RARE DISEASE
Obesity due to pro-opiomelanocortin deficiency
Obesity due to pro-opiomelanocortin deficiency
Obesity due to pro-opiomelanocortin deficiency
Synonyms: POMC deficiency
Synonyms: POMC deficiency
Synonyms: POMC deficiency
Drug discovery
3
drugs
With orphan designations
Overview
Obesity due to pro-opiomelanocortin (POMC) deficiency is a rare autosomal recessive disorder caused by biallelic POMC mutations, disrupting melanocortin signaling. It presents with severe hyperphagia, early-onset obesity, adrenal insufficiency, and hypopigmentation (red hair, pale skin). Neonates may experience hypoglycemia, seizures, and cholestasis [1][2][15]. Management focuses on glucocorticoid replacement and MC4R agonist therapy (e.g., setmelanotide), which targets hyperphagia and obesity [3][5][7].
Burden
Therapies
Categories: rare endocrine diseases, rare genetic diseases
Research Papers
626 drug discovery papers about Obesity due to pro-opiomelanocortin deficiency, with 2 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
626 drug discovery papers about Obesity due to pro-opiomelanocortin deficiency, with 2 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
2026-03-18 | Short Stature and Growth Hormone Deficiency in POMC Deficiency: An Unexpected Clinical Association.
Proopiomelanocortin (POMC) deficiency is a rare monogenic obesity syndrome typically characterized by early-onset obesity, red hair, and hypopigmentation, while linear growth is usually preserved. We report an adolescent girl with genetically confirmed POMC deficiency who developed short stature with biochemically confirmed growth hormone deficiency (GHD). She was diagnosed at 3.5 years of age with a homozygous c.64delA (p.Thr22Leufs*29) variant. Progressive growth deceleration became apparent after 12 years of age. At 13 years, her weight was 56.7 kg (+0.8 SDS), height was 143.0 cm (-2.5 SDS), and BMI was 27.1 kg/m² (+2.0 SDS). Growth velocity was 1.64 cm/year (-1.61 SDS), and pubertal stage was Tanner I. At 14 years of age, bone age was 10 years. IGF-1 was low at 82.8 µg/L (SDS: -2.28), and IGFBP-3 was 2.3 mg/L (SDS: -3.84). After euthyroidism had been achieved and estrogen priming had been completed, GH stimulation testing with L-DOPA and clonidine showed peak GH levels of 0.52 and 1.0 µg/L, respectively. Pituitary MRI was normal. Recombinant GH therapy (0.035 mg/kg/day) was initiated at 14 years 3 months. After 9 months, height increased to 150.2 cm (-1.95 SDS), BMI was 26.51 kg/m² (+1.79 SDS), and growth velocity improved to 11.29 cm/year, with no adverse events during follow-up. This case expands the clinical spectrum of POMC deficiency by demonstrating short stature with biochemically confirmed GHD and a notable early growth response to GH therapy. Further studies are needed to clarify the underlying mechanisms and to guide follow-up and management.
2025-10-17 | Effect of Tirzepatide in an Adolescent With Early-Onset Obesity, Hyperphagia, and Type 2 Diabetes
Early-onset severe obesity is rare and largely treatment-resistant to standard measures. Etiologies include syndromic disorders (Prader-Willi, Bardet-Biedl and Alström syndromes), monogenic defects of appetite-regulating pathways - most significantly melanocortin-4-receptor (MC4R) deficiency, but also leptin receptor (LEPR), pro-opiomelanocortin (POMC), and secondary hypothalamic injury, most commonly craniopharyngiomas. Most childhood obesity, however, is polygenic, arising from interactions of environmental and genetic factors. In many patients, no clear etiology is identified. Treatment remains challenging, particularly if hyperphagia and reduced satiety are predominant presenting features. We describe the case of a 19-year-old male with a history of autism spectrum disorder, attention-deficit hyperactivity disorder (ADHD), type 2 diabetes mellitus (T2DM) and morbid obesity, who showed a clinically significant response to tirzepatide therapy following failed conventional interventions. This case highlights the potential role of dual incretin therapy in adolescents with severe early-onset obesity and hyperphagia, even in the absence (based on present knowledge) of identifiable hypothalamic or genetic pathology.
2025-07-28 | Liraglutide induces enhanced suppression of food intake in mice lacking the growth hormone secretagogue receptor
The glucagon-like peptide-1 receptor (GLP-1R) and the growth hormone secretagogue receptor (GHSR) exert opposing effects on food intake. GLP-1R activation produces potent appetite-suppressing effects, whereas GHSR activation strongly stimulates food intake. Here, we tested the hypothesis that blocking GHSR could affect the anorectic and weight-reducing effects of liraglutide, a GLP-1R agonist widely used to treat diabetes and obesity. We first found that liraglutide induced a stronger reduction in food intake in ad libitum-fed GHSR-deficient mice compared to wild-type (WT) controls, regardless of sex. Liraglutide treatment also resulted in greater gastric content mass in ad libitum-fed GHSR-deficient mice than in WT mice. Interestingly, GLP-1R immunolabeling was elevated in the paraventricular nucleus of the hypothalamus (PVH) in GHSR-deficient mice, whereas the number of proopiomelanocortin (POMC) neurons and liraglutide-induced c-Fos activation-either in the entire arcuate nucleus or specifically within POMC neurons-remained unchanged compared to WT controls. Liraglutide-induced c-Fos expression in the lateral septum and PVH was reduced in GHSR-deficient mice. Conversely, pharmacological GHSR blockade using either JMV2959 or the endogenous antagonist/inverse agonist liver-expressed antimicrobial peptide 2 did not enhance liraglutide-induced food intake reduction. In conclusion, our findings reveal that genetic GHSR deficiency amplifies liraglutide's anorectic effects and provide new insight into the neurobiological mechanisms underlying this interaction. These results suggest that dual modulation of the GHSR and GLP-1R systems may represent a promising strategy for obesity treatment, though careful selection of GHSR-targeting agents and therapeutic protocols will be essential to optimize clinical outcomes.
2024-10-31 | Leptin-activated hypothalamic BNC2 neurons acutely suppress food intake.
