Hypothalamic obesity (HO) is a rare, complex disorder characterized by disruption of brain pathways regulating energy intake, expenditure, autonomic function, and hormonal signaling. It occurs in rare monogenic obesity syndromes affecting central leptin-melanocortin pathways or can be acquired (aHO) as a consequence of hypothalamic injury due to a tumor (e.g., craniopharyngioma), its treatment, or trauma. In this narrative review, we focus on aHO. Damage to specific hypothalamic nuclei leads to hyperphagia, central insulin and leptin resistance, decreased sympathetic activity, reduced energy expenditure, and rapid weight gain. Traditional obesity treatments, including lifestyle interventions, often fail to achieve sustained weight loss in patients with aHO. Recent advances in pharmacotherapy show promise by targeting the distinct pathophysiology of aHO. Effective treatment requires personalized approaches due to the heterogeneity of hypothalamic dysfunction and associated comorbidities. Early intervention may improve outcomes, as rapid postoperative weight gain frequently occurs. Emerging therapies target mechanisms of disturbed energy homeostasis pathways. These agents include stimulants, incretin-based therapies (e.g., glucagon-like peptide-1 receptor agonists), insulin modulators, and melanocortin receptor agonists such as setmelanotide. While monotherapies often fail in long-term treatment, combination therapies hold potential to restore energy balance and reduce or eliminate the need for bariatric surgery. Future research should focus on identifying clinical and biomarker profiles of aHO subtypes and evaluating combination therapies. Although challenging, aHO is no longer untreatable. Patients should be referred and managed at specialized centers, with pharmacological treatment preferably conducted within research settings to optimize and personalize care, and to develop evidence-based protocols for this debilitating condition.

Melanocortins regulate pigmentation via melanocortin receptors (MCRs), which are highly conserved across vertebrates. Unlike other MCRs, the melanocortin 2 receptor (MC2R) is exclusively activated by ACTH; however, its role in pigmentation remains unclear. Using CRISPR/Cas9-generated mc2r knockout zebrafish, we demonstrated that the loss of mc2r in zebrafish results in impaired interrenal steroidogenesis and pronounced hyperpigmentation characterized by an increased number of melanophores and xanthophores while preserving normal patterning. Transcriptomic analyses revealed the upregulation of genes involved in melanosome formation, melanin synthesis, lipid metabolism, and carotenoid accumulation. These findings demonstrate that, in addition to controlling steroidogenesis, mc2r plays a key role in pigment cell development and metabolic regulation.

Benign form of monogenic obesity conferred by the melanocortin 4 receptor.

Glucoprivation-induced nutrient preference relies on distinct NPY neurons that project to the paraventricular nucleus of the hypothalamus.

N-terminal domains and site-specific glycosylation regulate the secretion of avian melanocortin inverse agonists, agouti signaling protein (ASIP) and agouti-related protein (AGRP).

The effect of melanocortin-4 receptor agonist drugs on obesity and metabolic risk factors: a systematic review and meta-analysis.

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.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12974-025-03667-1.

Interplay Between Enteroendocrine Hormone (Leptin) and Adipokines (Ghrelin and Adiponectin) with Gastric Expression of FTO and MC4R Genes

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 MC4R and MRAP2 are associated with obesity. Here, we sought to determine whether MRAP2 affected the activity of MC3R, which is structurally similar to MC4R and which regulates sexual maturation, linear growth rate, and lean mass accumulation. Single-molecule pull-down assays showed that MC3R and MRAP2 interacted in HEK293 cells. Analysis of fluorescence photobleaching steps showed that MC3R and MRAP2 readily formed heterodimers, most commonly with a 1:1 stoichiometry. Mining of previously published human single-nucleus and spatial transcriptomic data showed coexpression of MRAP2 and MC3R in hypothalamic neurons that function in energy homeostasis and appetite control. In HEK293 cells, MRAP2 enhanced cAMP signaling downstream of MC3R, impaired β-arrestin recruitment to MC3R, and reduced MC3R internalization. The ability of MRAP2 to promote MC3R signaling was suppressed by alanine mutagenesis of five MRAP2 and two MC3R transmembrane residues identified by structural homology models as important for the interaction. We showed that variants of MRAP2 found in individuals who are overweight or obese did not enhance MC3R-driven signaling. Thus, these studies implicate MRAP2 as an important regulator of MC3R function and provide further evidence for the crucial role of MRAP2 in energy homeostasis.

