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Activity of SERCA (sarco/endoplasmic reticulum Ca In vivo [U- CDN1163 increased cardiac ATPase activity, decreased cytosolic Ca SERCA activation promotes flux from nonglucose substrates to fuel cardiac mitochondrial metabolism in obese mice. Show less

Melanocortin-2 receptor accessory protein-2 (MRAP2) modulates the activity of hypothalamic melanocortin-4 (MC4R) and growth hormone-secretagogue (GHSR) receptors, which suppress and promote appetite, respectively. We investigate whether obesity-associated variants of MRAP2 alter their ability to modulate MC4R and GHSR signalling as a possible mechanistic link to the development of obesity. Functional effects of five obesity-associated MRAP2 variants were analysed in HEK293 cells by co-expressing wild-type or variant MRAP2 with MC4R or GHSR. Endpoints included cell-surface and total expression, and ligand-induced second-messenger responses, β-arrestin-2 recruitment, and alternative G-protein activation. MRAP2 decreased basal MC4R cell-surface expression while GHSR cell-surface expression was not affected. In MC4R/MRAP2 expressing cells, maximal α-MSH-induced cAMP and β-arrestin-2 recruitment responses were increased. Similarly, ghrelin-induced Ca2+-mobilization in GHSR/MRAP2 expressing cells was increased, but β-arrestin-2 recruitment was suppressed. MRAP2 did not bias G-protein activation by either receptor, although previous reports show MRAP2 biases MC4R signalling towards Gαq/11. The variants did not significantly affect the ability of MRAP2 to modulate MC4R and GHSR signalling. Our results indicate that MRAP2 potentiates the ligand responsiveness of MC4R and GHSR, but has differential effects on β-arrestin-2 recruitment. The MRAP2 variants had no significant effects on the signalling endpoints tested. This suggests that, despite their association with obesity, the variants may be functionally benign, or that the absence of effects reflects limitations inherent to our cellular model. In addition, since MRAP2 can modulate multiple receptors and differentially modulate their signalling, we cannot rule out their influence on body weight regulation via other mechanisms. Show less

Among more than 300 candidate genes for obesity, A total of 231 healthy adults aged 19-64 years were recruited between March and May 2024. Anthropometric and clinical measurements, genotyping, dietary intake, and questionnaires on socioeconomic status, family history, and lifestyle behaviors were obtained. Associations between genotypes and obesity-related phenotypes were evaluated using ANOVA and ANCOVA, multivariable-adjusted models and multicollinearity analysis-based stepwise regression. In Koreans, MAFs for These findings support the relevance of Show less

Melanocortin 4 receptor (MC4R) gene mutations are the most common cause of monogenic non-syndromic childhood obesity, but their relationship with asthma remains unclear. We report four cases of children with the same MC4R gene variant who presented with asthma in the setting of obesity. The asthma phenotype, severity, and presentation were variable between these patients. Some but not all also had comorbid obstructive sleep apnea (OSA) and evidence of metabolic abnormalities, including insulin resistance and hypertension. These findings suggest that the MC4R mutation and its associated morbid obesity are associated with asthma. Future studies are warranted to define the underlying pathobiology of asthma among children with MC4R mutations. Show less

Genetic factors are key determinants in the pathophysiology of obesity, regulating energy homeostasis. Monogenic non-syndromic obesity accounts for 2-3% of obesity in both children and adults and is most often attributable to mutations in genes encoding components of the leptin-melanocortin pathway. Genetic testing is indicated in children with severe obesity before age 5, hyperphagia, a family history of obesity, and neurodevelopmental delay or organ dysfunction. Mutations associated with monogenic obesity follow autosomal recessive ( Show less