Leptin is an adipose tissue hormone that maintains homeostatic control of adipose tissue mass by regulating the activity of specific neural populations controlling appetite and metabolism1. Leptin regulates food intake by inhibiting orexigenic agouti-related protein (AGRP) neurons and activating anorexigenic pro-opiomelanocortin (POMC) neurons2. However, whereas AGRP neurons regulate food intake on a rapid time scale, acute activation of POMC neurons has only a minimal effect3-5. This has raised the possibility that there is a heretofore unidentified leptin-regulated neural population that rapidly suppresses appetite. Here we report the discovery of a new population of leptin-target neurons expressing basonuclin 2 (Bnc2) in the arcuate nucleus that acutely suppress appetite by directly inhibiting AGRP neurons. Opposite to the effect of AGRP activation, BNC2 neuronal activation elicited a place preference indicative of positive valence in hungry but not fed mice. The activity of BNC2 neurons is modulated by leptin, sensory food cues and nutritional status. Finally, deleting leptin receptors in BNC2 neurons caused marked hyperphagia and obesity, similar to that observed in a leptin receptor knockout in AGRP neurons. These data indicate that BNC2-expressing neurons are a key component of the neural circuit that maintains energy balance, thus filling an important gap in our understanding of the regulation of food intake and leptin action.
2024-06-14 | 1527-P: G Protein Gsα Is Required for Normal Glucose Sensing in POMC Neurons
Proopiomelanocortin (POMC) neurons are glucose-sensing neurons in which increased ambient glucose concentrations lead to neuronal activation by a mechanism involving KATP channels. Since glucose sensing in pancreatic β-cells occurs by a similar mechanism and requires G protein Gsα/cAMP signaling, we hypothesized that Gsα may also be involved in glucose sensing in POMC neurons. To test this hypothesis, we generated mouse models with POMC neuron-specific Gsα deficiency (POMCGsKO) or expression of a constitutively activated Gsα (POMCGsR201C). Despite having normal body weight and composition, POMCGsKO mice were hyperglycemic, hypoinsulinemic, glucose intolerant, and had impaired insulin response to glucose loading in vivo. In contrast, POMCGsR201C mice showed increased fat mass but improved glucose tolerance and enhanced insulin response to i.p. glucose administration. This altered glucose homeostasis by Gsα deficiency or activation in POMC neurons was not due to an autonomous pancreatic β-cell defect as both POMCGsKO and POMCGsR201C mice displayed normal pancreatic islet size and number, unchanged β-cell mass and intact glucose-stimulated insulin secretion from isolated islets ex vivo compared to controls. Instead, POMCGsKO mice lacked glucose-stimulated POMC neuron activation as determined by induction of c-fos expression, while POMCGsR201C mice exhibited higher basal c-fos activity in POMC neurons. These results indicate that Gsα is required for normal glucose sensing in POMC neurons which provide feedback to pancreatic islets to maintain glucose homeostasis. Disclosure D. Layton: None. H. Sun: None. M. Gupta: None. Z. Cui: None. M. Chen: None. O. Gavrilova: None. M.T. Collins: None. L. Weinstein: None. Funding NIDDK Intramural Research Program
small molecules
2026-08-14 | Precision Medicine in patients with rare forms of genetic obesity: Necessity for coordinated and structured care
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.
2026-04-21 | A systematic literature review of economic evaluations of setmelanotide.
PURPOSE: This systematic literature review (SLR) aimed to assess the economic value of setmelanotide, a selective melanocortin-4 receptor agonist, in the treatment of rare genetic diseases of obesity (RGDOs), specifically Bardet-Biedl syndrome (BBS), pro-opiomelanocortin (POMC) deficiency, and leptin receptor (LEPR) deficiency. METHODS: The SLR was conducted according to PRISMA guidelines and registered on PROSPERO. Systematic searches were performed in Embase, MEDLINE/PubMed, and Global Health, supplemented by manual searches and reference screening. Inclusion criteria included full economic evaluations (cost-effectiveness and cost-utility analyses) published in English since 2019. Data extraction and quality assessment followed established checklists (BMJ, CHEERS 2022), with findings synthesised descriptively due to heterogeneity in study designs and settings. RESULTS: Four studies (one CEA, three CUAs) met inclusion criteria, all employing model-based frameworks from a healthcare payer perspective with a lifetime horizon. Incremental cost-effectiveness ratios (ICERs) varied: NICE appraisals in the UK suggested potentially favorable or even negative ICERs, while the Canadian CADTH review reported ICERs exceeding CAD $2 million/QALY, far above conventional willingness-to-pay thresholds. Key drivers included drug acquisition cost, severity of hyperphagia, and caregiver burden. All studies noted significant uncertainty due to limited long-term data and small patient populations. CONCLUSIONS: While setmelanotide demonstrates clinical benefit in RGDOs, its high cost poses substantial challenges to conventional pharmacoeconomic evaluations. Adoption may require significant price reductions or alternative value assessment frameworks, particularly for rare diseases. Further research is needed to address long-term effectiveness and ethical considerations in economic evaluations.
2026-03-31 | TonEBP as a key regulator of hypothalamic leptin signaling and resistance
Tonicity-responsive enhancer binding protein (TonEBP) is a transcription factor implicated in cellular stress and inflammation. Here, we explore the role of TonEBP as a key regulator of leptin signaling and resistance. Using TonEBP haploinsufficient [TonEBP (+/-)] mice, we demonstrated that TonEBP negatively regulates leptin sensitivity by upregulating suppressor of cytokine signaling 3 (SOCS3). TonEBP (+/-) mice exhibited heightened leptin-induced anorexia, increased energy expenditure, and elevated STAT3 phosphorylation in proopiomelanocortin (POMC) neurons compared to wild-type [TonEBP (+/+)] controls. Additionally, TonEBP (+/-) mice were protected from high-fat diet-induced obesity and retained leptin sensitivity during chronic energy surplus conditions. Mechanistically, TonEBP deficiency suppressed SOCS3 expression through decreased NF-κB-mediated transcriptional activation, thereby suppressing the negative feedback signal on leptin signaling. Furthermore, elevated hypothalamic TonEBP expression during high-fat diet feeding and leptin treatment implicates its role in regulating leptin sensitivity. Taken together, these findings identify a novel role for TonEBP as a molecular mediator of hypothalamic leptin signaling.