Physical exercise affects multiple physiological processes, including those regulated by hormones, such as energy balance, stress responses, and pain perception. The prohormone precursor proopiomelanocortin (POMC) gives rise to β-endorphin, adrenocorticotropic hormone, β-lipotropin, and the melanocyte-stimulating hormones (MSH), which act through melanocortin (MC1-5) and opioid receptors to influence these key physiological responses. Here, we identified a mechanism by which full-length POMC interacts with small extracellular vesicles (sEVs) in the circulation. In healthy adults, the fraction of plasma POMC associated with sEVs increased fourfold following intense exercise, despite unchanged POMC and sEV concentrations. POMC-positive sEVs contained leukocyte or megakaryocyte/platelet markers, suggesting hematopoietic origin. A substantial subset of circulating sEVs expressed MC1-MC5 and μ-opioid receptors, and coimmunoisolation assays demonstrated binding of unprocessed POMC to MC1 and MC3 receptors. Molecular modeling indicated that POMC undergoes pH-dependent conformational changes that favor MC binding, a finding corroborated by in vitro binding assays under acidic conditions. Functionally, addition of POMC-positive sEVs to B16-F10 melanoma cells induced melanogenesis, consistent with POMC-derived MSH activity. The sEV-associated POMC had higher rates of transport than unbound POMC in assays mimicking the blood-brain barrier. These findings establish that exercise-induced, pH-dependent binding of POMC to circulating sEVs may facilitate hormone precursor transport and potentially influence transfer across the blood-brain barrier. This mechanism represents a separate paradigm for endocrine regulation, providing insight into how exercise modulates sEV interactions with systemic hormone distribution and signaling.

The fat mass and obesity-associated (FTO) and melanocortin-4 receptor (MC4R) genes have been implicated in the pathophysiology of obesity. However, their regulatory behavior in human gastric tissue and association with postoperative weight loss following metabolic and bariatric surgery (MBS) remain unclear. In this prospective case-control study, gastric tissue from 50 patients with obesity undergoing laparoscopic sleeve gastrectomy and 48 non-obese controls was analyzed for FTO and MC4R mRNA expression using quantitative PCR. Adjusted Inverse propensity score weighting (IPSW-adjusted) and age-/sex-adjusted linear regression were applied. Receiver operating characteristic (ROC) curves were used to evaluate discriminatory thresholds. Correlation with 12-month percent total weight loss (%TWL) was assessed. FTO expression was significantly upregulated (mean fold-change: 4.68, p < 0.001) and MC4R downregulated (mean fold-change: - 0.91, p < 0.001) in patients with obesity. ROC analysis identified thresholds of > 1.515 for FTO (AUC = 1.00) and < 0.525 for MC4R (AUC = 1.00), both with high sensitivity and specificity. No significant correlation was observed between gene expression and %TWL at 12-month follow-up. Gastric expression of FTO and MC4R accurately discriminates between individuals with and without obesity but does not predict postoperative weight loss outcomes after sleeve gastrectomy. These findings indicate diagnostic potential, whereas prognostic value remains unsubstantial.

