Introduction La voie leptine-mélanocortines contrôle la faim, la satiété et la dépense énergétique, régulant ainsi le poids corporel. Les patients présentant un déficit bi-alléliques en POMC (incluant PCSK1) – ou en LEPR présentent une altération de cette voie, conduisant à une hyperphagie et à une obésité précoce et sévère. Méthodes Les patients présentant un déficit bi-allélique en POMC ou en LEPR, ayant terminé un essai clinique de phase 2 ou 3 et présentant une réponse pondérale cliniquement significative, pouvaient poursuivre setmélanotide dans un essai d’extension à long terme (ELT). Cette analyse a évalué les variations de l’indice de masse corporelle (IMC) et du z-score d’IMC jusqu’à 6 ans de traitement. Résultats 35 patients ont été inclus dans l’ELT. A l’inclusion, L’IMC moyen (ET) de l’ensemble des participants était de 44,1kg/m2 (11,3 ; n=35), et le z-score moyen de l’IMC (ET) chez les patients < 18 ans était de 3,86 (0,75 ; n=16). La variation moyenne (ET) en pourcentage de l’IMC par rapport à l’inclusion était de –17,9 % (20,0 %) à l’année 4 (n=18), –23,1 % (17,4 %) à l’année 5 (n=13) et –28,4 % (17,3 %) chez 5 patients à l’année 6. La variation moyenne (ET) du z-score de l’IMC par rapport à l’inclusion chez les patients < 18 ans était de –1,22 (0,96) à l’année 4 (n=3) et de –0,79 (1,51) à l’année 5 (n=2) ; aucun patient pédiatrique n’a atteint 6 ans de traitement. Une raison fréquente d’arrêt était le passage au traitement commercial par setmélanotide. L’hyperpigmentation (28/35 ; 80,0 %) et l’érythème au site d’injection (24/35 ; 68,6 %) étaient fréquents. Conclusions Ces données confirment la réduction du poids à long terme sous setmélanotide chez les patients en situation d’obésité liée à un déficit bi-allélique en POMC ou en LEPR. La réduction moyenne du z-score d’IMC observée chez les patients<18 ans après 5 ans de traitement par setmélanotide souligne l’importance de la mise en place précoce d’une thérapie ciblée.

Cardiovascular diseases (CVD) remain a major global health challenge. Early markers of disease initiation and progression are urgently needed. We, and others, have previously shown changes in the gut microbiome in association with metabolic and CVD. Here, we demonstrate that gut microbiome-related changes can be detected in association with subclinical variations in heart and kidney function. Markers related to gut microbial metabolism of aromatic amino acids, phenylalanine and tyrosine, associate with circulating pro-atrial natriuretic peptide and estimated glomerular filtration rate in a metabolically healthy European population. Observational and genetic evidence further identify microbiome-related metabolites as mediators of this gut microbiome-kidney axis, with their baseline levels associating with incident CVD in an external Canadian population. Altogether, our work suggests that the gut microbiome interacts with the cardiorenal axis and participates in an interorgan crosstalk affecting host physiology and risk of CVD.

Nutrient availability influences white adipose tissue (WAT) inflammation, leading to decreased or increased adiposity. Tumor necrosis factor (TNF) is elevated in WAT under both conditions, being involved in lipolysis and regulation of interleukin 18 (IL-18) secretion, which may regulate lipolytic processes. However, the role of these cytokines in adiposity reduction due to low energy availability remains unclear. Wild-type (WT) mice fasted for 24 h showed decreased adiposity, whereas TNFR1 knockout mice (TNFR1-/-) were unresponsive to fat pad loss, even after 48-h fasting. TNFR1-/- mice were also resistant to β3-adrenergic receptor agonist CL316,243-induced fat mobilization, which was linked with reduced expression of lipases, β3-adrenergic receptors, and cytokines in WAT. Also, mice treated with the TNF-α inhibitor infliximab and fasted for 48 h showed resistance to adiposity loss, suggesting that prolonged fasting-induced TNF signaling may modulate adipose tissue reduction. Conversely, IL-18 does not seem to influence fat pad loss induced by 24-h fasting as IL-18 knockout mice (IL-18-/-) express TNF in WAT and respond to prolonged fasting similarly to WT animals. To assess the potential translational relevance of our findings to human obesity, we analyzed 53 samples from patients with obesity who underwent bariatric surgery. Interestingly, TNFR1 and IL-18 expressions in sWAT correlate with the expression of lipases and adipokines in the subcutaneous site despite no correlation with body weight or fat mass 1 year after surgery. In summary, this study suggests that the TNF/TNFR1 axis is crucial for metabolic adaptation and is a prerequisite for prolonged fasting-induced lipolysis in male mice.