2026-02-21 | Efficacy of GLP-1 analog peptides, semaglutide, tirzepatide, and retatrutide on MC4R deficient obesity and their comparison
INTRODUCTION: Melanocortin 4 receptor (MC4R) is a G-protein-coupled receptor expressed in the hypothalamus, playing a key role in regulating feeding behavior and energy homeostasis. MC4R is integral to the POMC-MC4R and leptin-MC4R pathways, which control food intake and body weight. Mutations in the POMC gene lead to severe early-onset obesity and increased food consumption. Recently, glucagon-like peptide-1 (GLP-1) analogs, including semaglutide, tirzepatide, and retatrutide, have been explored as potential anti-obesity therapies. METHODS: This study aimed to assess and compare the efficacy of these GLP-1 analogs in MC4R knockout (KO) mice, which are deficient in the POMC-MC4R pathway. GLP-1 analogs were administered for 21 days to MC4R KO mice and compared their efficacy. RESULTS: The percentage of body weight reduction was 19.7 ± 4.1% for semaglutide, 31.6 ± 7.6% for tirzepatide, and 24.1 ± 5.8% for retatrutide. Body composition analysis, including fat and lean mass, was performed using the Echo-MRI system, revealing significant suppression of both fat and lean mass by all three GLP-1 analogs. Furthermore, GLP-1 analogs improved plasma insulin levels, HOMA-IR, cholesterol levels, and markers of liver damage (AST and ALT), as well as reduced liver hypertrophy. While GLP-1 analogs suppressed genes related to fatty acid synthesis, they had no significant effect on inflammation-related gene expressions. Additionally, GLP-1 analogs reduced energy expenditure, with only tirzepatide showing a significant decrease in the respiratory quotient (RQ) in MC4R KO mice. CONCLUSION: Our findings demonstrate that all three GLP-1 analogs, semaglutide, tirzepatide, and retatrutide, exhibit significant anti-obesity effects in MC4R KO mice. These results suggest that GLP-1 analogs may provide an effective treatment option for patients with MC4R-POMC pathway deficiencies. Moreover, the efficacy of these drugs in MC4R KO mice aligns with clinical studies, indicating that MC4R KO mice serve as a reliable animal model for obesity research.
2026-02-09 | Monogenic and syndromic obesity in children: Clinical recognition, genetics, and precision management
ABSTRACT 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.
gene therapies
2026-04-16 | POMC neuron METTL14/m6A/YTHDC1/YTHDF2 pathways safeguard energy balance, body weight, and metabolism.
METTL14 mediates N6-methyladenosine (m6A) RNA modification, while YTHDC1 and YTHDF2 specifically bind m6A-methylated RNA to regulate RNA fate. POMC neurons constitute the core of the central melanocortin circuit, and POMC deficiency causes obesity in both mice and humans. However, how m6A-based epitranscriptomics regulates melanocortin circuit function remains unclear. Here, we generated and characterized POMC neuron-specific knockout mice lacking Mettl14 (Mettl14ΔPOMC), Ythdc1 (Ythdc1ΔPOMC), or Ythdf2 (Ythdf2 ΔPOMC). Mettl14ΔPOMC and Ythdc1ΔPOMC mice develop hyperphagia, obesity, glucose intolerance, insulin resistance, and hepatic steatosis in both sexes under standard chow conditions, accompanied by POMC downregulation. Conversely, POMC neuron-specific overexpression of METTL14 or YTHDC1 protects against diet-induced obesity. In contrast, Ythdf2 ΔPOMC mice are resistant to obesity, revealing an m6A-dependent balance between YTHDC1 and YTHDF2. Mechanistically, the METTL14/YTHDC1 pathway is indispensable for embryonic POMC neurogenesis, while in adults YTHDC1 maintains melanocortin circuit integrity/function. METTL14 and YTHDC1 directly target POMC and ISL1 transcripts to regulate protein expression. POMC neuron-specific restoration of POMC reverses obesity and metabolic phenotypes in Mettl14ΔPOMC and Ythdc1ΔPOMC mice, defining an anti-obesity METTL14/m6A/YTHDC1/POMC axis. These findings identify METTL14 as the m6A writer for POMC/ISL1 and YTHDC1 and YTHDF2 as their readers, uncovering a critical role of m6A epitranscriptomic regulation in melanocortin circuit development and maintenance.
2024-03-06 | Hypothalamic POMC neuron-specific knockout of MC4R affects insulin sensitivity by regulating Kir2.1
Abstract Background Imbalance in energy regulation is a major cause of insulin resistance and diabetes. Melanocortin-4 receptor (MC4R) signaling at specific sites in the central nervous system has synergistic but non-overlapping functions. However, the mechanism by which MC4R in the arcuate nucleus (ARC) region regulates energy balance and insulin resistance remains unclear. Methods The MC4R flox/flox mice with proopiomelanocortin (POMC) -Cre mice were crossed to generate the POMC-MC4R flox/+ mice. Then POMC-MC4R flox/+ mice were further mated with MC4R flox/flox mice to generate the POMC-MC4R flox/flox mice in which MC4R is selectively deleted in POMC neurons. Bilateral injections of 200 nl of AAV-sh-Kir2.1 (AAV-sh-NC was used as control) were made into the ARC of the hypothalamus. Oxygen consumption, carbon dioxide production, respiratory exchange ratio and energy expenditure were measured by using the CLAMS; Total, visceral and subcutaneous fat was analyzed using micro-CT. Co-immunoprecipitation assays (Co-IP) were used to analyze the interaction between MC4R and Kir2.1 in GT1-7 cells. Results POMC neuron-specific ablation of MC4R in the ARC region promoted food intake, impaired energy expenditure, leading to increased weight gain and impaired systemic glucose homeostasis. Additionally, MC4R ablation reduced the activation of POMC neuron, and is not tissue-specific for peripheral regulation, suggesting the importance of its central regulation. Mechanistically, sequencing analysis and Co-IP assay demonstrated a direct interaction of MC4R with Kir2.1. Knockdown of Kir2.1 in POMC neuron-specific ablation of MC4R restored the effect of MC4R ablation on energy expenditure and systemic glucose homeostasis, indicating by reduced body weight and ameliorated insulin resistance. Conclusion Hypothalamic POMC neuron-specific knockout of MC4R affects energy balance and insulin sensitivity by regulating Kir2.1. Kir2.1 represents a new target and pathway that could be targeted in obesity.
