RARE DISEASE
Obesity due to leptin receptor gene deficiency
Obesity due to leptin receptor gene deficiency
Obesity due to leptin receptor gene deficiency
Drug discovery
4
drugs
With orphan designations
Overview
Obesity due to leptin receptor (LEPR) gene deficiency is a rare autosomal recessive disorder characterized by severe early-onset obesity, hyperphagia, and hypogonadotropic hypogonadism. Caused by biallelic LEPR mutations, it disrupts leptin signaling, impairing satiety and energy regulation. Associated morbidities include recurrent infections, metabolic dysfunction, and delayed puberty. Diagnosis relies on genetic testing, as serum leptin levels are elevated but ineffective [1][6][12].
Burden
High mortality (9–26%) in childhood due to respiratory/gastrointestinal infections; survivors face lifelong obesity-related complications [2][10].
Significant psychosocial strain from hyperphagia-driven behaviors and care demands [9].
Limited access to genetic testing delays diagnosis and precision treatment [6][10].
Therapies
Categories: rare endocrine diseases, rare genetic diseases, rare gynecological and obstetric diseases, rare infertility disorders
Research Papers
232 drug discovery papers about Obesity due to leptin receptor gene deficiency, with 3 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
232 drug discovery papers about Obesity due to leptin receptor gene deficiency, with 3 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-09-21 | IL-1RA administration exerts diet-dependent metabolic effects on adipose tissue function and lipid handling in male mice.
Interleukin-1 (IL-1) signaling is a key mediator of metabolic inflammation, yet its tissue-specific contribution to obesity-associated dysfunction remains incompletely understood. Here, we investigated the effects of pharmacological IL-1 receptor antagonism on systemic metabolism, adipose tissue dysfunction, and hepatic lipid handling under distinct nutritional conditions. Male mice fed a normal diet (ND) or high-fat diet (HFD) were treated subcutaneously with the IL-1 receptor antagonist (IL-1RA) anakinra for three weeks. IL-1RA did not significantly affect body weight or global adiposity; however, under ND conditions, it reduced fat mass and circulating leptin levels and increased the adiponectin/leptin ratio, indicating improved adipose endocrine function. In adipose tissue, IL-1RA partially restored Acaca expression and selectively modulated extracellular matrix remodeling genes, including Mmp9, without broadly suppressing inflammatory markers. In the liver, triglyceride content was altered in a diet-dependent manner without changes in the expression of key metabolic genes (Fasn, Acaca, Ppara), suggesting that IL-1 blockade does not directly reprogram intrinsic hepatic lipid metabolism. Consistent with this, analyses in complementary models, including leptin-deficient mice, showed that Il1rn expression is regulated by local inflammatory and endocrine cues rather than adiposity per se. Together, these findings identify IL-1 signaling as a context-dependent modulator of adipose tissue function and systemic lipid handling. The dissociation between adipose tissue responses and hepatic triglyceride accumulation highlights the tissue-specific effects of IL-1 receptor antagonism and underscores the need for direct metabolic flux studies to define the mechanisms underlying these effects.
2026-03-14 | Inversed impaired osteogenic activity in children with severe obesity due to MC4R deficiency compared to LEP and LEPR deficiency.
Chronic obesity is associated with impaired bone health. However, few investigations have been conducted to assess bone physiology in early-onset obesity. In this study, we measured specific bone turnover and metabolic biomarkers in children with severe obesity with biallelic loss-of-function variants of the leptin (LEP), leptin receptor (LEPR), or melanocortin 4 receptor (MC4R) genes. Thirty-nine children aged 0.3-8.8 years with a BMI SDS ≥ 3, previously identified with pathogenic variants in LEP, LEPR, or MC4R, were recruited for the current study. Additionally, 13 age-matched children with severe obesity who tested negative for variants in known obesity-related genes were included, and another 13 unrelated age-matched children with normal body weight served as the control group. Serum osteocalcin, osteopontin, osteoprotegerin, and sclerostin levels were assessed using multi-analyte profiling. Serum leptin, insulin, and cortisol levels were determined using ELISA. Serum levels of osteocalcin and osteopontin, specific markers of bone formation, were significantly lower in children with LEP and LEPR biallelic variants than in the control group. In contrast, the values of these two biomarkers in children with MC4R deficiency were significantly higher than those in the other groups. No differences were observed in the bone resorption markers osteoprotegerin and sclerostin. Hyperleptinemia was more pronounced in children with LEPR deficiency. Serum insulin concentrations were elevated in individuals with MC4R deficiency, whereas serum cortisol levels were significantly higher in children with LEP deficiency than in all other groups. Our data demonstrate that osteogenic activity (but not resorption activity) is differentially affected in children with complete genetic disruption of the leptin-signaling pathway. Children with MC4R deficiency showed higher osteogenic markers, but children with LEP and LEPR deficiencies showed the opposite. Our results support the usefulness of bone turnover biomarkers for the assessment and management of bone health in different types of obesity.
2026-01-12 | Additive effect of leptin and palm-LEAP2(1-14) ameliorates obesity-induced metabolic stress in ob/ob mice.
Liver-enriched antimicrobial peptide 2 (LEAP2) can act as a natural antagonist or inverse agonist of the growth hormone secretagogue receptor, also known as the ghrelin receptor. In our previous studies, palm-LEAP2(1-14), a truncated palmitoylated analogue of LEAP2, proved highly stable and exerted an acute anorexigenic effect. Ghrelin, the endogenous agonist of the ghrelin receptor, and the anorexigenic hormone leptin have opposing effects on appetite. We hypothesized that leptin supplementation combined with long-term antagonism of the ghrelin receptor using palm-LEAP2(1-14) might have a beneficial and potentially additive effect on obesity-related metabolic stress in leptin-deficient ob/ob mice, influencing diabetes, liver steatosis, impaired locomotor activity, and hypothermia. Here, we demonstrated a clear additive effect of combined leptin and palm-LEAP2(1-14) treatment, which increased locomotor activity, reduced plasma cholesterol, liver steatosis, and mRNA expression of the metabolic stress marker Fgf21, and upregulated hypothalamic Pomc gene expression - outcomes not achieved by either treatment alone. Additionally, leptin, palm-LEAP2(1-14), and both treatments combined each reduced cumulative food intake and circulating FGF21 levels. Only leptin reduced body weight, elevated rectal temperature, increased Ucp1 and Pgc1 mRNA expression in brown adipose tissue, and attenuated hyperinsulinemia, indicating that the weight-reducing and antidiabetic effects were attributable to leptin - not palm-LEAP2(1-14). Liver metabolic stress was further alleviated by decreases in plasma FGF21 and hepatic expression of the lipogenic enzymes. Our study demonstrated the beneficial effects of palm-LEAP2(1-14) on obesity-induced metabolic stress, which were further attenuated when palm-LEAP2(1-14) was coadministered with leptin in ob/ob mice.
2025-11-18 | Obesity-induced leptin resistance is directly involved in skin fragility by decreasing type I collagen synthesis.
The relationship between obesity-induced leptin resistance and skin function remains unclear. In this study, we examined the effects of leptin signaling on collagen production in mouse skin. Mice were divided into three groups: control diet, high-fat diet, and switching diet (from the high-fat diet to the control diet). We measured the expression of leptin signaling-related genes and type I tropocollagen levels in the skin. In an additional experiment, leptin was administered to leptin-deficient ob/ob mice to examine the direct effect of leptin signaling on type I collagen synthesis in the skin. Type I tropocollagen levels and Ob-Rb gene expression were decreased in the high-fat diet group. These abnormalities were reversed by the switching diet. We also observed that type I tropocollagen levels were decreased in ob/ob mice, but this abnormality was reversed by leptin administration. It is likely that leptin will help to improve obesity-induced skin fragility.