During periodontitis, pathogenic oral bacteria like Porphyromonas gingivalis may exert systemic effects directly by translocating into the bloodstream and indirectly by deregulating the gut microbiota, aggravating obesity-related complications. This study aimed to evaluate the links between the periodontal infection, the oral and gut microbiota composition, and the inflammatory and metabolic profile during obesity. Thirty-nine patients suffering from severe obesity, with (n = 23) or without (n = 16) periodontitis, were enrolled. We examined the subgingival microbiota composition, periodontal status and salivary inflammatory response. The fecal microbiota composition was assessed by metagenomic analysis. Inflammatory and metabolic markers were measured in the plasma and epiploon visceral adipose tissue collected during bariatric surgery. Results show that patients with periodontitis exhibited an oral microbiota dysbiosis characterized by an increased abundance of bacteria from the red and orange complexes, worsened periodontal parameters (plaque index, bleeding index, gingival recession, probing depth and clinical attachment level), and higher IL-6 salivary levels. In fecal samples of patients with periodontitis, a higher proportion of the Proteobacteria phylum and changes in functional profile of bacteria were detected. Periodontitis was also linked to higher circulating concentrations of anti-P. gingivalis IgG, total cholesterol and lipoprotein (a). Moreover, periodontitis was associated with an enhanced production of TLR2, MyD88 and TGFβ, as well as higher activities of SOD and catalase antioxidant enzymes in the adipose tissue. Overall, these findings demonstrate that during obesity, the periodontal infection correlates with deregulated oral and gut microbiota composition, higher levels of pro-inflammatory mediators, and altered markers of oxidative stress and lipid metabolism.

Advances in research enable precision medicine for rare metabolic diseases. The approval of therapies as melanocortin-4 receptor (MC4R) agonists for the treatment of hyperphagia and obesity in monogenic disorders (POMC, PCSK1, and LEPR deficiencies) and Bardet-Biedl syndrome (BBS), affecting fewer than 1 in 20,000 (BBS) to fewer than 1 in 1,000,000 individuals, represents a major advance. These therapies have transformative potential but introduce new responsibilities due to limited patient numbers and lack of long-term data. Equitable access to diagnosis and treatment, expert care and structured monitoring systems facilitate efficient use of resources and can address gaps in knowledge. This article outlines a European expert consensus recommending the designation of centers of expertise to coordinate the diagnosis and treatment of patients with monogenic obesity. The need for structured care protocols based on continued analysis of real-world databases to optimize therapy in a responsible manner is emphasized. The goals are (1) early and precise diagnosis; (2) access for eligible patients to therapy; (3) continuous evaluation of treatment response allowing discontinuation without no measurable clinical benefit and (4) provision of clinical care by trained and experienced professionals.

In the mid-2000s, mouse studies suggested that the gut microbiome might influence energy harvest, fat storage, appetite, insulin sensitivity, and inflammation. Since then, our understanding of the gut microbiome's role in obesity has advanced significantly. Mechanistic studies identified microbial metabolites, such as short-chain fatty acids, bile acids, branched-chain amino acids, tryptophan catabolites, and imidazole propionate, as key modulators of metabolism, inflammation, and gut-brain communication. Metagenomic and multi-omics technologies now provide deeper insights into the intricate interactions between microbes, metabolites, and host factors, reshaping obesity research and reinforcing the need for phenotype stratification by recognizing microbiome-driven metabolic profiles. Integrating gut microbiome data into clinical strategies may enable targeted interventions for specific obesity subtypes, advancing prevention and personalized care. However, as new anti-obesity medications emerge, it is imperative to determine how microbiome-based therapies can complement them, considering efficacy, cost, and patient-specific variability.