2023-11-29 | CerS6-dependent ceramide synthesis in hypothalamic neurons promotes ER/mitochondrial stress and impairs glucose homeostasis in obese mice
Dysregulation of hypothalamic ceramides has been associated with disrupted neuronal pathways in control of energy and glucose homeostasis. However, the specific ceramide species promoting neuronal lipotoxicity in obesity have remained obscure. Here, we find increased expression of the C16:0 ceramide-producing ceramide synthase (CerS)6 in cultured hypothalamic neurons exposed to palmitate in vitro and in the hypothalamus of obese mice. Conditional deletion of CerS6 in hypothalamic neurons attenuates high-fat diet (HFD)-dependent weight gain and improves glucose metabolism. Specifically, CerS6 deficiency in neurons expressing pro-opiomelanocortin (POMC) or steroidogenic factor 1 (SF-1) alters feeding behavior and alleviates the adverse metabolic effects of HFD feeding on insulin sensitivity and glucose tolerance. POMC-expressing cell-selective deletion of CerS6 prevents the diet-induced alterations of mitochondrial morphology and improves cellular leptin sensitivity. Our experiments reveal functions of CerS6-derived ceramides in hypothalamic lipotoxicity, altered mitochondrial dynamics, and ER/mitochondrial stress in the deregulation of food intake and glucose metabolism in obesity.
2023-06-09 | Agrp-negative arcuate NPY neurons drive feeding under positive energy balance via altering leptin responsiveness in POMC neurons.
Neuropeptide Y (NPY) in the arcuate nucleus (ARC) is known as one of the most critical regulators of feeding. However, how NPY promotes feeding under obese conditions is unclear. Here, we show that positive energy balance, induced by high-fat diet (HFD) or in genetically obese leptin-receptor-deficient mice, leads to elevated Npy2r expression especially on proopiomelanocortin (POMC) neurons, which also alters leptin responsiveness. Circuit mapping identified a subset of ARC agouti-related peptide (Agrp)-negative NPY neurons that control these Npy2r expressing POMC neurons. Chemogenetic activation of this newly discovered circuitry strongly drives feeding, while optogenetic inhibition reduces feeding. Consistent with that, lack of Npy2r on POMC neurons leads to reduced food intake and fat mass. This suggests that under energy surplus conditions, when ARC NPY levels generally drop, high-affinity NPY2R on POMC neurons is still able to drive food intake and enhance obesity development via NPY released predominantly from Agrp-negative NPY neurons.
2023-04-06 | TLR4 in POMC neurons regulates thermogenesis in a sex-dependent manner
The rising prevalence of obesity has become a worldwide health concern. Obesity usually occurs when there is an imbalance between energy intake and energy expenditure. However, energy expenditure consists of several components, including metabolism, physical activity, and thermogenesis. Toll-like receptor 4 (TLR4) is a transmembrane pattern recognition receptor, and it is abundantly expressed in the brain. Here, we showed that pro-opiomelanocortin (POMC)-specific deficiency of TLR4 directly modulates brown adipose tissue thermogenesis and lipid homeostasis in a sex-dependent manner. Deleting TLR4 in POMC neurons is sufficient to increase energy expenditure and thermogenesis resulting in reduced body weight in male mice. POMC neuron is a subpopulation of tyrosine hydroxylase neurons and projects into brown adipose tissue, which regulates the activity of sympathetic nervous system and contributes to thermogenesis in POMC-TLR4-KO male mice. By contrast, deleting TLR4 in POMC neurons decreases energy expenditure and increases body weight in female mice, which affects lipolysis of white adipose tissue (WAT). Mechanistically, TLR4 KO decreases the expression of the adipose triglyceride lipase and lipolytic enzyme hormone-sensitive lipase in WAT in female mice. Furthermore, the function of immune-related signaling pathway in WAT is inhibited because of obesity, which exacerbates the development of obesity reversely. Together, these results demonstrate that TLR4 in POMC neurons regulates thermogenesis and lipid balance in a sex-dependent manner.
oligonucleotides
2023-03-22 | miRNA-383 and miRNA-384 Suppress Proopiomelanocortin Gene Expression in the Hypothalamus: Effects of Early Life Ethanol Exposure
Introduction: Early life ethanol exposure is known to program hypothalamic proopiomelanocortin (POMC) neurons to express a reduced level of POMC and its control of stress axis functions throughout the life span. In this study, we tested whether miRNAs contribute to the ethanol-induced suppression of Pomc gene expression during the developmental period. Methods: In in vivo studies, POMC-EGFP male mice were fed with 2.5 g/kg ethanol using milk formula (AF), pair-fed isocaloric milk formula, or left in the litter during postnatal days (PNDs) 2–6. In in vitro studies, mHypoA-POMC/GFP cells were treated with ethanol (50 m<sc>M</sc>) for a 24-h period. Hypothalamic tissues or cell extracts were used for measurement of miRNAs and POMC mRNA. Results: Determination of genome-wide microRNA expression profile identified 40 miRNAs significantly altered in hypothalamic tissues of AF mice. In silico analysis further identified miRNA-383, -384, and -488 have putative binding sites at the POMC 3′UTR. However, only miR-383 and miR-384 are identified to be responsive to ethanol. Administration of miR-383 or -384 inhibitor oligos suppressed ethanol-stimulated miR-383 or -384 expression and restored Pomc mRNA and protein expression in AF mice. mHypoA-POMC/GFP cells when treated with ethanol showed elevated levels of miR-383 and miR-384 and reduced level of Pomc mRNA. Treatment with miR-383 or -384 mimic oligos reduced the level of Pomc mRNA, while treatment with miR-383 or -384 inhibitor oligos increased the level of Pomc mRNA. Reporter assay further confirms the binding specificity of miR-383 and miR-384 to Pomc 3’UTR. Conclusion: These data suggest that miR-383 and miR-384 suppress Pomc gene expression and may contribute to the ethanol-induced alteration of the stress axis functions.