Endoplasmic reticulum (ER) stress plays a significant role in chronic pain, but its potential involvement in chronic itch remains largely unexplored and poorly understood. In the current study, we investigated whether ER stress signaling in keratinocytes contributes to the pathogenesis of chronic itch. Our behavioral tests showed that the ER stress inhibitor 4-PBA attenuated itch-related behaviors in both acute and chronic itching mouse models, and reduced compound 48/80 and serotonin-induced activity of dorsal root ganglion (DRG) neurons. qPCR and western blotting revealed that the ER stress-related proteins and Lipocalin-2 (LCN2) were significantly elevated in the affected skin under chronic itch conditions and in cultured keratinocyte HaCaT cells and mice skin keratinocytes. The ELISA test showed that the level of LCN2 increased significantly in plasma but not in DRG tissue, from both acetone-ether-water (AEW) induced dry skin and imiquimod (IMQ) induced psoriasis model mice. Current clamp recording demonstrated that LCN2 induced hyperexcitability in dorsal root ganglia neurons, which could be abolished by HS024, the inhibitor of melanocortin receptor 4 (MC4R). In addition, pharmacological inhibition of transient receptor potential vanilloid 1 (TRPV1) or TRPV1 knockout blocked LCN2-induced hyperexcitability in DRG neurons. In conclusion, this study demonstrated that keratinocyte ER stress is involved in chronic itch genesis by releasing LCN2, which sensitized primary sensory neurons via TRPV1. These findings suggested that inhibition of ER stress in keratinocytes could be a promising therapeutic strategy for treating chronic itch. Show less

Obesity is a major global health crisis, yet the molecular mechanisms underlying adult-onset metabolic dysfunction remain incompletely understood. The tubby mouse is a foundational genetic model of maturity-onset obesity; however, the specific tissues and cell populations responsible for its metabolic phenotype have long remained elusive. Here, we demonstrate that the loss of tubby disrupts the coordinated regulation of energy intake and expenditure, leading to a sustained positive energy balance. Using cell-type-specific genetic tools, we identified MC4R-expressing and VGLUT2-expressing neurons as essential sites of tubby function. We found that tubby acts through the combined contribution of these neuronal populations, as selective deletion in either MC4R or VGLUT2 neurons is sufficient to phenocopy key features of the global Tub mutant. Together, these findings establish tubby as a central neuronal regulator of systemic energy homeostasis and define an excitatory MC4R-VGLUT2 circuit that governs feeding behavior and metabolic output. Show less

Obesity is a complex, multifactorial disease influenced by genetic, hormonal, and metabolic factors. The fat mass and obesity-associated (FTO) and melanocortin 4 receptor (MC4R) genes have been implicated in body weight regulation through gut–brain signaling and their interactions with adipokines and enteroendocrine hormones. This study investigated the association between gastric expression of FTO and MC4R genes and circulating levels of leptin, adiponectin, and ghrelin in individuals with and without obesity. We conducted a case–control study including 50 patients with obesity undergoing sleeve gastrectomy and 50 controls undergoing diagnostic endoscopy. Gastric tissue gene expression was assessed by qRT-PCR, and serum hormone levels were quantified using ELISA. Inverse propensity score weighting was used to adjust for age and sex. FTO expression was significantly upregulated in patients with obesity (fold-change: 5.8 vs. 1.0, Show less

Obesity is a heritable disease, but its genetic basis is incompletely understood. Canine population history facilitates trait mapping. We performed a canine genome-wide association study for body condition score-a measure of obesity-in 241 Labrador retrievers. Using a cross-species approach, we showed that canine obesity genes are also associated with rare and common forms of obesity in humans. The lead canine association was within the gene DENN domain containing 1B ( Show less