Adults with neurodevelopmental disorders (NDD) are at high risk of developing obesity, yet systematic evaluations of their eating behavior profiles remain scarce. In this study, participants were adults with overweight or obesity associated with a genetically confirmed NDD with intellectual disability (ID). We characterized multidimensional eating behavior phenotypes across three groups: Prader-Willi syndrome (PWS) and Bardet-Biedl syndrome (BBS), the two most frequent syndromic forms of obesity, and other neurodevelopmental genetic conditions associated with obesity (“other NDD”). We then evaluated the glucagon-like peptide-1 receptor agonist (GLP1-RA) semaglutide-associated changes in real-world conditions. We assessed eating behavior in 149 adults with NDD (PWS, n = 90; BBS, n = 13; other NDD, n = 46) using the Dykens Hyperphagia Questionnaire (HQ), the Children’s Eating Behavior Questionnaire (CEBQ), and the Parental–Developmental Disorders Quality of Life questionnaire (Par-DD-QoL). In a subgroup with longitudinal follow-up (PWS, n = 8; other NDD, n = 12), changes in body weight and eating behavior were evaluated after 12 months of semaglutide treatment (2.4 mg/week). Given the limited sample size, these subgroup analyses were considered hypothesis-generating and were not adjusted for multiple comparisons. Groups exhibited marked hyperphagic traits, with earlier onset of food interest in PWS and BBS (mean 6.6 and 2.7 years, respectively) compared with other NDD group (10.5 years). Distinct profiles emerged: PWS was characterized by lower food fussiness and desire to drink, whereas BBS tended to show higher satiety responsiveness. Nearly half of caregivers (46.4

Background:In steatohepatitis trials, antifibrotic effects are measured by conventional histology, albeit with significant limitations. We assessed how artificial intelligence-assisted, single-fiber quantitative image analysis of hepatic fibrosis matrix measures fibrosis reversal following an intervention that results in major histological improvement. Methods: Fifty-eight patients underwent bariatric surgery with preoperative and follow-up (>1 y) liver biopsies. High-resolution, single-fiber quantitative image analysis extracted quantitative traits of fibrosis, which were combined in a continuous phenotypic fibrosis composite score (Ph-FCS) of fibrosis severity. Changes in Ph-FCS were compared between patients with increasing, decreasing, or stable histological fibrosis stage. Results: The mean follow-up between biopsies was 5.84 years (SD 2.59). Forty patients improved in histological fibrosis stage, 12 were unchanged, and 6 progressed. Median Ph-FCS was reduced from 5.25 at baseline to 3.75 at follow-up (p<0.001). Baseline Ph-FCS was correlated with Ph-FCS reduction after surgery (r=0.72, p<0.001). Ph-FCS reduction was higher in patients with a histological >= 1-stage reduction (-1.78, 95% CI: -2.15 to -1.04) than in those unchanged (-1.08, 95% CI: -1.93 to 0.01) or with progression (-0.28, 95% CI: -1.26 to 0.71) (p<0.02 for differences between groups). The Ph-FCS identified intrastage fibrosis reduction in 9 patients labeled unchanged by conventional histology. Of 34 patients with advanced fibrosis at baseline, 15 still had advanced fibrosis according to histological staging. Despite similar histological staging, their follow-up Ph-FCS was reduced from baseline, although it remained higher than that of the 19 who regressed. Conclusions: Artificial intelligence-assisted, single-fiber image analysis provides an automated measurement of fibrosis changes, which is quantitative and more sensitive to change than conventional pathology and thus can improve the feasibility of antifibrotic trials.

ObsGEN is a free, web-based clinical decision support tool developed to facilitate the identification of rare genetic forms of obesity, including monogenic and syndromic etiologies. Implemented on the REDCap platform, it guides clinicians through a structured 10-15-minute questionnaire covering key phenotypic domains: age of onset, weight trajectory, hyperphagia, neurodevelopmental features, and signs of hypothalamic dysfunction. Based on the inputted data, ObsGEN provides automated, phenotype-driven diagnostic hypotheses, genetic testing recommendations, and direct access to national expert centers. The tool aims to support early recognition of rare obesity syndromes, enabling timely referral, access to targeted therapies, and personalized care strategies. Since its implementation in 2019, ObsGEN has been used by over 1150 clinicians in France, incorporated into national clinical workflows, and contributed to the development of the French National Diagnosis and Care Protocol for rare obesities. By operationalizing a precision medicine approach, ObsGEN enhances diagnostic accuracy and promotes equitable access to expert evaluation in both pediatric and adult obesity care. More info: http://obsgen.nutriomics.org