2022-09-29 | MicroRNA-7 regulates melanocortin circuits involved in mammalian energy homeostasis
MicroRNAs (miRNAs) modulate physiological responses by repressing the expression of gene networks. We found that global deletion of microRNA-7 (miR-7), the most enriched miRNA in the hypothalamus, causes obesity in mice. Targeted deletion of miR-7 in Single-minded homolog 1 (Sim1) neurons, a critical component of the hypothalamic melanocortin pathway, causes hyperphagia, obesity and increased linear growth, mirroring Sim1 and Melanocortin-4 receptor (MC4R) haplo-insufficiency in mice and humans. We identified Snca (α-Synuclein) and Igsf8 (Immunoglobulin Superfamily Member 8) as miR-7 target genes that act in Sim1 neurons to regulate body weight and endocrine axes. In humans, MIR-7-1 is located in the last intron of HNRNPK, whose promoter drives the expression of both genes. Genetic variants at the HNRNPK locus that reduce its expression are associated with increased height and truncal fat mass. These findings demonstrate that miR-7 suppresses gene networks involved in the hypothalamic melanocortin pathway to regulate mammalian energy homeostasis.
2022-08-25 | Magel2 knockdown in hypothalamic POMC neurons innervating the medial amygdala reduces susceptibility to diet-induced obesity.
Hyperphagia and obesity profoundly affect the health of children with Prader–Willi syndrome (PWS). The Magel2 gene among the genes in the Prader–Willi syndrome deletion region is expressed in proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARC). Knockout of the Magel2 gene disrupts POMC neuronal circuits and functions. Here, we report that loss of the Magel2 gene exclusively in ARC POMC neurons innervating the medial amygdala (MeA) causes a reduction in body weight in both male and female mice fed with a high-fat diet. This anti-obesity effect is associated with an increased locomotor activity. There are no significant differences in glucose and insulin tolerance in mice without the Magel2 gene in ARC POMC neurons innervating the MeA. Plasma estrogen levels are higher in female mutant mice than in controls. Blockade of the G protein–coupled estrogen receptor (GPER), but not estrogen receptor-α (ER-α), reduces locomotor activity in female mutant mice. Hence, our study provides evidence that knockdown of the Magel2 gene in ARC POMC neurons innervating the MeA reduces susceptibility to diet-induced obesity with increased locomotor activity through activation of central GPER.
2019-05-18 | A Novel lnc-RNA, Named lnc-ORA, Is Identified by RNA-Seq Analysis, and Its Knockdown Inhibits Adipogenesis by Regulating the PI3K/AKT/mTOR Signaling Pathway
Obesity is closely associated with numerous adipogenic regulatory factors, including coding and non-coding genes. Long noncoding RNAs (lncRNAs) play a major role in adipogenesis. However, differential expression profiles of lncRNAs in inguinal white adipose tissue (iWAT) between wild-type (WT) and ob/ob mice, as well as their roles in adipogenesis, are not well understood. Here, a total of 2809 lncRNAs were detected in the iWAT of WT and ob/ob mice by RNA-Sequencing (RNA-Seq), including 248 novel lncRNAs. Of them, 46 lncRNAs were expressed differentially in WT and ob/ob mice and were enriched in adipogenesis signaling pathways as determined by KEGG enrichment analysis, including the PI3K/AKT/mTOR and cytokine-cytokine receptor interaction signaling pathways. Furthermore, we focused on one novel lncRNA, which we named lnc-ORA (obesity-related lncRNA), which had a seven-fold higher expression in ob/ob mice than in WT mice. Knockdown of lnc-ORA inhibited preadipocyte proliferation by decreasing the mRNA and protein expression levels of cell cycle markers. Interestingly, lnc-ORA knockdown inhibited adipocyte differentiation by regulating the PI3K/AKT/mTOR signaling pathway. In summary, these findings contribute to a better understanding of adipogenesis in relation to lncRNAs and provide novel potential therapeutic targets for obesity-related metabolic diseases.
2018-11-02 | MicroRNAs are involved in the hypothalamic leptin sensitivity
The central nervous system monitors modifications in metabolic parameters or hormone levels (leptin) and elicits adaptive responses such as food intake and glucose homeostasis regulation. Particularly, within the hypothalamus, pro-opiomelanocortin (POMC) neurons are crucial regulators of energy balance. Consistent with a pivotal role of the melanocortin system in the control of energy homeostasis, disruption of the Pomc gene causes hyperphagia and obesity. Pomc gene expression is tightly controlled by different mechanisms. Interestingly, recent studies pointed to a key role for micro ribonucleic acid (miRNAs) in the regulation of gene expression. However, the role of miRNAs in the leptin sensitivity in hypothalamic melanocortin system has never been assessed. We developed a transgenic mouse model (PDKO) with a partial deletion of the miRNA processing enzyme DICER specifically in POMC neurons. PDKO mice exhibited a normal body weight but a decrease of food intake. Interestingly, PDKO mice had decreased metabolic rate by reduction of VO2 consumption and CO2 production which could explain that PDKO mice have normal weight while eating less. Interestingly, we observed an increase of leptin sensitivity in the POMC neurons of PDKO mice which could explain the decrease of food intake in this model. We also observed an increase in the expression of genes involved in the function of brown adipose tissue that is in polysynaptic contact with the POMC neurons. In summary, these results support the hypothesis that Dicer-derived miRNAs may be involved in the effect of leptin on POMC neurons activity.
other
2022-03-23 | Adult-born proopiomelanocortin neurons derived from Rax-expressing precursors mitigate the metabolic effects of congenital hypothalamic proopiomelanocortin deficiency.
Proopiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus are essential regulators of energy balance. Selective loss of POMC production in these cells results in extreme obesity and metabolic comorbidities. Neurogenesis occurs in the adult hypothalamus, but it remains uncertain whether functional POMC neurons emerge in physiologically significant numbers during adulthood. Here, we tested whether Rax-expressing precursors generate POMC neurons in adult mice and rescue the metabolic phenotype caused by congenital hypothalamic POMC deficiency. Initially, we identified hypothalamic Rax-expressing cell types using wild-type and Rax-CreERT2:Ai34D mice. Then we generated compound Rax-CreERT2:ArcPomcloxTB/loxTB mice in which endogenous hypothalamic Pomc expression is silenced, but can be restored by tamoxifen administration selectively in neurons derived from Rax+ progenitors. The number of POMC neurons generated by Rax+ progenitors in adult mice and their axonal projections was determined. The metabolic effects of these neurons were assessed by measuring food intake, bodyweight, and body composition, along with glucose and insulin levels. We found that Rax is expressed by tanycytes and a previously unrecognized cell type in the hypothalamic parenchyma of adult mice. Rax+ progenitors generated ~10% of the normal adult hypothalamic POMC neuron population within two weeks of tamoxifen treatment. The same rate and steady state of POMC neurogenesis persisted from young adult to aged mice. These new POMC neurons established terminal projections to brain regions that were involved in energy homeostasis. Mice with Rax+ progenitor-derived POMC neurons had reduced body fat mass, improved glucose tolerance, increased insulin sensitivity, and decreased bodyweight in proportion to the number of new POMC neurons. These data demonstrate that Rax+ progenitors generate POMC neurons in sufficient numbers during adulthood to mitigate the metabolic abnormalities of hypothalamic POMC-deficient mice. The findings suggest that adult hypothalamic neurogenesis is a robust phenomenon in mice that can significantly impact energy homeostasis.