The stimulator of interferon genes (STING) is a central mediator of innate immune sensing and represents a critical regulator of chronic inflammation. Upon persistent infection, excessive neutrophil activation leads to the formation of neutrophil extracellular traps (NETs) that damage the tissues. However, the mechanism by which STING signaling regulates NETs formation under chronic inflammatory conditions remains poorly understood. In this study, using LPS-induced murine endometritis models in wild-type and STING-deficient mice, we demonstrated that STING deficiency significantly suppressed myeloperoxidase activity, and diminished NETs formation. We identified neutrophil surface molecular CD11b as a key downstream target of STING, whose expression was transcriptionally regulated via IRF7. Furthermore, the STING-IRF7 axis was found to drive lipocalin-2 (LCN2) expression, which acted through its receptor MC4R to upregulate intracellular adhesion molecule-1 (ICAM-1), thereby facilitating neutrophil recruitment and NETosis during LPS stimulation. The role of this pathway was validated both Our findings revealed a novel mechanism in which the STING-IRF7 pathway exacerbated endometrial inflammation and tissue damage by coordinately upregulating CD11b and activating the LCN2-ICAM-1 axis. Consequently, targeting the STING signaling pathway may offer a promising therapeutic strategy for chronic endometritis. Show less

The central melanocortin system links nutrition to energy expenditure. Melanocortin-4 receptor (MC4R) controls appetite and food intake, and its signaling is potentiated by melanocortin-2 receptor accessory protein 2 (MRAP2). Human mutations in Show less

A previous study of 200,000 exome-sequenced UK Biobank participants investigating the association between rare coding variants and BMI had implicated two genes, MC4R and PCSK1, at exome-wide significance. In addition, further 66 genes were significant with an uncorrected p value of <0.001. Exome sequence data have become available for further 270,000 participants, and weighted burden analyses to test for association with BMI were carried out in this sample for all the 68 genes highlighted by the previous study. Three novel genes, in addition to MC4R and PCSK1, were significant after correction for multiple testing: PTOV1, GALNT9, and ATP8B2. All five genes were exome-wide significant in the whole sample of 470,000 participants. Rare coding variants impairing gene function were associated with reduced BMI for ATP8B2 but increased BMI for the other genes, and for all genes, loss of function variants had larger effect sizes than nonsynonymous variants. The biological mechanisms whereby the novel genes might affect BMI are not clear, although impairment of ATP8B2 might possibly have an effect on insulin secretion. Functional studies might throw further light on how these genes are involved in regulation of body weight. Collectively, the identified variants are very rare and do not make a major contribution to variation in BMI in the population. This research has been conducted using the UK Biobank Resource. Show less

With the advancement of genomic technologies, precision lifestyle interventions tailored to individual genetic backgrounds have emerged as a novel approach for preventing and managing chronic diseases such as obesity. Several randomized controlled trials (RCTs) targeting obese or overweight populations have found that individuals with different genotypes exhibit varying responses to the same lifestyle intervention (gene-lifestyle intervention interactions). To date, more than 20 genes, including Show less

Astrocytes are key regulators of neuroinflammation in multiple sclerosis (MS). Electroacupuncture (EA), a safe and cost-effective adjuvant therapy, has shown benefits in neurodegenerative diseases, but its astrocyte-related mechanisms remain unclear. Here, we demonstrated that EA at ST36 alleviated blood-brain barrier (BBB) disruption and neuroinflammation during the peak period of experimental autoimmune encephalomyelitis (EAE). Additionally, EA at ST36 upregulated the expression of α-melanocyte-stimulating hormone (α-MSH) and its receptor melanocortin-4 receptor (MC4R) in spinal astrocytes. Pharmacological studies showed that MC4R agonist RO27-3225 mimicked the therapeutic effects of EA, whereas MC4R antagonist TCMCB07 weakened EA-mediated BBB protection and neuroinflammation suppression. Moreover, astrocyte-specific silencing of MC4R via adeno-associated virus (AAV) weakened EA-mediated BBB protection and neuroinflammation suppression. RNA-sequencing (RNA-seq) and western blot (WB) revealed that EA exerts neuroprotective effects by activating MC4R to inhibit MAPK and NF-κB signaling pathways. Moreover, in MC4R-overexpressing astrocytes, α-MSH and RO27-3225 reduced inflammation responses, while TCMCB07 reversed the effects by MAPK/NF-κB signaling pathways. Collectively, our findings identify astrocytic MC4R as a critical mediator of EA-driven neuroprotection by suppressing MAPK/NF-κB signaling, providing mechanistic insight and a promising therapeutic target for EAE and other neuroinflammatory disorders. Show less

