternal monosaccharide diets induce persistent alterations in the metabolic profiles of offspring and MC4R signaling, potentially contributing to the development of programmed metabolic and behavioral outcomes. Not applicable. The online version contains supplementary material available at 10.1007/s43440-025-00785-8. Show less

Adamantinomatous craniopharyngioma (ACP) is a histologically benign but clinically aggressive tumor arising from Rathke's pouch remnants, which is molecularly distinct from the other subtype, papillary craniopharyngioma (PCP). Despite advancements in surgery and radiotherapy, treatment outcomes remain unsatisfactory due to the tumor's invasiveness and resistance to conventional therapies. This review systematically examines the molecular pathogenesis of ACP and evaluates current and emerging therapeutic strategies to improve clinical management. ACP is driven by CTNNB1 mutations and dysregulated Wnt/β-catenin signaling, alongside inflammatory and senescence-associated pathways. Current pharmacological approaches, including interferon-α, IL-6 inhibitors (e.g., tocilizumab), and intracystic agents (e.g., bleomycin), exhibit limited efficacy. Promising emerging therapies target the angiogenesis (e.g., bevacizumab) and MAPK/ERK pathway, which is activated by somatic BRAF V600E mutations in PCP, has been successfully targeted with BRAF/MEK inhibitors, demonstrating significant efficacy in the majority of treated PCP patients. whereas immune checkpoint inhibitors and SHH pathway modulators face significant challenges. Additionally, ACP-related endocrine dysfunction and hypothalamic obesity require tailored interventions, such as GLP-1 receptor agonists and MC4R-targeted therapies. Precision medicine, informed by molecular subtyping and multi-omics data, holds transformative potential for ACP treatment. Future strategies should focus on combinatorial therapies to address tumor heterogeneity, microenvironment modulation, and senolytic approaches. Collaborative multidisciplinary efforts are crucial to translating these insights into clinical practice, ultimately enhancing patient outcomes and quality of life. Show less

Hypothalamic pro-opiomelanocortin (POMC) neurons are classically viewed as mediators of satiety, acting in response to metabolic and hormonal cues and in opposition to Agouti-related protein (AgRP) neurons to maintain energy balance. This model, centered on the appetite-suppressant effects of the POMC-derived neuropeptide α-melanocyte-stimulating hormone (α-MSH) through its activation of melanocortin-4 receptors (MC4R), has shaped our understanding of feeding and body weight regulation for decades. However, recent discoveries have challenged and expanded this traditional view, revealing that POMC neurons are not a uniform population dedicated solely to satiety control. Single-cell transcriptomic analyses have revealed striking molecular heterogeneity, reflected in distinct anatomical distributions, receptor expression profiles, electrophysiological properties, and projection patterns - all supporting the idea of functional specialization within this neuronal population. In this review, we propose a conceptual framework that integrates POMC neuronal heterogeneity with the regulation of appetite, metabolic physiology, and behavior beyond feeding. We highlight emerging evidence showing that discrete POMC neuronal subpopulations respond to specific combinations of interoceptive and environmental cues to orchestrate diverse adaptive responses. This perspective underscores the developmental plasticity and functional versatility of POMC neurons, offering new insights into the mechanisms of obesity and potentially paving the way for novel targeted therapeutic strategies. Show less

The central melanocortin system, composed of peptides derived from pro-opiomelanocortin (POMC) such as the melanocyte-stimulating hormones (α-, β-, γ-MSH) and melanocortin 4 receptors (MC4R), along with the agouti-related protein (AgRP), plays a pivotal role in controlling energy balance. To elucidate the dynamic role of α-MSH release in regulating appetite, specific, sensitive, and spatiotemporally resolved genetic sensors are required. The melanocortin 1 receptor (MC1R) scaffold was leveraged for its robust plasma membrane expression, high affinity for melanocortins and low affinity for AgRP to design a α-MSH selective sensor for in vivo use. This was achieved by integrating circularly permuted green fluorescent protein (cpGFP) into the receptor, which we named Fluorescence Amplified Receptor sensor for Melanocortin (FLARE The FLARE FLARE Show less