2018-08-10 | Faculty Opinions recommendation of Genetic identification of leptin neural circuits in energy and glucose homeostases.
Leptin, a hormone produced in white adipose tissue, acts in the brain to communicate fuel status, suppress appetite following a meal, promote energy expenditure and maintain blood glucose stability1,2. Dysregulation of leptin or its receptors (LEPR) results in severe obesity and diabetes3-5. Although intensive studies on leptin have transformed obesity and diabetes research2,6, clinical applications of the molecule are still limited 7 , at least in part owing to the complexity and our incomplete understanding of the underlying neural circuits. The hypothalamic neurons that express agouti-related peptide (AGRP) and pro-opiomelanocortin (POMC) have been hypothesized to be the main first-order, leptin-responsive neurons. Selective deletion of LEPR in these neurons with the Cre-loxP system, however, has previously failed to recapitulate, or only marginally recapitulated, the obesity and diabetes that are seen in LEPR-deficient Lepr db/db mice, suggesting that AGRP or POMC neurons are not directly required for the effects of leptin in vivo8-10. The primary neural targets of leptin are therefore still unclear. Here we conduct a systematic, unbiased survey of leptin-responsive neurons in streptozotocin-induced diabetic mice and exploit CRISPR-Cas9-mediated genetic ablation of LEPR in vivo. Unexpectedly, we find that AGRP neurons but not POMC neurons are required for the primary action of leptin to regulate both energy balance and glucose homeostasis. Leptin deficiency disinhibits AGRP neurons, and chemogenetic inhibition of these neurons reverses both diabetic hyperphagia and hyperglycaemia. In sharp contrast to previous studies, we show that CRISPR-mediated deletion of LEPR in AGRP neurons causes severe obesity and diabetes, faithfully replicating the phenotype of Lepr db/db mice. We also uncover divergent mechanisms of acute and chronic inhibition of AGRP neurons by leptin (presynaptic potentiation of GABA (γ-aminobutyric acid) neurotransmission and postsynaptic activation of ATP-sensitive potassium channels, respectively). Our findings identify the underlying basis of the neurobiological effects of leptin and associated metabolic disorders. PMID: 29670283 Funding information This work was supported by: NINDS NIH HHS, United States Grant ID: T32 NS061764 NINDS NIH HHS, United States Grant ID: P30 NS047243 NIDDK NIH HHS, United States Grant ID: R01 DK108797 NEI NIH HHS, United States Grant ID: P30 EY012196 NIDDK NIH HHS, United States Grant ID: P30 DK046200 NIDDK NIH HHS, United States Grant ID: K01 DK094943 NINDS NIH HHS, United States Grant ID: R21 NS097922 More Less keyboard_arrow_down
2016-11-21 | A rapidly acting glutamatergic ARC→PVH satiety circuit postsynaptically regulated by α-MSH
Hunger-promoting AgRP neurons and satiety-promoting POMC neurons in the arcuate nucleus mediate homeostatic regulation of hunger. Yet a rapidly acting satiety component analogous to rapidly hunger-promoting AgRP neurons has been missing. The authors identify this missing satiety signal and show that it is carried by a novel subset of arcuate glutamatergic neurons. Arcuate nucleus (ARC) neurons sense the fed or fasted state and regulate hunger. Agouti-related protein (AgRP) neurons in the ARC (ARCAgRP neurons) are stimulated by fasting and, once activated, they rapidly (within minutes) drive hunger. Pro-opiomelanocortin (ARCPOMC) neurons are viewed as the counterpoint to ARCAgRP neurons. They are regulated in an opposite fashion and decrease hunger. However, unlike ARCAgRP neurons, ARCPOMC neurons are extremely slow in affecting hunger (many hours). Thus, a temporally analogous, rapid ARC satiety pathway does not exist or is presently unidentified. Here we show that glutamate-releasing ARC neurons expressing oxytocin receptor, unlike ARCPOMC neurons, rapidly cause satiety when chemo- or optogenetically manipulated. These glutamatergic ARC projections synaptically converge with GABAergic ARCAgRP projections on melanocortin-4 receptor (MC4R)-expressing satiety neurons in the paraventricular hypothalamus (PVHMC4R neurons). Transmission across the ARCGlutamatergic→PVHMC4R synapse is potentiated by the ARCPOMC neuron-derived MC4R agonist, α-melanocyte stimulating hormone (α-MSH). This excitatory ARC→PVH satiety circuit, and its modulation by α-MSH, provides insight into regulation of hunger and satiety.
2007-03-21 | Transgenic MSH overexpression attenuates the metabolic effects of a high-fat diet
To determine whether long-term melanocortinergic activation can attenuate the metabolic effects of a high fat diet, mice overexpressing an NH 2 -terminal POMC transgene that includes α- and γ 3 -MSH were studied on either a 10% low-fat diet (LFD) or 45% high-fat diet (HFD). Weight gain was modestly reduced in transgenic (Tg-MSH) male and female mice vs. wild type (WT) on HFD ( P < 0.05) but not LFD. Substantial reductions in body fat percentage were found in both male and female Tg-MSH mice on LFD ( P < 0.05) and were more pronounced on HFD ( P < 0.001). These changes occurred in the absence of significant feeding differences in most groups, consistent with effects of Tg-MSH on energy expenditure and partitioning. This is supported by indirect calorimetry studies demonstrating higher resting oxygen consumption and lower RQ in Tg-MSH mice on the HFD. Tg-MSH mice had lower fasting insulin levels and improved glucose tolerance on both diets. Histological and biochemical analyses revealed that hepatic fat accumulation was markedly reduced in Tg-MSH mice on the HFD. Tg-MSH also attenuated the increase in corticosterone induced by the HFD. Higher levels of Agrp mRNA, which might counteract effects of the transgene, were measured in Tg-MSH mice on LFD ( P = 0.02) but not HFD. These data show that long-term melanocortin activation reduces body weight, adiposity, and hepatic fat accumulation and improves glucose metabolism, particularly in the setting of diet-induced obesity. Our results suggest that long-term melanocortinergic activation could serve as a potential strategy for the treatment of obesity and its deleterious metabolic consequences.
proteins
2026-03-18 | Short Stature and Growth Hormone Deficiency in POMC Deficiency: An Unexpected Clinical Association.
