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Non-olfactory G-protein-coupled receptors (GPCRs) regulate vital physiological functions and are targets for ∼34% of US Food and Drug Administration (FDA)-approved drugs. While small-molecule-activated GPCRs are well studied, there is growing interest in peptide GPCRs, particularly the melanocortin-4 receptor (MC4R), a key regulator of energy balance and appetite. Activation of MC4R by β-melanocyte-stimulating hormone (β-MSH) reduces food intake, and pathway dysfunction leads to obesity. However, current methods to study GPCR-peptide interactions are resource intensive and low throughput. To address this, we developed a high-throughput cell surface peptide display platform with a β-arrestin-based MC4R reporter to screen over 2,000 β-MSH point mutants. This approach identified peptide variants that significantly impact MC4R activation, including a novel D5H mutant with enhanced receptor activation. Our results demonstrate a scalable method to directly link GPCR activation to peptide variants, offering insights for therapeutic peptide design. Show less

The magnitude of weight reduction in the SURMOUNT-1 trial of the dual GLP-1 and GIP receptor agonist tirzepatide suggests that this treatment may be particularly effective in addressing the treatment needs of people with severe obesity (body mass index >40 kg m Show less

Hyperphagia is a hallmark of both congenital and acquired rare melanocortin-4 receptor (MC4R) pathway diseases. Currently, the medical community has no standard treatment guidelines or approach to establishing treatment benefit. This narrative review discusses current understandings of the pathophysiology, burden, and treatment of hyperphagia and summarizes findings from a systematic literature review of validated instruments for assessing the response to hyperphagia treatment. Hyperphagia can result from dysfunction within, or damage impacting, hypothalamic pathways including the MC4R pathway, a key regulator of energy balance. The burden of hyperphagia is substantial, with negative effects experienced across physiologic, emotional, and social domains. Approaches for hyperphagia management include environmental control, lifestyle intervention, pharmacotherapy, neurocognitive approaches, and neurostimulation. There are varied approaches to determine treatment response; however, standard methodology has not been determined and largely relies on questionnaires. Studies of rare MC4R pathway diseases have improved understanding of the etiology of hyperphagia and established the need for indication-specific treatment. Targeted treatments are limited, and methods for determining treatment efficacy are varied. There is a need for consensus guidelines to establish a standard approach for the management of hyperphagia and related assessment of treatment response to improve patient morbidity. Show less

Sarcopenia and frailty are complex geriatric syndromes influenced by a combination of genetic and environmental factors. Recent studies suggest that specific genetic variants, DNA methylation patterns and shortened telomeres are associated with age-related diseases and might contribute to the development of both sarcopenia and frailty. In this study, we investigated the contribution of multi-omics data to sarcopenia, frailty, lean mass index (LMI) and handgrip strength in an elderly Lithuanian population. A total of 204 participants (age 82.2 ± 7.6 years) were included, comprising 122 individuals diagnosed with sarcopenia and/or frailty and 82 healthy, community-dwelling older adults. The results showed that LMI was associated with various health and lifestyle factors. Two genetic variants, CLIC5 rs75652203 and GHITM rs17102732, were found to be significantly associated with handgrip strength at the genome-wide level. Additionally, 12 polymorphisms previously linked to sarcopenia were replicated in relationship to LMI: BOK rs76993203, VAMP5 rs1374370, TMEM18 rs12714414, SFMBT1 rs36033494, BANK1 rs13136118, TET2 rs2647239, FOXO3 rs9384679, L3MBTL3 rs13209574, ZFAT rs13267329, CEP57 rs35793328, PCGF2 rs1985352 and MC4R rs66922415. Furthermore, several genes, many of which are involved in immune system processes, were significantly enriched with differentially methylated sites associated with LMI. Shorter telomeres were also associated with both sarcopenia and frailty. Notably, a significant relationship was observed between telomere length and methylation levels in genes related to lifestyle traits and the risk of developing these conditions. These findings provide new insights into the biological mechanisms underlying sarcopenia and frailty, underscoring the important roles of genetic and epigenetic factors in their pathogenesis among older adults. 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