2025-07-16 | Supplementary file 2_High fat diet-induced loss of pituitary plasticity in aging female mice with ablated leptin signaling in somatotropes.pdf
Introduction Somatotropes lacking leptin receptors (LEPR) produce less growth hormone and are poorly responsive to growth hormone releasing hormone (GHRH). Transcriptomic analysis reveals that the mutant somatotropes contain progenitor cell markers (Sox9+) and multiple pituitary hormone transcripts-(Pomc, Prl, Lhb, Tshb and Cga), suggesting that the cells are progenitor cells. The resulting GH deficiency contributes to adult-onset obesity in the mutant, due to an increase in abdominal fat. Objectives This study examined how a high-fat diet (HFD) affected pituitary transcriptomic function in older (10-month) female mutants lacking leptin receptors (LEPR) in somatotropes and intact littermate controls. We hypothesized that pituitary cells from both the older control females and the female mutants would be greatly affected by the oxidative stress from the HFD. Methods Mice were exposed to a 60% HFD for 16 weeks, followed by glucose tolerance testing and 3-day monitoring in metabolic cages (CLAMS). Pituitaries were harvested, cells dispersed and subjected to single cell-RNA-seq (scRNA-seq) with bioinformatic analysis. Serum was collected and analyzed for pituitary hormones and cytokines. Results The HFD resulted in elevated serum leptin and IL-6 in both mutants and controls, and reduced serum growth hormone (GH) and prolactin (PRL) levels. However, adrenocorticotropin (ACTH) levels were elevated in controls but not mutants. Unexpectedly, whereas controls gained as much weight as younger females, somatotrope LEPR-null mutants on a HFD gained only 75% of the weight of controls, were more glucose tolerant, consumed less food, were more active in the metabolic cages, and had lower serum levels of insulin. Analysis of scRNA-seq revealed that the HFD induced differentially expressed genes (DEGs) in more distinct pituitary cell populations of older mice compared to previously reported findings in younger control females, indicating greater vulnerability in the older pituitary population. This was especially true in the mutant pituitary population. Ingenuity Pathway Analysis indicated that the DEGs included targets of critical upstream regulators important for pituitary cell function and plasticity (CREB, Fox01, cAMP, STAT3, insulin, TRH, GnRH, and leptin signaling pathways), with most pathways predicted to be downregulated by the HFD. Unlike controls, HFD-fed mutant cell populations exhibited DEGs consistent with the downregulation of translational regulatory pathways. Notably, the HFD reversed the increased expression of progenitor cell markers (Sox9+) and multiple pituitary hormone transcripts seen in the mutant on a control diet. Similarly, the HFD also reversed the expression of multiple pituitary hormone transcripts and progenitor markers in lactotropes, thyrotropes, and corticotropes from mutants. Conclusion The findings supported our hypothesis that both aging and the mutation (loss of LEPR in somatotropes) would render these mice more sensitive to a HFD as more pituitary cell types were affected transcriptionally. Collectively, these findings indicate that HFD and/or obese state may compromise pituitary plasticity by down-regulating translational processes and reducing expression in cells that may have multipotential functions. The oxidative stress of a HFD may thus limit the expression of pituitary progenitor cells.
small molecules
2026-08-24 | Leptin Resistance, Obesity, and Gut Dysbiosis: The Role of Bitter Phytonutrients, Niacin, and Zinc [Review/Hypothesis]
Leptin resistance is a hallmark of obesity and metabolic syndrome, yet its mechanisms remain incompletely understood. This paper proposes that leptin resistance is driven, in part, by a deficiency of bitter phytonutrients, niacin, and zinc—nutrients required for the gene transcription and function of bitter taste receptors. Bitter taste receptors, expressed not only on the tongue but also in the gut and hypothalamus, may support or co-regulate leptin receptors, as suggested by the efficacy of pomegranate ellagitannins in improving leptin resistance or which may be due to urolithin-A promotion of leptin receptors and/or promotion of PPAR and mitochondrial function. Bitter taste receptors and phytonutrients are also protective due to satiety hormone promotion including GLP-1. This review synthesizes the literature on leptin, pomegranate polyphenols, bitter taste receptors, niacin, zinc, mitochondria, and the gut microbiome, and proposes a testable hypothesis: that restoring bitter phytonutrients, resistant starches, niacin, and zinc in the diet can improve leptin sensitivity, reduce inflammation, and support metabolic health. The paper includes a hyperinflammation positive feedback loop (Figure 1) with a fully cited narrative (Appendix F), a clinical protocol (Appendix A), functional food guidance (Appendix B), a clinical guidance with a Table of histamine-producing microbial strains (Appendix C) and a diagnostic flowchart for histamine excess and Retinoid Toxicity (Appendix D), and a summary of genes associated with histamine sensitivity and Retinoid Toxicity (Appendix E). This is a hypothesis-driven review with practical clinical translations—offering a framework for patients and practitioners to address leptin resistance through targeted nutrition and lifestyle changes.
2026-08-21 | HACD3 integrates central leptin sensitivity and peripheral thermogenesis to oppositely regulate energy balance.
The enzyme 3-hydroxyacyl-CoA-dehydratase 3 (HACD3) is involved in fatty acid synthesis, but its systemic role in metabolism is unknown. This study investigated the physiological function of HACD3 in energy homeostasis. Systemic HACD3 deficiency protected mice from diet-induced obesity by increasing energy expenditure and activating adipose thermogenesis. Conversely, deleting HACD3 specifically in leptin receptor-expressing neurons caused obesity, hyperphagia, and leptin resistance. In adipocytes, HACD3 cell-autonomously repressed thermogenesis by forming a complex with Keratin 1 (KRT1), which sequestered thermogenic transcription factors and maintained repressive chromatin. HACD3 ablation disrupted this complex, enabling nuclear translocation of PPARγ/PGC-1α and increasing transcription of thermogenic genes. In neurons, HACD3 is required for leptin receptor stability and signaling. HACD3 acts as a critical, tissue-specific regulator that simultaneously governs both sides of the energy balance equation-suppressing energy expenditure in adipose tissue while facilitating anorexigenic signaling in the brain. This dual function identifies HACD3 as a novel, multifaceted target for therapeutic intervention in metabolic disorders.
2026-07-25 | Monogenic and syndromic obesity in children: Clinical recognition, genetics, and precision management.
Obesity is increasingly being recognized as a heterogeneous condition with strong genetic underpinnings. Monogenic obesity, caused by single-gene mutations, primarily affects the leptin-melanocortin pathway, which regulates hunger and satiety. Mutations in genes, such as LEP, LEPR, POMC, PCSK1, and MC4R, lead to hyperphagia, early onset severe obesity, and metabolic dysregulation. LEP and LEPR mutations impair leptin signaling, resulting in defective appetite suppression, whereas POMC and PCSK1 deficiencies disrupt prohormone processing. MC4R mutations, the most common cause of monogenic obesity, impair satiety signaling and are linked to rapid weight gain. Syndromic obesity, including the Bardet-Biedl and Alström syndromes, involves ciliary dysfunction, leading to developmental abnormalities alongside obesity. Other genes such as SH2B1, SIM1, and BDNF play crucial roles in hypothalamic development and energy regulation. Advances in genomic sequencing have improved the recognition of genetic etiologies; however, many patients remain undiagnosed due to limited testing availability and a lack of clinician awareness. Precision therapies, including set-melanotide for specific melanocortin pathway defects, demonstrate the promise of targeted treatments. However, management must extend beyond pharmacology; lifestyle interventions, psychosocial support, and family-centered care remain essential, especially when intellectual disability or behavioral challenges complicate adherence. Ethical considerations surrounding access and equity are critical, as high-cost therapies and the limited availability of genetic testing risk widening disparities between health systems. Polygenic risk scores and multi-omics approaches may expand precision medicine beyond rare genetic syndromes to common obesity, highlighting the importance of integrating genetics, psychosocial care, and policy advocacy in the management of pediatric obesity.
2025-09-26 | Polymorphism of Melanocortin Receptor Genes-Association with Inflammatory Traits and Diseases.