Proopiomelanocortin (POMC) deficiency is a rare monogenic obesity syndrome typically characterized by early-onset obesity, red hair, and hypopigmentation, while linear growth is usually preserved. We report an adolescent girl with genetically confirmed POMC deficiency who developed short stature with biochemically confirmed growth hormone deficiency (GHD). She was diagnosed at 3.5 years of age with a homozygous c.64delA (p.Thr22Leufs*29) variant. Progressive growth deceleration became apparent after 12 years of age. At 13 years, her weight was 56.7 kg (+0.8 SDS), height was 143.0 cm (-2.5 SDS), and BMI was 27.1 kg/m² (+2.0 SDS). Growth velocity was 1.64 cm/year (-1.61 SDS), and pubertal stage was Tanner I. At 14 years of age, bone age was 10 years. IGF-1 was low at 82.8 µg/L (SDS: -2.28), and IGFBP-3 was 2.3 mg/L (SDS: -3.84). After euthyroidism had been achieved and estrogen priming had been completed, GH stimulation testing with L-DOPA and clonidine showed peak GH levels of 0.52 and 1.0 µg/L, respectively. Pituitary MRI was normal. Recombinant GH therapy (0.035 mg/kg/day) was initiated at 14 years 3 months. After 9 months, height increased to 150.2 cm (-1.95 SDS), BMI was 26.51 kg/m² (+1.79 SDS), and growth velocity improved to 11.29 cm/year, with no adverse events during follow-up. This case expands the clinical spectrum of POMC deficiency by demonstrating short stature with biochemically confirmed GHD and a notable early growth response to GH therapy. Further studies are needed to clarify the underlying mechanisms and to guide follow-up and management.
2025-10-17 | Effect of Tirzepatide in an Adolescent With Early-Onset Obesity, Hyperphagia, and Type 2 Diabetes
Early-onset severe obesity is rare and largely treatment-resistant to standard measures. Etiologies include syndromic disorders (Prader-Willi, Bardet-Biedl and Alström syndromes), monogenic defects of appetite-regulating pathways - most significantly melanocortin-4-receptor (MC4R) deficiency, but also leptin receptor (LEPR), pro-opiomelanocortin (POMC), and secondary hypothalamic injury, most commonly craniopharyngiomas. Most childhood obesity, however, is polygenic, arising from interactions of environmental and genetic factors. In many patients, no clear etiology is identified. Treatment remains challenging, particularly if hyperphagia and reduced satiety are predominant presenting features. We describe the case of a 19-year-old male with a history of autism spectrum disorder, attention-deficit hyperactivity disorder (ADHD), type 2 diabetes mellitus (T2DM) and morbid obesity, who showed a clinically significant response to tirzepatide therapy following failed conventional interventions. This case highlights the potential role of dual incretin therapy in adolescents with severe early-onset obesity and hyperphagia, even in the absence (based on present knowledge) of identifiable hypothalamic or genetic pathology.
2025-07-28 | Liraglutide induces enhanced suppression of food intake in mice lacking the growth hormone secretagogue receptor
The glucagon-like peptide-1 receptor (GLP-1R) and the growth hormone secretagogue receptor (GHSR) exert opposing effects on food intake. GLP-1R activation produces potent appetite-suppressing effects, whereas GHSR activation strongly stimulates food intake. Here, we tested the hypothesis that blocking GHSR could affect the anorectic and weight-reducing effects of liraglutide, a GLP-1R agonist widely used to treat diabetes and obesity. We first found that liraglutide induced a stronger reduction in food intake in ad libitum-fed GHSR-deficient mice compared to wild-type (WT) controls, regardless of sex. Liraglutide treatment also resulted in greater gastric content mass in ad libitum-fed GHSR-deficient mice than in WT mice. Interestingly, GLP-1R immunolabeling was elevated in the paraventricular nucleus of the hypothalamus (PVH) in GHSR-deficient mice, whereas the number of proopiomelanocortin (POMC) neurons and liraglutide-induced c-Fos activation-either in the entire arcuate nucleus or specifically within POMC neurons-remained unchanged compared to WT controls. Liraglutide-induced c-Fos expression in the lateral septum and PVH was reduced in GHSR-deficient mice. Conversely, pharmacological GHSR blockade using either JMV2959 or the endogenous antagonist/inverse agonist liver-expressed antimicrobial peptide 2 did not enhance liraglutide-induced food intake reduction. In conclusion, our findings reveal that genetic GHSR deficiency amplifies liraglutide's anorectic effects and provide new insight into the neurobiological mechanisms underlying this interaction. These results suggest that dual modulation of the GHSR and GLP-1R systems may represent a promising strategy for obesity treatment, though careful selection of GHSR-targeting agents and therapeutic protocols will be essential to optimize clinical outcomes.
2024-10-31 | Leptin-activated hypothalamic BNC2 neurons acutely suppress food intake.
Leptin is an adipose tissue hormone that maintains homeostatic control of adipose tissue mass by regulating the activity of specific neural populations controlling appetite and metabolism1. Leptin regulates food intake by inhibiting orexigenic agouti-related protein (AGRP) neurons and activating anorexigenic pro-opiomelanocortin (POMC) neurons2. However, whereas AGRP neurons regulate food intake on a rapid time scale, acute activation of POMC neurons has only a minimal effect3-5. This has raised the possibility that there is a heretofore unidentified leptin-regulated neural population that rapidly suppresses appetite. Here we report the discovery of a new population of leptin-target neurons expressing basonuclin 2 (Bnc2) in the arcuate nucleus that acutely suppress appetite by directly inhibiting AGRP neurons. Opposite to the effect of AGRP activation, BNC2 neuronal activation elicited a place preference indicative of positive valence in hungry but not fed mice. The activity of BNC2 neurons is modulated by leptin, sensory food cues and nutritional status. Finally, deleting leptin receptors in BNC2 neurons caused marked hyperphagia and obesity, similar to that observed in a leptin receptor knockout in AGRP neurons. These data indicate that BNC2-expressing neurons are a key component of the neural circuit that maintains energy balance, thus filling an important gap in our understanding of the regulation of food intake and leptin action.