The melanocortin-4 receptor is a G protein-coupled receptor and a key regulator of appetite and metabolism. It can interact with the melanocortin-receptor accessory protein 2, a single transmembrane helix protein known to interact with several different G protein-coupled receptors. However, the consequences of this interaction are not completely understood. Here we report that co-expression of melanocortin-receptor accessory protein 2 has multiple effects on the melanocortin-4 receptor: it enhances G protein-mediated signaling and simultaneously impairs β-arrestin2 recruitment and, consequently, internalization. In addition, co-expression of melanocortin-receptor accessory protein 2 leads to an increased number of monomers of melanocortin-4 receptor by disrupting receptor oligomers. A structural homology model of the active state melanocortin-4 receptor - melanocortin-receptor accessory protein 2 - Gα 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

BackgroundStress is a major trigger for migraine attacks. Stress activates the hypothalamic-pituitary-adrenal (HPA) axis, releasing glucocorticoids (GCs) to maintain homeostasis, and migraine attacks may occur as an adverse effect of this response. We previously demonstrated in a mouse model that inhibiting corticosterone (CORT) synthesis by administering metyrapone before stress prevented stress-induced migraine-like behaviors. Given the unpredictable nature of stressors and their onset or termination, it is critical to better understand the adaptive and maladaptive effects of the HPA stress response. Here, we aimed to evaluate the effects of HPA axis modulation following the end of stress exposure.MethodsRepeated stress induces migraine-like behaviors and priming to sodium nitroprusside (SNP) in mice. Metyrapone (to inhibit CORT synthesis), CORT (to evaluate its effects after exogenous administration), and adrenocorticotropic hormone (ACTH) (to test the effects of a hormone upstream to CORT) were administered post-stress. Additionally, α-melanocyte-stimulating hormone (α-MSH, an ACTH cleavage product) and tetrahydroisoquinoline (THIQ), a melanocortin 4 receptor (MC4R) agonist, were administered to examine melanocortin receptor involvement. Facial hypersensitivity was assessed via von Frey testing and grimace scoring was used to evaluate non-evoked pain. Serum CORT levels were measured in both control and stressed mice following ACTH administration.ResultsWe examined post-stress HPA axis modulation on stress-induced facial hypersensitivity. Metyrapone reduced acute-phase hypersensitivity and reduced priming to SNP, suggesting sustained synthesis of CORT after stress plays a role in development of migraine-like behavior. Surprisingly, both CORT and ACTH treatments at 1- and 24-h post-stress alleviated stress-induced behaviors and priming. To determine if ACTH effects were mediated by an elevation in circulating CORT, metyrapone was administered before the ACTH injection. Metyrapone increased the ACTH reversal of stress effects on facial hypersensitivity. Furthermore, post-stress ACTH injections significantly increased serum CORT levels within 30 min. In addition to ACTH effects on CORT levels, ACTH effects could be mediated by the melanocortin system. Post-stress administration of α-MSH or the MC4R agonist THIQ, reduced migraine-like behaviors.ConclusionsThere is a complex relationship between stress, the HPA axis, and melanocortin signaling, in the effects of repeated stress exposure on migraine-like behaviors. In the early post-stress response phase, there are contributions from both CORT and MC4R signaling in the maintenance of behavioral effects. These findings suggest that targeting the HPA axis and MC4R after stress may be a potential therapeutic approach for stress-induced migraine attacks. Show less

Disruptive eating behaviors can negatively impact psychological well-being and increase the risk of metabolic diseases such as obesity, type 2 diabetes, and cardiovascular disease. While behavioral strategies remain central to dietary interventions, emerging research highlights genetic factors, particularly single nucleotide polymorphisms (SNPs), as contributors to individual differences in eating behaviors. This scoping review maps existing research on genetic modifiers of adult eating behaviors, identifying key variants and genetic predispositions. An extensive systematic search was conducted across 12 electronic databases, including PubMed, MEDLINE, and EMBASE, alongside relevant grey literature. Sixty-five studies published from 2014 to April 2024 met inclusion criteria. Data were synthesized using Covidence and NVivo for thematic mapping. Studies were eligible if they utilized genotyping to examine genetic markers, variations, or SNPs in relation to adult eating behaviors using validated questionnaires and/or dietary interventions. Six key themes emerged: taste perception; appetite and satiety; emotional eating; disinhibition; food timing and eating habits; and snacking, craving and binge eating. Frequently studied genes included CD36, MC4R, FTO, TAS1R, TAS2R, SLC4A5, SLC6A2, SLC6A4, DRD2, CLOCK, ADIPOQ and CA6, with some studies incorporating genetic risk scores. Across reviewed studies, there was a female predominance (female-to-male ratio of 1.6:1), while older adults were underrepresented (mean age: 35.2 ± 8.4 years). Cross-sectional study designs (58 %), highlighted a methodological gap, underscoring the need for longitudinal research to explore causality. This review provides valuable insights into the genetic underpinnings of eating behaviors and emphasizes the need for future research in more diverse populations to support precision nutrition strategies. 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