Melanocortin receptors (MCRs) are responsible for various functions ranging from skin pigmentation, regulation of appetite, stress response and cognition, steroid synthesis, and energy balance to cellular regeneration and immunomodulation. The genetic polymorphism with tissue distribution ranging from the brain, limbic system, and adrenal cortex to neutrophils, monocytes, and macrophages is evident in MCRs. The mutations in MC1R, MC2R, MC3R, and MC4R genes are associated with risk of melanoma, familial glucocorticoid deficiency, obesity, and type 2 diabetes mellitus, respectively. Meanwhile, MC1R, MC2R, and MC5R genes are involved in the risk of major depressive disorder. Melanocortin receptors are involved in different inflammatory disorders, i.e., atopic dermatitis, autoimmune uveitis, sarcoidosis, respiratory diseases, multiple sclerosis, scleroderma, inflammatory bowel disease, amyotrophic lateral sclerosis, Alzheimer's disease, arthritis, and reperfusion injury. Several newer therapeutic agents related to MCRs have numerous advantages over the current anti-inflammatory drugs, demonstrating therapeutic relevance. Among them, α-MSH analogs play a role in atopic dermatitis and scleroderma, and MC1R agonist Dersimelagon has shown effectiveness in systemic sclerosis. The FDA has recently approved the repository corticotropin injection (RCI) to treat sarcoidosis. The FDA has also approved various melanocortin agonists, i.e., Bremelanotide, Afamelanotide, and Setmelanotide, for the treatment of hypoactive sexual desire disorder, Erythropoietic protoporphyria, and obesity, due to pro-opiomelanocortin and leptin receptor deficiency, respectively. Therefore, this review aims to summarize the function and genetic polymorphism of melanocortin receptors, regulatory pathways involving MCRs, and the existing evidence of the prime effect of MCRs on inflammatory responses via different mechanisms and their potential therapeutic use in inflammatory diseases.
2025-02-01 | Real-life experience on efficacy and safety of setmelanotide treatment in prepubertal children.
Monogenic obesity, characterized by severe, early-onset obesity due to single-gene defects, often resists traditional weight management strategies. This report presents real-life experiences on the efficacy and safety of setmelanotide, an MC4R agonist, in 4 prepubertal children (ages 3-9) with LEPR and POMC deficiencies. Findings indicate that setmelanotide is effective at lower doses in our patients with POMC deficiency (0.3-0.5 mg/day) than the patients with LEPR deficiency (2.5 mg/day). Treatment was generally well-tolerated, with injection site reactions and hyperpigmentation as common side effects. As novel findings, gonadotropin-related effects such as hypothalamo-pituitary-gonadal axis activation and testicular descent were observed in 2 patients. Growth deceleration was noted in 2 children, and recovery from central hypothyroidism in 1 patient with POMC deficiency. Overall, setmelanotide appears to be effective and well-tolerated in young children with monogenic obesity. However, further studies are necessary to evaluate the long-term effects of early intervention on growth and pubertal development.
antibodies
2025-10-04 | Leptin: 30 Years Later.
The discovery of leptin as an adipocyte-secreted hormone encoded by the ob gene whose absence produces severe obesity that is corrected by leptin repletion in both mice and humans was a transformative event in metabolic science. Leptin's discovery in 1994 accelerated the identification of central neuronal circuitry responsive to peripheral signals that regulate energy balance as well as metabolic, neuroendocrine, and other vital functions. Leptin's primary physiological role was initially viewed as preventing obesity by its levels rising, but subsequent research has emphasized the key role of falling levels to signal starvation. Resistance to leptin action, though partial, characterizes common forms of obesity. Despite much being learned about leptin signal transduction over 30 years, the precise molecular mechanisms for leptin resistance and common obesity remain unclear. Leptin therapy is effective in rare patients with congenital leptin deficiency and other low leptin conditions but not common obesity. Interestingly, reducing hyperleptinemia may prove useful in treating common obesity.
2025-02-28 | Blocking the SIRPα-CD47 axis promotes macrophage phagocytosis of exosomes derived from visceral adipose tissue and improves inflammation and metabolism in mice.
Adipose tissue plays a pivotal role in systemic metabolism and maintaining bodily homeostasis. Exosomes from adipose tissues, known as AT-Exos, are recognized as important messengers in the communication between adipose tissue and other organs. Despite this, the alterations in exosome composition and the functional disparities among depot-specific AT-Exos in obesity remain elusive. In this work, we utilized lipidomics and microRNA (miRNA) sequencing to elucidate the lipid and miRNA profiles of AT-Exos in a diet-induced obesity model. We identified obesity-related miRNAs in AT-Exos and further explored their mechanisms using gain- and loss-of-function experiments. To evaluate the metabolic effects of AT-Exos on adipocytes, we conducted RNA-sequencing (RNA-seq) and confirmed our findings through Quantitative Real-time PCR (qPCR) and Western bolt analyses. Meanwhile, a mouse model with intraperitoneal injections was utilized to validate the role of exosomes derived from visceral white adipose tissue (vWAT-Exos) in obesity progression in vivo. Finally, we explored potential therapeutic intervention strategies targeting AT-Exos, particularly focusing on modulating the SIRPα-CD47 axis to enhance macrophage phagocytosis using Leptin-deficient (ob/ob) mice and SIRPα knock-out mice. Our study revealed that obesity-related metabolism affects the biological processes of AT-Exos, with depot-specific secretion patterns. In obesity, the lipidome profile of AT-Exos was significantly altered, and diet can modify the miRNA content and function within these exosomes, influencing lipid metabolism and inflammatory pathways that contribute to metabolic dysregulation. Specifically, we identified that miR-200a-3p and miR-200b-3p promoted lipid accumulation in 3T3L1 cells partly through the PI3K/AKT/mTOR pathway. RNA-Seq analysis revealed that AT-Exos from different fat depots exerted distinct effects on adipocyte metabolism, with obese vWAT-Exos being notably potent in triggering inflammation and lipid accumulation in diet-induced obesity. Additionally, we found that inhibiting the SIRPα-CD47 axis can mitigate metabolic disorders induced by obese vWAT-Exos or ob/ob mice, partly due to the enhanced clearance of vWAT-Exos. Consistent with this, SIRPα-deficient mice exhibited a reduction in vWAT-Exos and displayed greater resistance to obesity. This study elucidates that diet-induced obesity altered the lipid and miRNA profiles of AT-Exos, which involved in modulating adipocyte inflammation and metabolic balance. The SIRPα-CD47 axis emerges as a potential therapeutic target for obesity and its associated complications.
2021-12-13 | IL-20 is involved in obesity by modulation of adipogenesis and macrophage dysregulation.
IL-20 is a proinflammatory cytokine of the IL-10 family and involved in several diseases. However, the regulatory role of IL-20 in obesity is not well understood. We explored the function of IL-20 in the pathogenesis of obesity-induced insulin resistance by ELISA, Western blotting and flow cytometry. The therapeutic potential of IL-20 monoclonal antibody 7E for ameliorating diet-induced obesity was analysed in murine models. Higher serum IL-20 levels were detected in obese patients. It was upregulated in leptin-deficient (ob/ob), leptin-resistant (db/db) and high-fat diet (HFD)-induced murine obesity models. In vitro, IL-20 regulated the adipocyte differentiation and the polarization of bone marrow-derived macrophages into proinflammatory M1 type. It also caused inflammation and macrophage retention in adipose tissues by upregulating TNF-α, monocyte chemotactic protein 1 (MCP-1), netrin 1 and unc5b (netrin receptor) expression in macrophages and netrin 1, leptin and MCP-1 in adipocytes. IL-20 promoted insulin resistance by inhibiting glucose uptake in mature adipocytes through the SOCS-3 pathway. In HFD-induced obesity in mice, 7E treatment reduced body weight and improved glucose tolerance and insulin sensitivity; it also reduced local inflammation and the number of M1-like macrophages in adipose tissues. We have identified a critical role of IL-20 in obesity-induced inflammation and insulin resistance, and we conclude that IL-20 may be a novel target for treating obesity and insulin resistance in patients with metabolic disorders.
2020-05-14 | Gut-derived GIP activates central Rap1 to impair neural leptin sensitivity during overnutrition.