OBJECTIVES:Obesity and type 2 diabetes (T2D) are associated with altered secretion of enteroendocrine hormones, including the glucagon-like peptide-1 (GLP-1). The mechanisms underlying this dysregulation remain poorly understood, partly due to the rarity of enteroendocrine cells (EECs) and technical difficulties in humans. Our aim was to generate an in vitro human jejunal enteroids (HJEs) derived from individuals with obesity and T2D as a simplified intestinal epithelium in a controlled environment, in order to explore GLP-1 secretion in metabolic diseases. SUBJECTS AND METHODS:HJEs were obtained from jejunum fragments sampled during gastric bypass surgery in individuals with severe obesity and normoglycemia (Ob, n = 12), prediabetes (ObPreD, n = 12), or T2D (ObD, n = 10). HJEs were characterized through gene and protein expression analyses and immunofluorescence. To promote the EEC lineage, HJEs were treated with the Notch pathway inhibitor DAPT. Active GLP-1 secretion was assessed by ELISA. RESULTS:HJEs were successfully generated whatever the metabolic group Ob, ObPreD, ObD, exhibiting epithelial cell lineages and expressing critical genes involved in GLP-1 cell lineage, biosynthesis, and secretion. HJEs secreted active GLP-1 in response to both low and high glucose concentrations, regardless of subject metabolic status. However, HJEs from individuals with severe obesity and T2D exhibited a reduced capacity to release GLP-1 in response to high glucose concentrations compared to those from individuals with severe obesity or with obesity and prediabetes. CONCLUSIONS:HJEs represent a robust human-derived model to investigate EEC function and GLP-1 secretion in metabolic diseases. While HJEs retain functional GLP-1-producing cells, their secretory capacity is impaired in the presence of T2D, confirming functional endocrine alterations. These findings support the use of HJEs in preclinical studies targeting enteroendocrine dysfunction.

Introduction Le syndrome de Bardet-Biedl (BBS), est une maladie neuroendocrinienne rare, associé à certains variants génétiques de la voie leptine-mélanocortines. L’altération de cette voie peut entraîner une hyperphagie et une obésité précoce. Méthodes Les patients avec BBS ayant terminé un essai de phase 2 ou 3 et présentant une réponse pondérale pouvaient poursuivre setmélanotide dans une étude d’extension à long terme (ELT). Cette analyse a évalué les variations de l’indice de masse corporelle (IMC) et du z-score d’IMC jusqu’à 5 ans. Résultats 54 participants ont été inclus dans l’ELT. A l’inclusion, L’IMC moyen (ET) était de 42,2kg/m2 (9,2 ; n=53) ; l’IMC moyen (ET) chez les patients ≥ 18 ans était de 47,2kg/m2 (6,7 ; n=25) ; et le z-score moyen de l’IMC (ET) chez les patients < 18 ans était de 4,26 (1,65 ; n=28). La variation moyenne (ET) en pourcentage de l’IMC par rapport à l’inclusion était de –10,7 % (6,3 %) à l’année 1 (n=44), –9,1 % (11,1 %) à l’année 2 (n=34), –7,6 % (15,8 %) à l’année 3 (n=27), –8,8 % (18,8 %) à l’année 4 (n=13) et –8,8 % (22,0 %) chez 4 patients à l’année 5. Chez les adultes (≥ 18 ans), la variation moyenne (ET) en pourcentage de l’IMC par rapport à l’inclusion était de –9,8 % (6,1 %) à l’année 1 (n=20), –7,9 % (11,6 %) à l’année 2 (n=15), –11,9 % (15,6 %) à l’année 3 (n=11) et –8,2 % (31,3 %) chez 3 patients à l’année 4.Chez les patients < 18 ans, la variation moyenne (ET) du z-score d’IMC par rapport à l’inclusion était de –1,03 (0,66) à l’année 1 (n=24), –1,03 (0,82) à l’année 2 (n=18), –0,62 (0,83) à l’année 3 (n=14) et –0,76 (1,23) chez 7 patients à l’année 4.Une raison fréquente d’arrêt était le passage au traitement commercial par setmélanotide. L’hyperpigmentation (36/54 ; 66,7 %) et l’érythème au site d’injection (29/54 ; 53,7 %) étaient fréquents. Conclusions La poursuite du traitement a permis des réductions durables du poids chez les patients avec BBS. Ces résultats plaident en faveur d’un traitement ciblé instauré précocement.