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

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

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

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

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

Energy expenditure (EE) is essential for metabolic homeostasis, yet its central regulation remains poorly understood. Here, we identify arcuate Kiss1 neurons as key regulators of EE in male mice. Ablation of these neurons induced obesity, while their chemogenetic activation increased brown adipose tissue (BAT) thermogenesis without affecting food intake. This action is mediated by glutamatergic projections from Kiss1 Show less

To clarify the possible mechanism of leptin and α-MSH on the onset of puberty in female offspring rats after prenatal androgen exposure. Sixteen 8-week-old specific pathogen free (SPF) healthy Sprague Dawley (SD) pregnant rats were randomly divided into the testosterone-treated group (TG, female offspring termed PNA group) or the olive oil control group (OOG, female offspring termed VEH group). The female offspring rats of two groups were raised to 21 days (PND21) and weaned. Six female offspring rats at PND21 (VEH:PNA = 3:3) were randomly selected for transcriptome sequencing. Twenty-seven offspring female rats were randomly divided into three groups (VEHI:VEHII:PNA = 9:9:9). VEHI group was observed until the onset of puberty, VEHII and PNA groups were observed until the 8th week. Compared with VEH group, onset of puberty was not observed in PNA group, and hypothalamic Pomc gene expression at PND21 was lower. Compared with the VEHI group, the body weight, abdominal fat, serum testosterone (T), dehydroepiandrosterone (DHEA) and leptin (LEP) levels were upregulated in the PNA group, while serum gonadotropin-releasing hormone (GnRH), mRNA of hypothalamic estrogen receptor α (ERα), α-melanocyte stimulating hormone (α-MSH), melanocortin receptor-4 (MC4R), GnRH and adipose AR, and the protein of androgen receptor (AR) and leptin receptor (LEPR) in the hypothalamic arcuate nucleus (ARC) were decreased. In the PNA group, there were positive correlations between serum DHEA and mRNA of hypothalamic ERα, MC4R and AR, negative correlations between mRNA of adipose AR and serum T and free testosterone (FT). Prenatal androgen exposure delayed the onset of puberty in female offspring, the possible mechanism of which is that prenatal androgen exposure may increase the levels of androgen and LEP, decreases their sensitivity and the expression of AR, LEPR, and MC4R, reducing GnRH secretion. Show less

There are no validated measures to assess hyperphagia associated with rare MC4R pathway diseases, such as Bardet-Biedl Syndrome (BBS). Symptoms of Hyperphagia© (SoH) and Impacts of Hyperphagia© (IoH) are novel questionnaires designed to assess signs and symptoms of hyperphagia and their impacts on patients and caregivers. We evaluated the psychometric performance of the caregiver-versions of the SoH: Caregiver (Observer-reported) and IoH: Caregiver (Observer-reported and Self-reported subscales). Reliability and validity were evaluated using data from a multi-country cross-sectional survey of adult caregivers of patients with BBS experiencing hyperphagia and obesity. Other instruments included were Impact of Weight on Quality of Life (IWQOL)-Kids (Parent Proxy), PROMIS Scale Global Health of Caregiver, Revised Impact on Family Scale (RIOFS), and Work Productivity and Activity Impairment. 242 eligible caregivers completed the survey. Exploratory factor analysis identified 1 factor per subscale. Strong internal consistency was observed for IoH: Caregiver (Observer) (Cronbach's a = 0.66) and IoH: Caregiver (Self) (a = 0.72) and moderate for SoH: Caregiver (Observer) (a = 0.40). Moderate-to-strong correlations were observed with school days missed and all domains of IWQOL-Kids except Physical Comfort (range = 0.315-0.573, p's < 0.001). Known-groups indicated significantly worse SoH: Caregiver subscores for patients using appetite suppressants or implementing more weight management approaches (6-10 vs. ≤5 or > 10). Caregivers reporting greater strain on RIOFS items and worse mental health had worse IoH subscores. The SoH: Caregiver and IoH: Caregiver demonstrated preliminary validity, reliability, and consistency in a real-world setting. Research is underway to further validate these measures for use in clinical trials for BBS and other MC4R pathway-related diseases associated with obesity. Show less