Nutrient excess, a major driver of obesity, diminishes hypothalamic responses to exogenously administered leptin, a critical hormone of energy balance. Here, we aimed to identify a physiological signal that arises from excess caloric intake and negatively controls hypothalamic leptin action. We found that deficiency of the gastric inhibitory polypeptide receptor (Gipr) for the gut-derived incretin hormone GIP protected against diet-induced neural leptin resistance. Furthermore, a centrally administered antibody that neutralizes GIPR had remarkable antiobesity effects in diet-induced obese mice, including reduced body weight and adiposity, and a decreased hypothalamic level of SOCS3, an inhibitor of leptin actions. In contrast, centrally administered GIP diminished hypothalamic sensitivity to leptin and increased hypothalamic levels of Socs3. Finally, we show that GIP increased the active form of the small GTPase Rap1 in the brain and that its activation was required for the central actions of GIP. Altogether, our results identify GIPR/Rap1 signaling in the brain as a molecular pathway linking overnutrition to the control of neural leptin actions.
2015-07-13 | Monoclonal antibody targeting of fibroblast growth factor receptor 1c ameliorates obesity and glucose intolerance via central mechanisms.
We have generated a novel monoclonal antibody targeting human FGFR1c (R1c mAb) that caused profound body weight and body fat loss in diet-induced obese mice due to decreased food intake (with energy expenditure unaltered), in turn improving glucose control. R1c mAb also caused weight loss in leptin-deficient ob/ob mice, leptin receptor-mutant db/db mice, and in mice lacking either the melanocortin 4 receptor or the melanin-concentrating hormone receptor 1. In addition, R1c mAb did not change hypothalamic mRNA expression levels of Agrp, Cart, Pomc, Npy, Crh, Mch, or Orexin, suggesting that R1c mAb could cause food intake inhibition and body weight loss via other mechanisms in the brain. Interestingly, peripherally administered R1c mAb accumulated in the median eminence, adjacent arcuate nucleus and in the circumventricular organs where it activated the early response gene c-Fos. As a plausible mechanism and coinciding with the initiation of food intake suppression, R1c mAb induced hypothalamic expression levels of the cytokines Monocyte chemoattractant protein 1 and 3 and ERK1/2 and p70 S6 kinase 1 activation.
gene therapies
2023-11-03 | Single-Gene Defects and Obesity
Genetic forms of obesity are primarily linked to alteration in energy homeostasis (i.e., food intake and energy expenditure) involving hypothalamic neuronal networks. The leptin–melanocortin pathway, located within hypothalamic nuclei, plays a major role in regulating energy balance in humans. Disruption in this pathway is associated with severe early-onset obesity, due to impairment in hunger and satiety, leading to eating disorders such as hyperphagia, food impulsivity, and food-seeking behavior. Carriers of genetic variants in the leptin–melanocortin pathway can also display neurodevelopmental disorders, sensory impairments, endocrine deficiencies, and/or organ malformations. The genes initially described and involved in these genetic forms of obesity were those coding for leptin (LEP), leptin receptor (LEPR), proopiomelanocortin (POMC), prohormone convertase 1 (PC1), and melanocortin 4 receptor (MC4R). Recently, with the widespread use of powerful genetic sequencing tools, new genes coding for proteins located in the hypothalamic leptin–melanocortin pathway or regulating it have been identified. Some molecular mechanisms linking single-gene defects to obesity have been deciphered using in vitro and in vivo models. This has allowed innovative therapies to emerge. In patients with severe early-onset obesity, the implementation of genetic diagnosis in clinical practice now enables personalized medicine including comprehensive multidisciplinary and coordinated care.
2023-03-03 | LepRb+ cell-specific deletion of Slug mitigates obesity and nonalcoholic fatty liver disease in mice.
Leptin exerts its biological actions by activating the long-form leptin receptor (LepRb). LepRb signaling impairment and leptin resistance are believed to cause obesity. The transcription factor Slug - also known as Snai2 - recruits epigenetic modifiers and regulates gene expression by an epigenetic mechanism; however, its epigenetic action has not been explored in leptin resistance. Here, we uncover a proobesity function of neuronal Slug. Hypothalamic Slug was upregulated in obese mice. LepRb+ cell-specific Slug-knockout (SlugΔLepRb) mice were resistant to diet-induced obesity, type 2 diabetes, and liver steatosis and experienced decreased food intake and increased fat thermogenesis. Leptin stimulated hypothalamic Stat3 phosphorylation and weight loss to a markedly higher level in SlugΔLepRb than in Slugfl/fl mice, even before their body weight divergence. Conversely, hypothalamic LepRb+ neuron-specific overexpression of Slug, mediated by AAV-hSyn-DIO-Slug transduction, induced leptin resistance, obesity, and metabolic disorders in mice on a chow diet. At the genomic level, Slug bound to and repressed the LepRb promoter, thereby inhibiting LepRb transcription. Consistently, Slug deficiency decreased methylation of LepRb promoter H3K27, a repressive epigenetic mark, and increased LepRb mRNA levels in the hypothalamus. Collectively, these results unravel what we believe to be a previously unrecognized hypothalamic neuronal Slug/epigenetic reprogramming/leptin resistance axis that promotes energy imbalance, obesity, and metabolic disease.
2019-08-21 | Deficient ganglioside synthesis restores responsiveness to leptin and melanocortin signaling in obese KKAy mice.
GM3, a precursor for synthesis of a- and b-series gangliosides, is elevated in adipocytes of obese model animals and in sera of obese human patients with type 2 diabetes and/or dyslipidemia. GM3 synthase (GM3S)-KO C57BL/6 mice display enhanced insulin sensitivity and reduced development of high-fat diet-induced insulin resistance. However, the pathophysiological roles of GM3 and related gangliosides in the central control of feeding and metabolism remain unclear. We found that a mouse model (KKAy GM3S KO) generated by KO of the GM3S gene in the yellow obese strain, KKAy, displayed significant amelioration of obese phenotype. Whereas KKAy mice were hyperphagic and developed severe obesity, KKAy GM3S KO mice had significantly lower body weight and food intake, and greater glucose and insulin tolerance. The hypothalamic response to intraperitoneal administration of leptin was greatly reduced in KKAy mice, but was retained in KKAy GM3S KO mice. In studies of a cultured mouse hypothalamic neuronal cell line, enhanced leptin-dependent phosphorylation of ERK was observed in GM3S-deficient cells. Furthermore, KKAy GM3S KO mice did show altered coat color, suggesting that GM3S is also involved in melanocortin signaling. Our findings, taken together, indicate that GM3-related gangliosides play key roles in leptin and melanocortin signaling.
2016-05-12 | The thermogenic effect of leptin is dependent on a distinct population of prolactin-releasing peptide neurons in the dorsomedial hypothalamus.
Leptin is a critical regulator of metabolism, which acts on brain receptors (Lepr) to reduce energy intake and increase energy expenditure. Some of the cellular pathways mediating leptin's anorectic actions are identified, but those mediating the thermogenic effects have proven more difficult to decipher. We define a population of neurons in the dorsomedial hypothalamic nucleus (DMH) containing the RFamide PrRP, which is activated by leptin. Disruption of Lepr selectively in these cells blocks thermogenic responses to leptin and causes obesity. A separate population of leptin-insensitive PrRP neurons in the brainstem is required, instead, for the satiating actions of the gut-derived hormone cholecystokinin (CCK). Global deletion of PrRP (in a loxSTOPlox-PrRP mouse) results in obesity and attenuated responses to leptin and CCK. Cre-recombinase-mediated reactivation of PrRP in brainstem rescues the anorectic actions of CCK, but reactivation in the hypothalamus is required to re-establish the thermogenic effect of leptin.
2012-10-03 | IRS2 signaling in LepR-b neurons suppresses FoxO1 to control energy balance independently of leptin action.
Irs2-mediated insulin/IGF1 signaling in the CNS modulates energy balance and glucose homeostasis; however, the site for Irs2 function is unknown. The hormone leptin mediates energy balance by acting on leptin receptor (LepR-b)-expressing neurons. To determine whether LepR-b neurons mediate the metabolic actions of Irs2 in the brain, we utilized Lepr(cre) together with Irs2(L/L) to ablate Irs2 expression in LepR-b neurons (Lepr(ΔIrs2)). Lepr(ΔIrs2) mice developed obesity, glucose intolerance, and insulin resistance. Leptin action was not altered in young Lepr(ΔIrs2) mice, although insulin-stimulated FoxO1 nuclear exclusion was reduced in Lepr(ΔIrs2) mice. Indeed, deletion of Foxo1 from LepR-b neurons in Lepr(ΔIrs2) mice normalized energy balance, glucose homeostasis, and arcuate nucleus gene expression. Thus, Irs2 signaling in LepR-b neurons plays a crucial role in metabolic sensing and regulation. While not required for leptin action, Irs2 suppresses FoxO1 signaling in LepR-b neurons to promote energy balance and metabolism.
proteins
2026-09-21 | IL-1RA administration exerts diet-dependent metabolic effects on adipose tissue function and lipid handling in male mice.