Hyperphagia is a condition associated with rare obesity-related diseases, presenting as a pathologic, insatiable hunger accompanied by abnormal food-seeking behaviors. In October 2023, a group of researchers and clinicians with expert knowledge on hyperphagia convened at the annual ObesityWeek meeting to discuss the need for a unified definition of hyperphagia and key items necessary to improve the identification, assessment, and treatment of hyperphagia in patients with melanocortin 4 receptor (MC4R) pathway–associated diseases. The definition of hyperphagia proposed by this group is a pathologic, insatiable hunger accompanied by abnormal food-seeking behaviors. Suggested methods to accurately identify patients with hyperphagia include increased physician and parent/caregiver education and standardized efficient screening procedures for use in the clinic. The etiology of hyperphagia as related to abnormal MC4R signaling was also reviewed and proposed as a central cause of the condition across several underlying diseases. Given this potential unified underlying pathology, the expert group recommends that patients with hyperphagia undergo genetic testing and that treatment include comprehensive weight-management strategies incorporating lifestyle and pharmacotherapies targeted at addressing hyperphagia.

The bone marrow microenvironment is a dynamic and complex niche that plays a central role in the development, progression, and therapeutic resistance of leukemia. Among the various stromal and immune cells that compose this microenvironment, adipocytes are increasingly recognized as active participants rather than passive bystanders. These cells contribute to leukemia pathophysiology by supplying leukemic cells with vital metabolic fuels such as free fatty acids and glutamine, which support cellular bioenergetics and biosynthesis. Furthermore, adipocytes secrete adipokines—including leptin, adiponectin, and others—that influence leukemic cell proliferation, apoptosis, and chemoresistance. Leukemic cells, in turn, are not merely recipients of these signals, but actively remodel the marrow niche to their advantage. They can suppress adipogenesis, inhibit the differentiation of mesenchymal stem cells into adipocytes, or reprogram existing adipocytes to adopt a tumor-supportive phenotype. These transformed adipocytes may enhance leukemic cell survival, dampen immune responses, and create a metabolic sanctuary that enables resistance to standard chemotherapies. This reciprocal and dynamic interaction between leukemic cells and adipocytes contributes significantly to minimal residual disease and relapse, posing a major challenge for durable remission. Recent advances in tissue engineering—such as organ-on-chip and 3D co-culture systems—offer promising platforms to recapitulate and study these leukemia–adipocyte interactions with high fidelity. These models facilitate mechanistic insights and provide a foundation for developing novel therapeutic strategies aimed at disrupting the metabolic and paracrine crosstalk within the leukemic niche. Targeting the adipocyte–leukemia axis represents a compelling and underexplored avenue for improving leukemia treatment by sensitizing malignant cells to existing therapies and overcoming the protective influence of the bone marrow microenvironment.

Advances in our understanding of the molecular causes of rare genetic obesities, particularly those affecting hypothalamic function, have paved the way for current and emerging, therapies specifically targeting appetite regulation. These conditions are typically marked by severe early onset obesity, hyperphagia, and a combination of endocrine and neurodevelopmental comorbidities. Management of genetic forms of obesity remains particularly challenging, as behavioral interventions are often insufficient, and bariatric surgery may be less effective or even contraindicated in some cases. Recent pharmacological treatments aim to restore energy balance by targeting disrupted pathways, most notably the leptin–melanocortin axis, to enhance satiety and reduce hyperphagia. These targeted therapies mark a significant shift from conventional weight-loss approaches by directly addressing the underlying biological mechanisms driving obesity in affected individuals. This review provides an overview of the current therapeutic landscape for genetic and syndromic obesities, including approved treatments such as setmelanotide and semaglutide, as well as emerging investigational drugs. In addition to outlining their place within evolving treatment algorithms, we discuss future directions, ongoing clinical challenges, and key points of vigilance—including long-term efficacy, safety, access, and the need for integrated, multidisciplinary care within a precision medicine framework. Clearly defining their place in treatment algorithms is essential to integrate these therapies into a precision medicine framework for the management of genetic and syndromic obesities.