The melanocortin-4 receptor (MC4R) agonists have emerged as potential treatments for obesity, particularly in patients with rare genetic syndromes. However, their overall effects on obesity and cardiometabolic risk factors remain uncertain. To systematically evaluate the efficacy of MC4R agonists on weight-related outcomes and cardiometabolic risk factors. We conducted this study following PRISMA 2020 guidelines. Eligible studies included clinical trials ((RCTs and single-arm trials) of the effects of MC4R agonist drugs on anthropometric factors and cardiovascular risk factors. Random model effects meta-analyses were performed for this meta-analysis, with heterogeneity and small-study effects explored through sensitivity and publication bias analyses. A total of 12 studies were included. Treatment with MC4R agonists significantly reduced body weight compared with placebo in RCTs (WMD − 5.07 kg; 95% CI − 8.13 to − 2.02), with even larger reductions in single-arm studies (–11.23%; 95% CI − 15.43 to − 7.04). MC4R agonists also lowered BMI by − 13.67% (95% CI − 17.21 to − 10.12), waist circumference by − 11.75 cm, BMI Z-score by − 0.98, and hunger scores by − 3.38. These agents reduced triglyceride levels by − 35.53 mg/dL and LDL-C levels by − 9.14 mg/dL, while HDL-C levels showed a nonsignificant increase of + 2.37 mg/dL. Systolic blood pressure declined by − 4.38 mmHg, while diastolic pressure showed no meaningful change. MC4R agonists produce clinically meaningful weight reduction and improvements in several cardiometabolic risk factors. These findings support MC4R agonists as a promising therapy for genetic forms of obesity, while their role in nonspecific obesity requires confirmation in large, long-term randomized trials. The online version contains supplementary material available at 10.1186/s13098-025-02071-2. Show less

Central melanocortin signaling plays a critical role in maintaining energy homeostasis by regulating energy intake and expenditure, with impairment of this system closely related to metabolic diseases such as obesity. Among melanocortin receptor subtypes, melanocortin receptor 4 (MC4R) is the primary mediator of these effects within the central nervous system. Accumulating evidence suggests that MC4R contributes to stress-induced disruptions in feeding behavior and energy homeostasis. However, the precise neural mechanisms by which stress alters MC4R activity remain incompletely understood. In this study, we compared brain-wide c-Fos expression patterns induced by two distinct stress paradigms: lipopolysaccharide (LPS)-induced inflammatory stress and restraint stress in male mice, and further examined the involvement of MC4R-expressing (MC4R Show less

Hypothalamic obesity (HO) is a disabling disease caused by central nervous system (CNS) damage due to neurosurgery, trauma, or tumors, especially in hypothalamus. The pathological mechanism of its neural circuits is still unclear, and there is currently no corresponding drug due to the complex etiology. G protein-coupled receptors (GPCRs) regulate neural function in many CNS diseases. Among them, melanocortin 4 receptor (MC4R) regulate metabolism and appetite in the hypothalamus. Setmelanotide, an MC4R agonist, has demonstrated anti-obesity effects in genetic forms of obesity; however, its efficacy and mechanisms in HO remain unexplored. This study explored the potential of treating HO by setmelanotide-targeted activation of MC4R in the paraventricular nucleus (PVN). We established a rat hypothalamic injury model to replicate human HO symptoms, such as hyperphagia (50% increase in food intake), elevated Lee index, and more than 25% weight gain. Immunofluorescence and immunoblot analysis showed that HO disrupted the PVN neuropeptides, leading to the inhibition of MC4R via calmodulin-dependent protein kinase kinase 2 (CaMKK2) and AMP-activated protein kinase (AMPK) signaling. Crucially, administration of setmelanotide restored CaMKK2/AMPK activity, reactivated MC4R neurons, and normalized appetite and feeding behavior during fasting-refeeding and the long-term treatment of obese rats (60% reduction in food intake), ultimately reversing obesity (23% weight loss). These findings underscore the critical role of MC4R dysfunction in hypothalamic injury and highlight the strategies to pharmacologically activate MC4R via CaMKK2/AMPK signaling to restore metabolic homeostasis, proposing a translatable therapeutic agent to manage obesity caused by CNS injury. Show less