Interleukin-1 (IL-1) signaling is a key mediator of metabolic inflammation, yet its tissue-specific contribution to obesity-associated dysfunction remains incompletely understood. Here, we investigated the effects of pharmacological IL-1 receptor antagonism on systemic metabolism, adipose tissue dysfunction, and hepatic lipid handling under distinct nutritional conditions. Male mice fed a normal diet (ND) or high-fat diet (HFD) were treated subcutaneously with the IL-1 receptor antagonist (IL-1RA) anakinra for three weeks. IL-1RA did not significantly affect body weight or global adiposity; however, under ND conditions, it reduced fat mass and circulating leptin levels and increased the adiponectin/leptin ratio, indicating improved adipose endocrine function. In adipose tissue, IL-1RA partially restored Acaca expression and selectively modulated extracellular matrix remodeling genes, including Mmp9, without broadly suppressing inflammatory markers. In the liver, triglyceride content was altered in a diet-dependent manner without changes in the expression of key metabolic genes (Fasn, Acaca, Ppara), suggesting that IL-1 blockade does not directly reprogram intrinsic hepatic lipid metabolism. Consistent with this, analyses in complementary models, including leptin-deficient mice, showed that Il1rn expression is regulated by local inflammatory and endocrine cues rather than adiposity per se. Together, these findings identify IL-1 signaling as a context-dependent modulator of adipose tissue function and systemic lipid handling. The dissociation between adipose tissue responses and hepatic triglyceride accumulation highlights the tissue-specific effects of IL-1 receptor antagonism and underscores the need for direct metabolic flux studies to define the mechanisms underlying these effects.
2026-03-14 | Inversed impaired osteogenic activity in children with severe obesity due to MC4R deficiency compared to LEP and LEPR deficiency.
Chronic obesity is associated with impaired bone health. However, few investigations have been conducted to assess bone physiology in early-onset obesity. In this study, we measured specific bone turnover and metabolic biomarkers in children with severe obesity with biallelic loss-of-function variants of the leptin (LEP), leptin receptor (LEPR), or melanocortin 4 receptor (MC4R) genes. Thirty-nine children aged 0.3-8.8 years with a BMI SDS ≥ 3, previously identified with pathogenic variants in LEP, LEPR, or MC4R, were recruited for the current study. Additionally, 13 age-matched children with severe obesity who tested negative for variants in known obesity-related genes were included, and another 13 unrelated age-matched children with normal body weight served as the control group. Serum osteocalcin, osteopontin, osteoprotegerin, and sclerostin levels were assessed using multi-analyte profiling. Serum leptin, insulin, and cortisol levels were determined using ELISA. Serum levels of osteocalcin and osteopontin, specific markers of bone formation, were significantly lower in children with LEP and LEPR biallelic variants than in the control group. In contrast, the values of these two biomarkers in children with MC4R deficiency were significantly higher than those in the other groups. No differences were observed in the bone resorption markers osteoprotegerin and sclerostin. Hyperleptinemia was more pronounced in children with LEPR deficiency. Serum insulin concentrations were elevated in individuals with MC4R deficiency, whereas serum cortisol levels were significantly higher in children with LEP deficiency than in all other groups. Our data demonstrate that osteogenic activity (but not resorption activity) is differentially affected in children with complete genetic disruption of the leptin-signaling pathway. Children with MC4R deficiency showed higher osteogenic markers, but children with LEP and LEPR deficiencies showed the opposite. Our results support the usefulness of bone turnover biomarkers for the assessment and management of bone health in different types of obesity.
2026-01-12 | Additive effect of leptin and palm-LEAP2(1-14) ameliorates obesity-induced metabolic stress in ob/ob mice.
Liver-enriched antimicrobial peptide 2 (LEAP2) can act as a natural antagonist or inverse agonist of the growth hormone secretagogue receptor, also known as the ghrelin receptor. In our previous studies, palm-LEAP2(1-14), a truncated palmitoylated analogue of LEAP2, proved highly stable and exerted an acute anorexigenic effect. Ghrelin, the endogenous agonist of the ghrelin receptor, and the anorexigenic hormone leptin have opposing effects on appetite. We hypothesized that leptin supplementation combined with long-term antagonism of the ghrelin receptor using palm-LEAP2(1-14) might have a beneficial and potentially additive effect on obesity-related metabolic stress in leptin-deficient ob/ob mice, influencing diabetes, liver steatosis, impaired locomotor activity, and hypothermia. Here, we demonstrated a clear additive effect of combined leptin and palm-LEAP2(1-14) treatment, which increased locomotor activity, reduced plasma cholesterol, liver steatosis, and mRNA expression of the metabolic stress marker Fgf21, and upregulated hypothalamic Pomc gene expression - outcomes not achieved by either treatment alone. Additionally, leptin, palm-LEAP2(1-14), and both treatments combined each reduced cumulative food intake and circulating FGF21 levels. Only leptin reduced body weight, elevated rectal temperature, increased Ucp1 and Pgc1 mRNA expression in brown adipose tissue, and attenuated hyperinsulinemia, indicating that the weight-reducing and antidiabetic effects were attributable to leptin - not palm-LEAP2(1-14). Liver metabolic stress was further alleviated by decreases in plasma FGF21 and hepatic expression of the lipogenic enzymes. Our study demonstrated the beneficial effects of palm-LEAP2(1-14) on obesity-induced metabolic stress, which were further attenuated when palm-LEAP2(1-14) was coadministered with leptin in ob/ob mice.
2025-11-18 | Obesity-induced leptin resistance is directly involved in skin fragility by decreasing type I collagen synthesis.
The relationship between obesity-induced leptin resistance and skin function remains unclear. In this study, we examined the effects of leptin signaling on collagen production in mouse skin. Mice were divided into three groups: control diet, high-fat diet, and switching diet (from the high-fat diet to the control diet). We measured the expression of leptin signaling-related genes and type I tropocollagen levels in the skin. In an additional experiment, leptin was administered to leptin-deficient ob/ob mice to examine the direct effect of leptin signaling on type I collagen synthesis in the skin. Type I tropocollagen levels and Ob-Rb gene expression were decreased in the high-fat diet group. These abnormalities were reversed by the switching diet. We also observed that type I tropocollagen levels were decreased in ob/ob mice, but this abnormality was reversed by leptin administration. It is likely that leptin will help to improve obesity-induced skin fragility.