Disruption of the gut mucus barrier is a critical step in the development of infec-tious or chronic inflammatory diseases. However, there are no clear links between developmental stages, diet, and the mechanical and biochemical properties of mucus. The transition from suckling to weaning is a pivotal stage in the devel-opment of the mucus barrier in mammals, with significant implications for the health and morbidity of mammalian infants. Here, using a novel microfluidic device, we investigate the penetration and organizational properties of motile Escherichia coli bacteria at the mucus interface using purified intestinal mucus collected from cohorts of piglets before and after weaning. In weaned piglets, E. coli penetrate more than 100 µ m into the mucus, a distance greater than the physiological thickness of the mucus layer in vivo . In contrast, for suckling piglets significant bacterial aggregation is observed at the interface, hindering the pene-tration process. Using the supernatant obtained from purified mucus of suckling piglets, we were able to restore bacterial aggregation in weaned piglet mucus and limit penetration. Interestingly, we also achieved the same result using purified human breast milk immunoglobulin A (IgA), which is known to promote bacterial aggregation. Our results emphasize the importance of mucosal immunoglobulin A (IgA) specificity in relation to the mother’s immunological history, which is primarily transmitted through breast milk and lost during weaning. This also might explain why the suckling/weaning transition is, among other issues, a crit-ical window associated with a high incidence of gastrointestinal infections, before autologous IgA-mediated definite protection is acquired. Studying bacterial pen-etration in complex fluids using this new in vitro microfluidic device will pave the way for future research and the development of predictive tools for use in medical research trials. ### Competing Interest Statement The authors have declared no competing interest. This study received grants from European Union’s MSCA grant MEDMOTILUS project (grant N°101024357), The National Agency of Research ANR PushPull (ANR-22-CE30), the PEPR microbiota JEMINI, INSERM_IRP (Parasum), and Institut Carnot France Futur Elevage (“OrganoPig” project)". Axel Ranson is recipient of a Ph.D. Fellowship from Ecole Normale Supérieure (ENS). The authors acknowldege Corinne Lencina (UMR GenPhySE, INRAE, Toulouse) for the quantification of IgA in mucus. EC thanks the Institut Universitaire de France (IUF) for support. Work in the Gorochov lab is supported by Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université and the French Foundation for Medical Research (FRM) Paris, France (FRM EQU202203014622).

Introduction Early-onset obesity increases the risk of developing comorbidities and decreases life expectancy with many variables such as age of onset, severity, and duration of obesity each having an individual influence. Here, we present findings from a model that aims to assess the impact of early-onset obesity. Methods The Early-Onset Obesity Model (EOObesity Model) was built by integrating data from clinical studies with demographic information. It categorizes information into four primary groups: prevalence, morbidity risk, mortality risk, and impact of obesity duration. Type 2 diabetes, cardiovascular events (fatal and non-fatal events, cardiovascular disease, and coronary heart disease), metabolic dysfunction-associated steatotic liver disease, asthma, obstructive sleep apnea, and cancer were evaluated over a range of age and body mass index (BMI) z-scores. Results The EOObesity Model provides a systematic approach for estimating the impact of early-onset obesity on risk of comorbidities and on life expectancy by considering individual patient weight trajectories. We test different scenarios to illustrate the potential impact of age of onset and severity of obesity on the risk of various comorbidities, on life expectancy, and on disability-adjusted life years. The model indicates that severe early-onset obesity has a high impact on life expectancy with, for example, up to 42 years of life lost if a patient has a BMI z-score of 4 by the age of 4 years. Discussion The model and these scenarios underscore the predicted substantially detrimental effects of early-onset and prolonged obesity on life expectancy, and the increased risks of obesity-related comorbidities. They suggest that morbidity and mortality risks increase with obesity duration and severity in a nonlinear manner, thereby supporting the view that early weight loss intervention and obesity prevention strategies may reduce long-term health risks substantially.

We report the outcomes of early treatment with setmelanotide in 2 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.