Setmelanotide is a recently approved medication for patients over two years of age with monogenic obesity that emerges from POMC, LEPR, PCSK1 mutations, or Bardet-Biedl syndrome. While primarily targeting melanocortin-4 receptors (MC4R), setmelanotide also weakly stimulates melanocortin-1 receptors (MC1R), which may affect pigmentation. Clinical outcomes of this treatment modality remain limited due to the rarity of disorders mentioned above. We present a 12-year-old boy with a homozygous LEPR mutation who experienced skin hyperpigmentation shortly after the initiation of setmelanotide treatment. By the third month of treatment, gradual darkening of nevi was noted. At six-month follow-up, two nevi were excised due to pigmentation changes, and histopathology revealed dysplastic features in both. This case raises concerns about potential MC1R-mediated melanocytic activity during setmelanotide treatment. Therapy was temporarily discontinued. To our knowledge, this is the first reported pediatric case with LEPR-related monogenic obesity developing dysplastic nevi during setmelanotide use. Show less

Cardiovascular diseases (CVDs), including myocardial infarction (MI), heart failure (HF), atrial fibrillation (AF), and arrhythmia, are major contributors to global mortality and often share overlapping risk factors and pathophysiological mechanisms. While genome-wide association studies (GWAS) have identified many loci for individual CVDs, the shared genetic architecture across related traits-particularly in East Asian populations-remains underexplored. We integrated large-scale GWAS summary statistics from East Asian populations to perform genome-wide and local genetic correlation analyses across four CVD phenotypes and five cardiometabolic traits (blood pressure and lipid levels). Using stratified LD score regression, we assessed tissue-specific heritability enrichment. Multi-trait analysis of GWAS (MTAG) was then employed to identify pleiotropic loci associated with multiple traits, with functional annotation and expression quantitative trait loci (eQTL) data used to explore biological relevance. We observed extensive genetic correlations among CVDs and between CVDs and cardiometabolic traits, with HF showing the strongest connections to both MI and arrhythmia. Notable genome-wide correlations were found between MI and SBP (rg = 0.35, Our findings provide comprehensive insight into the shared genetic determinants of cardiovascular and metabolic diseases in East Asian populations. The identification of pleiotropic and ancestry-specific loci, along with tissue-specific regulatory patterns, underscores the need for integrative multi-trait and population-informed approaches in cardiovascular genetics and risk prediction. Show less

Biallelic variants in the pro-opiomelanocortin gene (POMC) can cause hypocortisolism, hypopigmentation, and early-onset obesity. Following the identification of 2 patients of combined pituitary hormone deficiency (CPHD), we investigated the prevalence of this association among carriers of rare pathogenic or likely pathogenic (P/LP) POMC variants. This study is a case report and systematic literature review. Genetic analysis was conducted in a family with 2 cousins with childhood-onset obesity and CPHD. We assessed CPHD in carriers for biallelic pathogenic POMC variants using data from the literature and Human Gene Mutation Database. Clinical and biological data were collected, including pituitary axis involvement, obesity onset age, and pituitary imaging results. The 2 cousins, compound heterozygous for POMC variants, developed CPHD following initial hypocortisolism, with subsequent hypothyroidism, growth hormone deficiency, and hypogonadism. Among 41 patients with biallelic POMC variants identified in the literature, 20 had rare homozygous/compound heterozygous P/LP POMC variants and detailed endocrine evaluations. Of these, 40% presented with CPHD, always associated with early-onset severe obesity and hypocortisolism. Growth hormone deficiency was the most frequent (75%), followed by thyrotropic and gonadotropic deficiencies (62.5%). No anomalies were revealed in pituitary imaging. Two patients recovered the gonadotropic axis after treatment with the MC4R agonist. These findings underscore the potential for CPHD to occur in carriers of biallelic pathogenic POMC variants. Sequencing the full POMC, including coding and regulatory regions, is crucial in CPHD cases, alongside evaluating all pituitary axes in neonatal hypocortisolism. Beyond weight regulation, setmelanotide may modulate hypothalamic-pituitary function, with implications for fertility. Show less