2025-07-16 | Supplementary file 2_High fat diet-induced loss of pituitary plasticity in aging female mice with ablated leptin signaling in somatotropes.pdf
Introduction Somatotropes lacking leptin receptors (LEPR) produce less growth hormone and are poorly responsive to growth hormone releasing hormone (GHRH). Transcriptomic analysis reveals that the mutant somatotropes contain progenitor cell markers (Sox9+) and multiple pituitary hormone transcripts-(Pomc, Prl, Lhb, Tshb and Cga), suggesting that the cells are progenitor cells. The resulting GH deficiency contributes to adult-onset obesity in the mutant, due to an increase in abdominal fat. Objectives This study examined how a high-fat diet (HFD) affected pituitary transcriptomic function in older (10-month) female mutants lacking leptin receptors (LEPR) in somatotropes and intact littermate controls. We hypothesized that pituitary cells from both the older control females and the female mutants would be greatly affected by the oxidative stress from the HFD. Methods Mice were exposed to a 60% HFD for 16 weeks, followed by glucose tolerance testing and 3-day monitoring in metabolic cages (CLAMS). Pituitaries were harvested, cells dispersed and subjected to single cell-RNA-seq (scRNA-seq) with bioinformatic analysis. Serum was collected and analyzed for pituitary hormones and cytokines. Results The HFD resulted in elevated serum leptin and IL-6 in both mutants and controls, and reduced serum growth hormone (GH) and prolactin (PRL) levels. However, adrenocorticotropin (ACTH) levels were elevated in controls but not mutants. Unexpectedly, whereas controls gained as much weight as younger females, somatotrope LEPR-null mutants on a HFD gained only 75% of the weight of controls, were more glucose tolerant, consumed less food, were more active in the metabolic cages, and had lower serum levels of insulin. Analysis of scRNA-seq revealed that the HFD induced differentially expressed genes (DEGs) in more distinct pituitary cell populations of older mice compared to previously reported findings in younger control females, indicating greater vulnerability in the older pituitary population. This was especially true in the mutant pituitary population. Ingenuity Pathway Analysis indicated that the DEGs included targets of critical upstream regulators important for pituitary cell function and plasticity (CREB, Fox01, cAMP, STAT3, insulin, TRH, GnRH, and leptin signaling pathways), with most pathways predicted to be downregulated by the HFD. Unlike controls, HFD-fed mutant cell populations exhibited DEGs consistent with the downregulation of translational regulatory pathways. Notably, the HFD reversed the increased expression of progenitor cell markers (Sox9+) and multiple pituitary hormone transcripts seen in the mutant on a control diet. Similarly, the HFD also reversed the expression of multiple pituitary hormone transcripts and progenitor markers in lactotropes, thyrotropes, and corticotropes from mutants. Conclusion The findings supported our hypothesis that both aging and the mutation (loss of LEPR in somatotropes) would render these mice more sensitive to a HFD as more pituitary cell types were affected transcriptionally. Collectively, these findings indicate that HFD and/or obese state may compromise pituitary plasticity by down-regulating translational processes and reducing expression in cells that may have multipotential functions. The oxidative stress of a HFD may thus limit the expression of pituitary progenitor cells.
small molecules
2026-08-24 | Leptin Resistance, Obesity, and Gut Dysbiosis: The Role of Bitter Phytonutrients, Niacin, and Zinc [Review/Hypothesis]
Leptin resistance is a hallmark of obesity and metabolic syndrome, yet its mechanisms remain incompletely understood. This paper proposes that leptin resistance is driven, in part, by a deficiency of bitter phytonutrients, niacin, and zinc—nutrients required for the gene transcription and function of bitter taste receptors. Bitter taste receptors, expressed not only on the tongue but also in the gut and hypothalamus, may support or co-regulate leptin receptors, as suggested by the efficacy of pomegranate ellagitannins in improving leptin resistance or which may be due to urolithin-A promotion of leptin receptors and/or promotion of PPAR and mitochondrial function. Bitter taste receptors and phytonutrients are also protective due to satiety hormone promotion including GLP-1. This review synthesizes the literature on leptin, pomegranate polyphenols, bitter taste receptors, niacin, zinc, mitochondria, and the gut microbiome, and proposes a testable hypothesis: that restoring bitter phytonutrients, resistant starches, niacin, and zinc in the diet can improve leptin sensitivity, reduce inflammation, and support metabolic health. The paper includes a hyperinflammation positive feedback loop (Figure 1) with a fully cited narrative (Appendix F), a clinical protocol (Appendix A), functional food guidance (Appendix B), a clinical guidance with a Table of histamine-producing microbial strains (Appendix C) and a diagnostic flowchart for histamine excess and Retinoid Toxicity (Appendix D), and a summary of genes associated with histamine sensitivity and Retinoid Toxicity (Appendix E). This is a hypothesis-driven review with practical clinical translations—offering a framework for patients and practitioners to address leptin resistance through targeted nutrition and lifestyle changes.
2026-08-21 | HACD3 integrates central leptin sensitivity and peripheral thermogenesis to oppositely regulate energy balance.
The enzyme 3-hydroxyacyl-CoA-dehydratase 3 (HACD3) is involved in fatty acid synthesis, but its systemic role in metabolism is unknown. This study investigated the physiological function of HACD3 in energy homeostasis. Systemic HACD3 deficiency protected mice from diet-induced obesity by increasing energy expenditure and activating adipose thermogenesis. Conversely, deleting HACD3 specifically in leptin receptor-expressing neurons caused obesity, hyperphagia, and leptin resistance. In adipocytes, HACD3 cell-autonomously repressed thermogenesis by forming a complex with Keratin 1 (KRT1), which sequestered thermogenic transcription factors and maintained repressive chromatin. HACD3 ablation disrupted this complex, enabling nuclear translocation of PPARγ/PGC-1α and increasing transcription of thermogenic genes. In neurons, HACD3 is required for leptin receptor stability and signaling. HACD3 acts as a critical, tissue-specific regulator that simultaneously governs both sides of the energy balance equation-suppressing energy expenditure in adipose tissue while facilitating anorexigenic signaling in the brain. This dual function identifies HACD3 as a novel, multifaceted target for therapeutic intervention in metabolic disorders.
2026-07-25 | Monogenic and syndromic obesity in children: Clinical recognition, genetics, and precision management.
Obesity is increasingly being recognized as a heterogeneous condition with strong genetic underpinnings. Monogenic obesity, caused by single-gene mutations, primarily affects the leptin-melanocortin pathway, which regulates hunger and satiety. Mutations in genes, such as LEP, LEPR, POMC, PCSK1, and MC4R, lead to hyperphagia, early onset severe obesity, and metabolic dysregulation. LEP and LEPR mutations impair leptin signaling, resulting in defective appetite suppression, whereas POMC and PCSK1 deficiencies disrupt prohormone processing. MC4R mutations, the most common cause of monogenic obesity, impair satiety signaling and are linked to rapid weight gain. Syndromic obesity, including the Bardet-Biedl and Alström syndromes, involves ciliary dysfunction, leading to developmental abnormalities alongside obesity. Other genes such as SH2B1, SIM1, and BDNF play crucial roles in hypothalamic development and energy regulation. Advances in genomic sequencing have improved the recognition of genetic etiologies; however, many patients remain undiagnosed due to limited testing availability and a lack of clinician awareness. Precision therapies, including set-melanotide for specific melanocortin pathway defects, demonstrate the promise of targeted treatments. However, management must extend beyond pharmacology; lifestyle interventions, psychosocial support, and family-centered care remain essential, especially when intellectual disability or behavioral challenges complicate adherence. Ethical considerations surrounding access and equity are critical, as high-cost therapies and the limited availability of genetic testing risk widening disparities between health systems. Polygenic risk scores and multi-omics approaches may expand precision medicine beyond rare genetic syndromes to common obesity, highlighting the importance of integrating genetics, psychosocial care, and policy advocacy in the management of pediatric obesity.
2025-09-26 | Polymorphism of Melanocortin Receptor Genes-Association with Inflammatory Traits and Diseases.
Melanocortin receptors (MCRs) are responsible for various functions ranging from skin pigmentation, regulation of appetite, stress response and cognition, steroid synthesis, and energy balance to cellular regeneration and immunomodulation. The genetic polymorphism with tissue distribution ranging from the brain, limbic system, and adrenal cortex to neutrophils, monocytes, and macrophages is evident in MCRs. The mutations in MC1R, MC2R, MC3R, and MC4R genes are associated with risk of melanoma, familial glucocorticoid deficiency, obesity, and type 2 diabetes mellitus, respectively. Meanwhile, MC1R, MC2R, and MC5R genes are involved in the risk of major depressive disorder. Melanocortin receptors are involved in different inflammatory disorders, i.e., atopic dermatitis, autoimmune uveitis, sarcoidosis, respiratory diseases, multiple sclerosis, scleroderma, inflammatory bowel disease, amyotrophic lateral sclerosis, Alzheimer's disease, arthritis, and reperfusion injury. Several newer therapeutic agents related to MCRs have numerous advantages over the current anti-inflammatory drugs, demonstrating therapeutic relevance. Among them, α-MSH analogs play a role in atopic dermatitis and scleroderma, and MC1R agonist Dersimelagon has shown effectiveness in systemic sclerosis. The FDA has recently approved the repository corticotropin injection (RCI) to treat sarcoidosis. The FDA has also approved various melanocortin agonists, i.e., Bremelanotide, Afamelanotide, and Setmelanotide, for the treatment of hypoactive sexual desire disorder, Erythropoietic protoporphyria, and obesity, due to pro-opiomelanocortin and leptin receptor deficiency, respectively. Therefore, this review aims to summarize the function and genetic polymorphism of melanocortin receptors, regulatory pathways involving MCRs, and the existing evidence of the prime effect of MCRs on inflammatory responses via different mechanisms and their potential therapeutic use in inflammatory diseases.