Abstract Introduction Female Sexual Dysfunction (FSD) encompasses conditions affecting desire, arousal, orgasm, or causing sexual pain, impacting a large proportion of women across age groups. Hypoactive Sexual Desire Disorder (HSDD) is the most prevalent subtype, affecting up to 28% of premenopausal women. FSD negatively influences quality of life and relationships, yet remains underdiagnosed due to stigma, limited provider training, and underutilization of effective therapies. Flibanserin and bremelanotide are FDA-approved for HSDD, though their mechanisms and comparative efficacy are not fully defined. Testosterone therapy, while not FDA-approved in the U.S., is frequently prescribed off-label and has shown benefit in improving libido, adding complexity to treatment decisions. Objective To compare the mechanisms of action, efficacy, safety, and clinical considerations of FDA-approved treatments for FSD, flibanserin and bremelanotide, in addition to off-label testosterone therapy. Methods This narrative review draws from randomized controlled trials, meta-analyses, and clinical guidelines focused on pre- and postmenopausal women with HSDD. Primary outcomes included changes in sexual desire, satisfying sexual events (SSEs), FSFI scores, and adverse effects. Secondary outcomes included patient distress, adherence, and tolerability. Results Flibanserin, typically administered as a daily oral tablet, has demonstrated statistically significant improvements across all domains of the Female Sexual Function Index (FSFI), including desire, arousal, lubrication, orgasm, satisfaction, and pain (p &amp;lt; 0.05). Trials report an increase of 0.5 to 1 SSE/month and a mean FSFI total score improvement of 2.5 points in premenopausal women vs. placebo. Bremelanotide, an on-demand melanocortin receptor agonist, increases desire and reduces distress, with ~0.7 additional SSEs/month. Bremelanotide has shown statistically significant improvements across all FSFI domains, including desire, arousal, lubrication, orgasm, satisfaction, and pain. On average, premenopausal women taking bremelanotide experienced a 1.7-point improvement in FSFI total score compared to placebo (p &amp;lt; 0.05). Testosterone therapy has been shown in clinical trials to significantly improve sexual desire, arousal, orgasm, and the frequency of sexually satisfying events in both naturally and surgically menopausal women. On average, it is associated with 1 to 2 additional sexually satisfying events per month compared to placebo. FSFI total scores significantly improved in the testosterone group (7.2 vs 4.6 in control), with meaningful improvements also observed across individual FSFI domains (p &amp;lt; 0.05). Although not FDA-approved, the Global Consensus Position Statement supports its use in postmenopausal women with HSDD, provided a thorough risk-benefit discussion is conducted and modifiable contributing factors are addressed. Testosterone is contraindicated in women with androgen-sensitive conditions, and regular monitoring of serum testosterone levels is recommended to ensure safet Conclusions HSDD remains underrecognized, yet growing pharmacologic options offer meaningful benefits. Flibanserin, bremelanotide, and testosterone each present unique mechanisms and efficacy profiles. Personalizing treatment based on patient goals, safety considerations, and lifestyle factors is key. Ongoing research is needed to guide long-term use, improve clinician confidence, and expand access to care. Disclosure No

Abstract We report the outcomes of early treatment with setmelanotide in two young children with leptin receptor deficiency, highlighting a notable effect on psychomotor development. The dizygotic twins from Réunion Island presented with severe early-onset obesity and hyperphagia, with excessive weight gain beginning at 6 months of age and food-seeking behavior. A homozygous pathogenic variant in the leptin receptor gene was identified at 2.5 years. Because of parental emotional exhaustion, medical follow-up was delayed. Compassionate use of setmelanotide, a melanocortin receptor agonist, was initiated at age 4. Treatment produced rapid and sustained improvements in hyperphagia, weight trajectory, metabolic parameters, motor coordination, emotional regulation, and observable psychomotor milestones such as climbing stairs and catching up on school learning delays. The children gained autonomy, and caregivers reported enhanced quality of life and family functioning. These findings support the hypothesis that early MC4R-targeted therapy may influence not only metabolic but also neurodevelopmental trajectories in monogenic obesity.

Capturing G protein-coupled receptors into native lipid-bilayer nanodiscs using new diisobutylene/maleic acid (DIBMA) copolymers.

Exploratory safety investigations in normal, freely moving Göttingen Minipigs using telemetry: Pharmacological validation.

Investigating the role of melanocortinergic, glutamatergic and neuropeptide Y systems on hypophagia caused by gastric inhibitory polypeptide (GIP) in broilers

Mahogunin ring finger 1 (MGRN1) is a membrane-tethered E3 ligase that fine-tunes signaling sensitivity by targeting surface receptors for ubiquitylation and degradation. Although MGRN1 is known to regulate the Hedgehog signaling effector Smoothened (SMO) via 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 interacts with the RING domain of MGRN1. Functional assays suggest that ATRN and ATRNL1 work with MGRN1 to promote the ubiquitylation and degradation of the melanocortin receptors MC1R and MC4R, in a process analogous to its regulation of SMO. Loss of MGRN1 or ATRN leads to increased surface and ciliary localization of MC4R in fibroblasts and elevated MC1R levels in melanocytes, resulting in enhanced eumelanin production. These findings expand the known repertoire of MGRN1-regulated receptors and provide new insight into a shared mechanism by which membrane-tethered E3 ligases utilize transmembrane adapters to facilitate substrate receptor specificity.

ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Journal of Cell Science, helping researchers promote themselves alongside their papers. Pragya Parashara is first author on ‘ The E3 ubiquitin ligase MGRN1 targets melanocortin receptors MC1R and MC4R via interactions with transmembrane adapters’, published in JCS. Pragya is a Postdoctoral Scholar in the lab of Jennifer Kong at the Department of Biochemistry, University of Washington, Seattle, USA, investigating how alterations in fundamental cellular pathways contribute to pathological conditions.

Cachexia, a syndrome marked by nonintentional weight loss, muscle wasting, functional decline and poor prognosis, affects 50%-80% of cancer patients, severely impacting quality of life, treatment tolerance and survival. A 'Regulatory and Trial Update Workshop' was organized by the Society on Cachexia and Wasting Disorders (SCWD) in December 2024 in Washington, DC, focused on clinical trial endpoints, standards of care and recent advancements. This article provides a summary of the discussions that were held during the first day of the workshop. Despite ongoing research, effective therapies for cachexia remain limited. Existing treatments, such as nutritional supplements, progestins, anti-inflammatories and anabolic agents, have shown mixed results, often improving appetite or lean mass without consistent functional benefits. Common muscle mass measurements, like CT scans of the L3 vertebra, are inadequate as primary endpoints because of biological variability and small effect sizes and because they do not necessarily translate into clinical benefit. Trials continue to face challenges in meeting regulatory requirements, which mandate improvements in both body composition and functional outcomes. Regulatory consensus emphasizes demonstrating clinically meaningful benefits in patient-reported outcomes/physical function and/or morbidity-mortality using validated instruments, adequate safety exposure, recognition that handgrip and weight alone are insufficient, feasibility in advanced disease, consideration of general activity measures, optional but informative body composition data and, for a pan-cancer label, benefits across at least three distinct cancers. Patient-centred endpoints, emphasizing real-life functioning and social participation, are essential as patients prioritize daily activity and independence over isolated physical measures. Clinical trials presented during the meeting included the MENAC trial, which tested a multimodal intervention combining nutrition, exercise, anti-inflammatory drugs and cancer therapy, achieved modest weight stabilization but no significant improvements in muscle mass or activity. In contrast, TCMCB07, an MC-4 receptor antagonist, demonstrated promising results in preclinical and early-phase human studies, showing weight stabilization and improved caloric intake with good tolerability. ART27.13, a dual CB1/CB2 receptor agonist, also demonstrated positive effects in appetite stimulation and weight stabilization. For S-pindolol, which targets appetite and metabolism, Phase IIb/III trials are to be initiated, following an earlier Phase II trial that showed improved muscle mass and muscle strength (hand grip strength). Future treatments must focus on integrating patient-centred goals, therapeutic mechanisms and meaningful clinical outcomes.

Adipocyte deposition is believed to be a primary characteristic of age-related thymic involution, but the underlying cellular and molecular mechanisms remain unknown. We show here that thymic mesenchymal stromal cells (tMSCs) have a higher tendency to differentiate into adipocytes and melanocortin-2 receptor accessory protein (MRAP) is a potential driver of tMSCs adipogenesis. Furthermore, we discover that thymosin-α1 promotes MRAP expression in tMSCs through FoxO1 signaling pathway. Additionally, the proportion of tMSCs increase in older mice compared to young mice. Importantly, MRAP is also necessary for human thymic MSCs to differentiate into adipocytes when exposed to thymosin-α1. Single-cell RNA-seq analysis of human thymus revealed an accumulation of tMSCs and adipocytes during aging, indicating a strong potential for adipogenic differentiation in age-related thymic involution. Thus, we have revealed MRAP as a key factor in promoting thymic MSCs adipogenesis triggered by thymosin-α1 and FoxO1 pathway, which may serve as potential target to hinder adiposity in age-related thymic involution.