Mammalian opsin 3 (OPN3) is a member of the opsin family of G-protein-coupled receptors with ambiguous light sensitivity. OPN3 was first identified in the brain (and named encephalopsin) and subsequently found to be expressed in other tissues. In adipocytes, OPN3 is necessary for light responses that modulate lipolysis and glucose uptake, while OPN3 in human skin melanocytes regulates pigmentation in a light-independent manner. Despite its initial discovery in the brain, OPN3 functional mechanisms in the brain remain elusive. Here, we investigated the molecular mechanism of OPN3 function in the paraventricular nucleus (PVN) of the hypothalamus. We show that Show less

The melanocortin receptors are a class of centrally and peripherally expressed G protein-coupled receptors, of which the MC3R and MC4R subtypes are implicated in the regulation of appetite and energy homeostasis and can serve as potential therapeutic targets for disorders such as obesity and cachexia. An unbiased high-throughput mixture-based library screen was implemented to identify novel ligands with an emphasis on the identification of nanomolar-potent agonists of the mouse melanocortin-3 receptor. This screen yielded the discovery of an N-branched tricyclic guanidine scaffold (TPI2408) that contained three nanomolar potent mMC3R agonists and additional compounds that possessed antagonism for the mMC4R. The antagonist character of this scaffold library at the mMC4R was confirmed by a follow-up positional scanning antagonist screen. Additionally, molecular dynamics simulations herein provide mechanistic insight into the polypharmacological characteristics of melanocortin receptors. The disclosed materials have the potential to serve as important tools and SAR scaffolds in the study of melanocortin receptor function. Show less

Obesity-related genetic disorders are marked by severe, early-onset obesity caused by mutations that disrupt key biological mechanisms regulating hunger, energy balance, and fat storage. These disorders commonly impact systems such as the hypothalamic leptin-melanocortin signaling network, which plays a crucial role in controlling appetite and body weight, mainly through the melanocortin-4 receptor (MC4R) pathway. This review explores current management strategies and emerging therapies for genetic obesity disorders, highlighting the importance of treatment approaches and expanded genetic diagnostics to improve outcomes for affected individuals. Show less

Obesity and weight regulation disorders are determined by the combined effects of genetics and environment. Polygenic obesity results from the combination of common variants in several genes which predisposes the individual to obesity and its related complications. In contrast, monogenic obesity results from changes in single genes, especially those in leptin-melanocortin pathway, and presents with early onset severe obesity, with or without other syndromic features. Rare variants in melanocortin 4 receptor are the commonest form of monogenic obesity. In addition, structural variation in small or large segments of chromosomes may also present with syndromic forms of obesity. Prader-Willi Syndrome, caused by imprinting errors in chromosome 15q11-13, is the most prevalent genetic cause of severe hyperphagia and obesity. With the advances in technologies, the past decade has witnessed a revolution in the identification of novel genetic causes of obesity, primarily in genes related to the leptin melanocortin pathway. The availability of safe melanocortin analogs holds the potential for targeted therapies for some of these disorders. This review summarizes known and novel rare genetic forms of obesity, along with approaches for the clinical investigation of copy number and sequence variants. The goal is to provide a reference for practicing clinicians to encourage genetic testing in obesity. IMPACT: What does this article add to the existing literature? Genetic obesity is an expanding frontier with potential to change management. Here, we summarize current information on the genetic causes of obesity and provide guidance for genetic testing. Emerging treatments may provide targeted precise treatment and change management practices. Show less