2025-02-01 | Real-life experience on efficacy and safety of setmelanotide treatment in prepubertal children.
Monogenic obesity, characterized by severe, early-onset obesity due to single-gene defects, often resists traditional weight management strategies. This report presents real-life experiences on the efficacy and safety of setmelanotide, an MC4R agonist, in 4 prepubertal children (ages 3-9) with LEPR and POMC deficiencies. Findings indicate that setmelanotide is effective at lower doses in our patients with POMC deficiency (0.3-0.5 mg/day) than the patients with LEPR deficiency (2.5 mg/day). Treatment was generally well-tolerated, with injection site reactions and hyperpigmentation as common side effects. As novel findings, gonadotropin-related effects such as hypothalamo-pituitary-gonadal axis activation and testicular descent were observed in 2 patients. Growth deceleration was noted in 2 children, and recovery from central hypothyroidism in 1 patient with POMC deficiency. Overall, setmelanotide appears to be effective and well-tolerated in young children with monogenic obesity. However, further studies are necessary to evaluate the long-term effects of early intervention on growth and pubertal development.
antibodies
2025-10-04 | Leptin: 30 Years Later.
The discovery of leptin as an adipocyte-secreted hormone encoded by the ob gene whose absence produces severe obesity that is corrected by leptin repletion in both mice and humans was a transformative event in metabolic science. Leptin's discovery in 1994 accelerated the identification of central neuronal circuitry responsive to peripheral signals that regulate energy balance as well as metabolic, neuroendocrine, and other vital functions. Leptin's primary physiological role was initially viewed as preventing obesity by its levels rising, but subsequent research has emphasized the key role of falling levels to signal starvation. Resistance to leptin action, though partial, characterizes common forms of obesity. Despite much being learned about leptin signal transduction over 30 years, the precise molecular mechanisms for leptin resistance and common obesity remain unclear. Leptin therapy is effective in rare patients with congenital leptin deficiency and other low leptin conditions but not common obesity. Interestingly, reducing hyperleptinemia may prove useful in treating common obesity.
2025-02-28 | Blocking the SIRPα-CD47 axis promotes macrophage phagocytosis of exosomes derived from visceral adipose tissue and improves inflammation and metabolism in mice.
Adipose tissue plays a pivotal role in systemic metabolism and maintaining bodily homeostasis. Exosomes from adipose tissues, known as AT-Exos, are recognized as important messengers in the communication between adipose tissue and other organs. Despite this, the alterations in exosome composition and the functional disparities among depot-specific AT-Exos in obesity remain elusive. In this work, we utilized lipidomics and microRNA (miRNA) sequencing to elucidate the lipid and miRNA profiles of AT-Exos in a diet-induced obesity model. We identified obesity-related miRNAs in AT-Exos and further explored their mechanisms using gain- and loss-of-function experiments. To evaluate the metabolic effects of AT-Exos on adipocytes, we conducted RNA-sequencing (RNA-seq) and confirmed our findings through Quantitative Real-time PCR (qPCR) and Western bolt analyses. Meanwhile, a mouse model with intraperitoneal injections was utilized to validate the role of exosomes derived from visceral white adipose tissue (vWAT-Exos) in obesity progression in vivo. Finally, we explored potential therapeutic intervention strategies targeting AT-Exos, particularly focusing on modulating the SIRPα-CD47 axis to enhance macrophage phagocytosis using Leptin-deficient (ob/ob) mice and SIRPα knock-out mice. Our study revealed that obesity-related metabolism affects the biological processes of AT-Exos, with depot-specific secretion patterns. In obesity, the lipidome profile of AT-Exos was significantly altered, and diet can modify the miRNA content and function within these exosomes, influencing lipid metabolism and inflammatory pathways that contribute to metabolic dysregulation. Specifically, we identified that miR-200a-3p and miR-200b-3p promoted lipid accumulation in 3T3L1 cells partly through the PI3K/AKT/mTOR pathway. RNA-Seq analysis revealed that AT-Exos from different fat depots exerted distinct effects on adipocyte metabolism, with obese vWAT-Exos being notably potent in triggering inflammation and lipid accumulation in diet-induced obesity. Additionally, we found that inhibiting the SIRPα-CD47 axis can mitigate metabolic disorders induced by obese vWAT-Exos or ob/ob mice, partly due to the enhanced clearance of vWAT-Exos. Consistent with this, SIRPα-deficient mice exhibited a reduction in vWAT-Exos and displayed greater resistance to obesity. This study elucidates that diet-induced obesity altered the lipid and miRNA profiles of AT-Exos, which involved in modulating adipocyte inflammation and metabolic balance. The SIRPα-CD47 axis emerges as a potential therapeutic target for obesity and its associated complications.
2021-12-13 | IL-20 is involved in obesity by modulation of adipogenesis and macrophage dysregulation.
IL-20 is a proinflammatory cytokine of the IL-10 family and involved in several diseases. However, the regulatory role of IL-20 in obesity is not well understood. We explored the function of IL-20 in the pathogenesis of obesity-induced insulin resistance by ELISA, Western blotting and flow cytometry. The therapeutic potential of IL-20 monoclonal antibody 7E for ameliorating diet-induced obesity was analysed in murine models. Higher serum IL-20 levels were detected in obese patients. It was upregulated in leptin-deficient (ob/ob), leptin-resistant (db/db) and high-fat diet (HFD)-induced murine obesity models. In vitro, IL-20 regulated the adipocyte differentiation and the polarization of bone marrow-derived macrophages into proinflammatory M1 type. It also caused inflammation and macrophage retention in adipose tissues by upregulating TNF-α, monocyte chemotactic protein 1 (MCP-1), netrin 1 and unc5b (netrin receptor) expression in macrophages and netrin 1, leptin and MCP-1 in adipocytes. IL-20 promoted insulin resistance by inhibiting glucose uptake in mature adipocytes through the SOCS-3 pathway. In HFD-induced obesity in mice, 7E treatment reduced body weight and improved glucose tolerance and insulin sensitivity; it also reduced local inflammation and the number of M1-like macrophages in adipose tissues. We have identified a critical role of IL-20 in obesity-induced inflammation and insulin resistance, and we conclude that IL-20 may be a novel target for treating obesity and insulin resistance in patients with metabolic disorders.
2020-05-14 | Gut-derived GIP activates central Rap1 to impair neural leptin sensitivity during overnutrition.
Nutrient excess, a major driver of obesity, diminishes hypothalamic responses to exogenously administered leptin, a critical hormone of energy balance. Here, we aimed to identify a physiological signal that arises from excess caloric intake and negatively controls hypothalamic leptin action. We found that deficiency of the gastric inhibitory polypeptide receptor (Gipr) for the gut-derived incretin hormone GIP protected against diet-induced neural leptin resistance. Furthermore, a centrally administered antibody that neutralizes GIPR had remarkable antiobesity effects in diet-induced obese mice, including reduced body weight and adiposity, and a decreased hypothalamic level of SOCS3, an inhibitor of leptin actions. In contrast, centrally administered GIP diminished hypothalamic sensitivity to leptin and increased hypothalamic levels of Socs3. Finally, we show that GIP increased the active form of the small GTPase Rap1 in the brain and that its activation was required for the central actions of GIP. Altogether, our results identify GIPR/Rap1 signaling in the brain as a molecular pathway linking overnutrition to the control of neural leptin actions.
2015-07-13 | Monoclonal antibody targeting of fibroblast growth factor receptor 1c ameliorates obesity and glucose intolerance via central mechanisms.