Metabolic dysfunction-associated steatotic liver disease (MASLD) can progress to steatohepatitis (MASH), which is closely associated with obesity and insulin resistance. Resmetirom, and semaglutide, have been shown to have therapeutic effects in clinical studies. We compared these mechanisms in western diet (WD)-fed melanocortin 4 receptor knockout (MC4R-KO) mice, a human MASH pathology model. Male MC4R-KO mice were fed WD for 6 weeks starting from 22 weeks of age for disease induction and were administered drugs for 7 weeks with WD feeding, for a total duration of 13 weeks. Both resmetirom and semaglutide treatments for 7 weeks substantially improved these parameters. Although resmetirome and semaglutide improved liver hydroxyproline deposition and total fat mass, semaglutide markedly suppressed total lean mass. Moreover, resmetirom enhanced oxygen consumption, whereas semaglutide reduced energy expenditure. Histopathological evaluation showed that resmetirom significantly and semaglutide tended to improve liver steatosis score. On the fibrosis score, semaglutide significantly reduced it. Resmetirom and semaglutide have different mechanisms of action against MASH. Similar to clinical evidence, semaglutide treatment, might cause muscle mass reduction due to food intake suppression. This is the first study to simultaneously compare the effects of resmetirom and semaglutide on MASH phenotypes and reveal the differences on their mechanisms of action in WD-fed MC4R-KO mice. Show less

This study identified genomic variants and potential candidate genes associated with 11 primal cut traits (back fat, belly fat, total fat, loin fat, ham fat, picnic fat, butt fat, loin intramuscular fat content, ham side fat, shoulder dorsal fat, and belly side fat thicknesses) in Canadian commercial crossbred pigs. Genome-wide association studies using whole genome sequencing data were conducted using genotyping data from 1118 commercial crossbred pigs. This analysis revealed multiple QTLs across chromosomes SSC1, 2, 3, 6, 7, 9, 14, 15, and 17, associated with fat traits. Notably, an SNP at position 160,230,075 bp on SSC1 was significantly associated with multiple fat traits, including belly fat, butt fat, ham fat, loin fat, picnic fat, and side fat. Common genes in windows associated with multiple traits, such as Show less

Obesity is a global health challenge characterized by significant heterogeneity in causes and treatment responses, complicating sustainable management. This narrative review explores the genomic architecture of obesity and its implications for personalized interventions, focusing on how genetic variations influence key biological pathways and treatment outcomes. A comprehensive literature search, guided by the authors' expertise, was conducted to identify key publications on the genomics of obesity and personalized approaches. The selection of articles prioritized those that provided direct insights into the genomic basis of obesity and its potential for informing tailored strategies. Genomic studies reveal both monogenic and polygenic influences on obesity, identifying numerous susceptibility loci. Genome-wide association studies (GWASs) have linked common variants in genes like Show less

The preoptic area (POA) is a well-established regulator of body temperature, but its role in feeding behavior remains underexplored. Our study identifies leptin receptor (Lepr)-expressing neurons in the POA (POA Show less

Many membrane proteins, including G protein-coupled receptors (GPCRs), are susceptible to denaturation when extracted from their native membrane by detergents. Therefore, alternative methods have been developed, including amphiphilic copolymers that enable the direct extraction of functional membrane proteins along with their surrounding lipids. Among these amphiphilic copolymers, styrene/maleic acid (SMA) and diisobutylene/maleic acid (DIBMA) polymers have been extensively studied. Despite their many benefits, SMA and DIBMA polymers also have considerable drawbacks limiting their applications. Herein, we describe a series of new amphiphilic copolymers derived from DIBMA via partial amidation of the carboxylate pendant groups with various biocompatible amines. We characterize the new polymer's nanodisc-forming properties and ability to extract the melanocortin 4 receptor (MC Show less