Wernicke encephalopathy (WE) is a life-threatening neuropsychiatric disorder caused by thiamine deficiency (TD). One cause of TD is restrictive food intake. We present a girl with severe, treatment-resistant obesity from infancy due to hyperphagia caused by melanocortin 4 receptor (MC4R) deficiency. When aged 16 years, she presented at the emergency department with diplopia, headache, confusion, and ataxia. She had lost 25 kg in the previous 2 months because of anxiety-induced avoidant and restrictive food intake, despite persistent hyperphagia. Her anxiety had been triggered by a period of nausea and fear of vomiting. Neurological examination revealed horizontal and vertical nystagmus and bilateral abducens nerve palsy. Brain MRI showed typical lesions for WE, such as T2/fluid-attenuated inversion recovery hyperintensities in the medial thalamus, leading to a prompt diagnosis, which was later confirmed by a low thiamine value. Daily intravenous thiamine treatment resulted in significant neurological improvement within days. Her eating behavior gradually normalized with psychological support. This case is notable for the coexistence of hyperphagia and restrictive eating in a patient with MC4R deficiency, demonstrating that limited and restrictive food intake can occur even in the presence of monogenic obesity. This suggests complex interactions between hunger and fear pathways, warranting further research to better understand the pathophysiology of hyperphagia and identify new therapeutic targets for MC4R deficiency. Clinicians should consider WE, even in patients with (severe) obesity. Important signs are restrictive eating and neurological symptoms. Prompt thiamine therapy should be initiated when suspected. Show less

Amino acids in the brain modulate eating behavior and energy balance. The aim of the present study was to investigate the effects of DL-methionine (DL-Met), l-lysine monohydrochloride (L-Lys-HCl), and taurine (Tau) on feed intake and the mRNA expression levels of appetite-related hypothalamic neuropeptides in chicks. DL-Met, l-Lys-HCl, or Tau was intracerebroventricularly (ICV) administered to 5-day-old layer-type chicks, and the feed intake was recorded until 1 h post-injection. Quantitative PCR was performed to determine the hypothalamic mRNA expression levels of neuropeptide Y (NPY) and its receptors, agouti-related protein (AgRP), pro-opiomelanocortin (POMC), cocaine- and amphetamine-regulated transcript (CART), and melanocortin receptors. Our results indicated that injection time and treatment have a significant effect on food intake. Food intake decreased significantly at 30 and 60 min after ICV administration of DL-Met (1.678 μmol), l-Lys-HCl (6.856 μmol), and Tau (5.006 μmol) compared to the control group (P > 0.05). On the contrary, a high dose of each amino acid did not alter feed intake (P > 0.05). The result showed that ICV injection of DL-Met (1.678 μmol) significantly decreased the mRNA expressions of NPY,NPY4R, and NPY6R (P < 0.05), but had no significant effect on the mRNA expressions of NPY1R, NPY5R, and AgRP in the hypothalamus (P > 0.05). Similarly, ICV injection of l-Lys-HCl (6.856 μmol) and Tau (5.006 μmol) significantly decreased mRNA levels of NPY, NPY4R, and NPY6R (P < 0.05), without affecting the mRNA expressions of NPY1R, NPY5R, and AgRP (P > 0.05). DL-Met had no effect on anorexigenic gene expression (P > 0.05). l-Lys-HCl upregulated MC1R (P < 0.05), and Tau upregulated POMC and MC3R (P < 0.05), and both had no influence on CART, MC4R, or MC5R (P > 0.05). The result suggests that both orexigenic and anorexigenic neuropeptide genes are involved in the effects of DL-Met, l-Lys-HCl, and Tau. The effect of DL-Met, l-Lys-HCl, and Tau acts in a dose-dependent manner in the hypothalamus to influence feed intake. Show less

Polycystic ovary syndrome (PCOS) is a multifactorial disorder influenced by both environmental and genetic factors. The aim of this study was to evaluate associations between selected polymorphisms ( A total of 50 women (25 with PCOS and 25 healthy controls) were included. Genetic variants were identified using Polymerase Chain Reaction (PCR)-based methods. The frequencies of genotypes and alleles were compared between groups. Clinical symptoms such as irregular menstruation, hirsutism, acne, androgenetic alopecia, and overweight were assessed in relation to genotype. No significant differences were found in genotype distributions for Although most analyzed variants were not directly associated with PCOS in this cohort, the observed link between Show less