We have generated a novel monoclonal antibody targeting human FGFR1c (R1c mAb) that caused profound body weight and body fat loss in diet-induced obese mice due to decreased food intake (with energy expenditure unaltered), in turn improving glucose control. R1c mAb also caused weight loss in leptin-deficient ob/ob mice, leptin receptor-mutant db/db mice, and in mice lacking either the melanocortin 4 receptor or the melanin-concentrating hormone receptor 1. In addition, R1c mAb did not change hypothalamic mRNA expression levels of Agrp, Cart, Pomc, Npy, Crh, Mch, or Orexin, suggesting that R1c mAb could cause food intake inhibition and body weight loss via other mechanisms in the brain. Interestingly, peripherally administered R1c mAb accumulated in the median eminence, adjacent arcuate nucleus and in the circumventricular organs where it activated the early response gene c-Fos. As a plausible mechanism and coinciding with the initiation of food intake suppression, R1c mAb induced hypothalamic expression levels of the cytokines Monocyte chemoattractant protein 1 and 3 and ERK1/2 and p70 S6 kinase 1 activation.
gene therapies
2023-11-03 | Single-Gene Defects and Obesity
Genetic forms of obesity are primarily linked to alteration in energy homeostasis (i.e., food intake and energy expenditure) involving hypothalamic neuronal networks. The leptin–melanocortin pathway, located within hypothalamic nuclei, plays a major role in regulating energy balance in humans. Disruption in this pathway is associated with severe early-onset obesity, due to impairment in hunger and satiety, leading to eating disorders such as hyperphagia, food impulsivity, and food-seeking behavior. Carriers of genetic variants in the leptin–melanocortin pathway can also display neurodevelopmental disorders, sensory impairments, endocrine deficiencies, and/or organ malformations. The genes initially described and involved in these genetic forms of obesity were those coding for leptin (LEP), leptin receptor (LEPR), proopiomelanocortin (POMC), prohormone convertase 1 (PC1), and melanocortin 4 receptor (MC4R). Recently, with the widespread use of powerful genetic sequencing tools, new genes coding for proteins located in the hypothalamic leptin–melanocortin pathway or regulating it have been identified. Some molecular mechanisms linking single-gene defects to obesity have been deciphered using in vitro and in vivo models. This has allowed innovative therapies to emerge. In patients with severe early-onset obesity, the implementation of genetic diagnosis in clinical practice now enables personalized medicine including comprehensive multidisciplinary and coordinated care.
2023-03-03 | LepRb+ cell-specific deletion of Slug mitigates obesity and nonalcoholic fatty liver disease in mice.
Leptin exerts its biological actions by activating the long-form leptin receptor (LepRb). LepRb signaling impairment and leptin resistance are believed to cause obesity. The transcription factor Slug - also known as Snai2 - recruits epigenetic modifiers and regulates gene expression by an epigenetic mechanism; however, its epigenetic action has not been explored in leptin resistance. Here, we uncover a proobesity function of neuronal Slug. Hypothalamic Slug was upregulated in obese mice. LepRb+ cell-specific Slug-knockout (SlugΔLepRb) mice were resistant to diet-induced obesity, type 2 diabetes, and liver steatosis and experienced decreased food intake and increased fat thermogenesis. Leptin stimulated hypothalamic Stat3 phosphorylation and weight loss to a markedly higher level in SlugΔLepRb than in Slugfl/fl mice, even before their body weight divergence. Conversely, hypothalamic LepRb+ neuron-specific overexpression of Slug, mediated by AAV-hSyn-DIO-Slug transduction, induced leptin resistance, obesity, and metabolic disorders in mice on a chow diet. At the genomic level, Slug bound to and repressed the LepRb promoter, thereby inhibiting LepRb transcription. Consistently, Slug deficiency decreased methylation of LepRb promoter H3K27, a repressive epigenetic mark, and increased LepRb mRNA levels in the hypothalamus. Collectively, these results unravel what we believe to be a previously unrecognized hypothalamic neuronal Slug/epigenetic reprogramming/leptin resistance axis that promotes energy imbalance, obesity, and metabolic disease.
2019-08-21 | Deficient ganglioside synthesis restores responsiveness to leptin and melanocortin signaling in obese KKAy mice.
GM3, a precursor for synthesis of a- and b-series gangliosides, is elevated in adipocytes of obese model animals and in sera of obese human patients with type 2 diabetes and/or dyslipidemia. GM3 synthase (GM3S)-KO C57BL/6 mice display enhanced insulin sensitivity and reduced development of high-fat diet-induced insulin resistance. However, the pathophysiological roles of GM3 and related gangliosides in the central control of feeding and metabolism remain unclear. We found that a mouse model (KKAy GM3S KO) generated by KO of the GM3S gene in the yellow obese strain, KKAy, displayed significant amelioration of obese phenotype. Whereas KKAy mice were hyperphagic and developed severe obesity, KKAy GM3S KO mice had significantly lower body weight and food intake, and greater glucose and insulin tolerance. The hypothalamic response to intraperitoneal administration of leptin was greatly reduced in KKAy mice, but was retained in KKAy GM3S KO mice. In studies of a cultured mouse hypothalamic neuronal cell line, enhanced leptin-dependent phosphorylation of ERK was observed in GM3S-deficient cells. Furthermore, KKAy GM3S KO mice did show altered coat color, suggesting that GM3S is also involved in melanocortin signaling. Our findings, taken together, indicate that GM3-related gangliosides play key roles in leptin and melanocortin signaling.
2016-05-12 | The thermogenic effect of leptin is dependent on a distinct population of prolactin-releasing peptide neurons in the dorsomedial hypothalamus.
Leptin is a critical regulator of metabolism, which acts on brain receptors (Lepr) to reduce energy intake and increase energy expenditure. Some of the cellular pathways mediating leptin's anorectic actions are identified, but those mediating the thermogenic effects have proven more difficult to decipher. We define a population of neurons in the dorsomedial hypothalamic nucleus (DMH) containing the RFamide PrRP, which is activated by leptin. Disruption of Lepr selectively in these cells blocks thermogenic responses to leptin and causes obesity. A separate population of leptin-insensitive PrRP neurons in the brainstem is required, instead, for the satiating actions of the gut-derived hormone cholecystokinin (CCK). Global deletion of PrRP (in a loxSTOPlox-PrRP mouse) results in obesity and attenuated responses to leptin and CCK. Cre-recombinase-mediated reactivation of PrRP in brainstem rescues the anorectic actions of CCK, but reactivation in the hypothalamus is required to re-establish the thermogenic effect of leptin.
2012-10-03 | IRS2 signaling in LepR-b neurons suppresses FoxO1 to control energy balance independently of leptin action.
Irs2-mediated insulin/IGF1 signaling in the CNS modulates energy balance and glucose homeostasis; however, the site for Irs2 function is unknown. The hormone leptin mediates energy balance by acting on leptin receptor (LepR-b)-expressing neurons. To determine whether LepR-b neurons mediate the metabolic actions of Irs2 in the brain, we utilized Lepr(cre) together with Irs2(L/L) to ablate Irs2 expression in LepR-b neurons (Lepr(ΔIrs2)). Lepr(ΔIrs2) mice developed obesity, glucose intolerance, and insulin resistance. Leptin action was not altered in young Lepr(ΔIrs2) mice, although insulin-stimulated FoxO1 nuclear exclusion was reduced in Lepr(ΔIrs2) mice. Indeed, deletion of Foxo1 from LepR-b neurons in Lepr(ΔIrs2) mice normalized energy balance, glucose homeostasis, and arcuate nucleus gene expression. Thus, Irs2 signaling in LepR-b neurons plays a crucial role in metabolic sensing and regulation. While not required for leptin action, Irs2 suppresses FoxO1 signaling in LepR-b neurons to promote energy balance and metabolism.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
4 orphan drug designations for Obesity due to leptin receptor gene deficiency, including 2 approved therapies.
4 orphan drug designations for Obesity due to leptin receptor gene deficiency, including 2 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
small molecule agonist of the melanocortin 4 receptor (MC4R) | small molecules | FDA | Palatin Technologies, Inc. | |
Small molecule melanocortin 4 receptor agonist | small molecules | FDA | Rhythm Pharmaceuticals, Inc. | |
Setmelanotide [Imcivree] | peptides | EMA | Approved | Rhythm Pharmaceuticals Netherlands B.V. |
setmelanotide [Imcivree] | peptides | FDA | Approved | Rhythm Pharmaceuticals, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.