During the periparturient period, dairy cows experience negative energy balance due to reduced feed intake, leading to adipose tissue breakdown, liver damage, and fat accumulation. This study examined the gut-liver-brain axis to explore the link between fatty liver disease, changes in hypothalamic appetite-related neurons, and microbiome shifts in dairy cows. Thirty cows were monitored, with daily DMI recordings and blood sampling. Postpartum brain, liver, and ileal contents were collected from 10 selected cows, divided into two groups: H-DMI (slight DMI decrease) and L-DMI (severe DMI decrease). The L-DMI group of cows exhibited higher plasma NEFA, BHBA, ALT, and AST levels, along with severe hepatic steatosis and lipid accumulation. Transcriptome sequencing of the hypothalamic arcuate nucleus (ARC) revealed decreased expression of Hypocretin Neuropeptide Precursor (HCRT), orexin-A (OX-A), Orexin Receptor Type 1 (OX1R), and Cannabinoid Receptor 1 (CB1) in the L-DMI group, while Pro-opiomelanocortin (POMC) and Melanocortin 4 Receptor (MC4R) expression increased. Metagenomic analysis of ileal contents showed reduced abundance of Ruminococcus spp. in the L-DMI group, which may be associated with fatty liver disease (FL). Integrated omics analysis showed that increased MC4R expression was correlated with the elevated abundance of bacteria such as Akkermansia glycaniphila, and reduced abundance of species such as Methanobrevubacter thaueri and Ruminococcus spp. Decreased HCRT expression was also linked to Akkermansia glycaniphila. In conclusion, these changes may affect DMI through the OX-A/POMC pathway, with neurological and gut microbiome alterations potentially leading to appetite suppression, negative energy balance, and the development of fatty liver disease. Show less

Setmelanotide, a melanocortin-4 receptor (MC4R) agonist, has been shown to reduce hunger and weight in patients aged 6 years and older with proopiomelanocortin (POMC) deficiency (including biallelic variants in proprotein convertase subtilisin/kexin type 1 [PCSK1]), leptin receptor (LEPR) deficiency, or Bardet-Biedl syndrome (BBS). No approved therapies for patients younger than 6 years old currently exist. The phase 3, open-label VENTURE trial aimed to evaluate the efficacy and safety of setmelanotide in patients aged 2-5 years with POMC or LEPR deficiency or BBS. This phase 3, open-label, multicentre trial, conducted across six sites in the USA, the UK, Spain, and Australia, enrolled eligible patients aged 2-5 years who had hyperphagia and obesity due to biallelic POMC (including PCSK1) or LEPR variants or genetically confirmed BBS. Open-label subcutaneous setmelanotide was administered once daily for 52 weeks, starting at 0·5 mg with doses increasing every 2 weeks in 0·5 mg increments until reaching the maximum dose based on weight. The co-primary endpoints at week 52 were the percentage of patients reaching a 0·2-point decrease or greater in BMI Z score (a statistical measure used to assess BMI in paediatric patients considering a patient's BMI and comparing it to reference values for the same age and sex) and mean percent change in BMI. Additional endpoints measured safety, hunger, weight-related outcomes, and caregiver burden. The study is registered at ClinicalTrials.gov (NCT04966741) and is complete. Between March 8, 2022, and Sept 18, 2023, 13 patients were screened at the six sites, and 12 patients were enrolled in the study (seven with POMC or LEPR and five with BBS); one patient with BBS was excluded as their BMI was not at the 97th percentile or above. Of the 12 patients enrolled, most were male (seven [58%] vs five [42%] for female) and the mean age was 3·6 years (SD 0·9). 11 patients completed the trial. Ten (83%) of the 12 overall participants reached a 0·2-point reduction or more in BMI Z score per WHO methodology at week 52 (95% CI 58·7-99·8). The mean percent change in BMI from baseline at week 52 was -18% (SD 13) in the overall safety population. Mean percent change in BMI at week 52 was -26% (SD 11) in patients with POMC or LEPR deficiency and -10% (9) in patients with BBS. Mean reductions in secondary endpoints of BMI Z score (3·4 [2·5]) and percent of the BMI 95th percentile (32·5 [22·9]) were seen at Week 52. 91% of caregivers reported that patients were less hungry than at baseline. All adverse events were mild or moderate; skin hyperpigmentation, vomiting, nasopharyngitis, upper respiratory tract infection, and injection site reactions were most common. No serious adverse events or adverse events leading to study discontinuation or death were reported. To our knowledge this is the first trial of setmelanotide in patients younger than 6 years old. These results support the benefit of the drug as an early intervention to manage obesity in this population. Rhythm Pharmaceuticals. Show less