Obesity rates continue to rise in children and adolescents worldwide. The heritability of obesity is estimated to be 40-80 %. Genetic testing for monogenic causes of obesity in the clinical setting is increasing; however, how results of these tests affect family behaviors is unclear. The objective of this study was to understand caregiver intent to change family behaviors following genetic testing for obesity. The sample from this qualitative analysis derives from a larger study identifying mutations on the melanocortin 4 receptor (MC4R) pathway. Inclusion criteria included participation in the main study, aged 2-17 years, and a history of severe obesity and hyperphagia. Caregiver-child dyads were recruited to ensure equal representation of genetic results across racial/ethnic subgroups (Non-Hispanic White, Black, Hispanic). A third of participants in the main study enrolled in the sub-study. Structured caregiver interviews were analyzed using grounded theory. Twenty caregivers were female, 55 % White, 45 % Black, and 5 % Hispanic. Mean caregiver age was 42.3 ± 6.5 years and BMI 40.5 ± 7.9 kg/m Genetic testing for pediatric obesity, regardless of test outcome, motivates caregivers to move forward within the SoC Model or to remain in their current stage. These findings suggest that engaging caregivers to have their child with obesity tested for a genetic cause of obesity does not cause families to stop engaging in behavior change, unless the family was not ready to engage in behavior change prior to genetic testing. Show less

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

Obesity is a highly complex, multifactorial disease influenced by dynamic interactions among genetic, epigenetic, environmental, and behavioral determinants that explicitly position genetics as the core. While advances in multi-omic integration have revolutionized our understanding of adiposity pathways, translation into personalized clinical nutrition remains a critical challenge. This review systematically consolidates emerging insights into the molecular and nutrigenomic architecture of obesity by integrating data from large-scale GWAS, functional epigenomics, nutrigenetic interactions, and microbiome-mediated metabolic programming. The primary aim is to systematically organize and synthesize recent genetic and genomic findings in obesity, while also highlighting how these discoveries can be contextualized within precision nutrition frameworks. A comprehensive literature search was conducted across PubMed, Scopus, and Web of Science up to July 2024 using MeSH terms, nutrigenomic-specific queries, and multi-omics filters. Eligible studies were classified into five domains: monogenic obesity, polygenic GWAS findings, epigenomic regulation, nutrigenomic signatures, and gut microbiome contributions. Over 127 candidate genes and 253 QTLs have been implicated in obesity susceptibility. Monogenic variants (e.g., 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

This case describes the resolution of refractory chronic idiopathic urticaria (CIU) with setmelanotide in a patient with Bardet-Biedl Syndrome (BBS). While setmelanotide is approved for syndromic obesity, this report highlights a novel anti-inflammatory effect potentially mediated by melanocortin-4 receptor (MC4R) agonism, expanding current understanding of its immunomodulatory role in mast cell-mediated disease. The patient presented with lifelong hyperphagia and class III obesity beginning in childhood, along with multiple features fulfilling BBS clinical criteria: visual impairment with night vision difficulties, renal abnormalities with proteinuria, irregular menses with polycystic ovaries, and neurodevelopmental delay. She also reported refractory CIU with pruritic hives occurring several times weekly despite dual antihistamine therapy. On examination, BMI was 40.5 kg/m Genetic testing revealed a heterozygous pathogenic Setmelanotide produced durable remission of refractory CIU in a patient with BBS, suggesting MC4R agonism may exert immunomodulatory effects beyond weight regulation. This finding underscores the broader potential of precision therapies for rare obesity syndromes to reveal new mechanisms of inflammation control. Show less