2024-06-14 | 1527-P: G Protein Gsα Is Required for Normal Glucose Sensing in POMC Neurons
Proopiomelanocortin (POMC) neurons are glucose-sensing neurons in which increased ambient glucose concentrations lead to neuronal activation by a mechanism involving KATP channels. Since glucose sensing in pancreatic β-cells occurs by a similar mechanism and requires G protein Gsα/cAMP signaling, we hypothesized that Gsα may also be involved in glucose sensing in POMC neurons. To test this hypothesis, we generated mouse models with POMC neuron-specific Gsα deficiency (POMCGsKO) or expression of a constitutively activated Gsα (POMCGsR201C). Despite having normal body weight and composition, POMCGsKO mice were hyperglycemic, hypoinsulinemic, glucose intolerant, and had impaired insulin response to glucose loading in vivo. In contrast, POMCGsR201C mice showed increased fat mass but improved glucose tolerance and enhanced insulin response to i.p. glucose administration. This altered glucose homeostasis by Gsα deficiency or activation in POMC neurons was not due to an autonomous pancreatic β-cell defect as both POMCGsKO and POMCGsR201C mice displayed normal pancreatic islet size and number, unchanged β-cell mass and intact glucose-stimulated insulin secretion from isolated islets ex vivo compared to controls. Instead, POMCGsKO mice lacked glucose-stimulated POMC neuron activation as determined by induction of c-fos expression, while POMCGsR201C mice exhibited higher basal c-fos activity in POMC neurons. These results indicate that Gsα is required for normal glucose sensing in POMC neurons which provide feedback to pancreatic islets to maintain glucose homeostasis. Disclosure D. Layton: None. H. Sun: None. M. Gupta: None. Z. Cui: None. M. Chen: None. O. Gavrilova: None. M.T. Collins: None. L. Weinstein: None. Funding NIDDK Intramural Research Program
small molecules
2026-08-14 | Precision Medicine in patients with rare forms of genetic obesity: Necessity for coordinated and structured care
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.
2026-04-21 | A systematic literature review of economic evaluations of setmelanotide.
PURPOSE: This systematic literature review (SLR) aimed to assess the economic value of setmelanotide, a selective melanocortin-4 receptor agonist, in the treatment of rare genetic diseases of obesity (RGDOs), specifically Bardet-Biedl syndrome (BBS), pro-opiomelanocortin (POMC) deficiency, and leptin receptor (LEPR) deficiency. METHODS: The SLR was conducted according to PRISMA guidelines and registered on PROSPERO. Systematic searches were performed in Embase, MEDLINE/PubMed, and Global Health, supplemented by manual searches and reference screening. Inclusion criteria included full economic evaluations (cost-effectiveness and cost-utility analyses) published in English since 2019. Data extraction and quality assessment followed established checklists (BMJ, CHEERS 2022), with findings synthesised descriptively due to heterogeneity in study designs and settings. RESULTS: Four studies (one CEA, three CUAs) met inclusion criteria, all employing model-based frameworks from a healthcare payer perspective with a lifetime horizon. Incremental cost-effectiveness ratios (ICERs) varied: NICE appraisals in the UK suggested potentially favorable or even negative ICERs, while the Canadian CADTH review reported ICERs exceeding CAD $2 million/QALY, far above conventional willingness-to-pay thresholds. Key drivers included drug acquisition cost, severity of hyperphagia, and caregiver burden. All studies noted significant uncertainty due to limited long-term data and small patient populations. CONCLUSIONS: While setmelanotide demonstrates clinical benefit in RGDOs, its high cost poses substantial challenges to conventional pharmacoeconomic evaluations. Adoption may require significant price reductions or alternative value assessment frameworks, particularly for rare diseases. Further research is needed to address long-term effectiveness and ethical considerations in economic evaluations.
2026-03-31 | TonEBP as a key regulator of hypothalamic leptin signaling and resistance
Tonicity-responsive enhancer binding protein (TonEBP) is a transcription factor implicated in cellular stress and inflammation. Here, we explore the role of TonEBP as a key regulator of leptin signaling and resistance. Using TonEBP haploinsufficient [TonEBP (+/-)] mice, we demonstrated that TonEBP negatively regulates leptin sensitivity by upregulating suppressor of cytokine signaling 3 (SOCS3). TonEBP (+/-) mice exhibited heightened leptin-induced anorexia, increased energy expenditure, and elevated STAT3 phosphorylation in proopiomelanocortin (POMC) neurons compared to wild-type [TonEBP (+/+)] controls. Additionally, TonEBP (+/-) mice were protected from high-fat diet-induced obesity and retained leptin sensitivity during chronic energy surplus conditions. Mechanistically, TonEBP deficiency suppressed SOCS3 expression through decreased NF-κB-mediated transcriptional activation, thereby suppressing the negative feedback signal on leptin signaling. Furthermore, elevated hypothalamic TonEBP expression during high-fat diet feeding and leptin treatment implicates its role in regulating leptin sensitivity. Taken together, these findings identify a novel role for TonEBP as a molecular mediator of hypothalamic leptin signaling.
2026-02-21 | Efficacy of GLP-1 analog peptides, semaglutide, tirzepatide, and retatrutide on MC4R deficient obesity and their comparison
INTRODUCTION: Melanocortin 4 receptor (MC4R) is a G-protein-coupled receptor expressed in the hypothalamus, playing a key role in regulating feeding behavior and energy homeostasis. MC4R is integral to the POMC-MC4R and leptin-MC4R pathways, which control food intake and body weight. Mutations in the POMC gene lead to severe early-onset obesity and increased food consumption. Recently, glucagon-like peptide-1 (GLP-1) analogs, including semaglutide, tirzepatide, and retatrutide, have been explored as potential anti-obesity therapies. METHODS: This study aimed to assess and compare the efficacy of these GLP-1 analogs in MC4R knockout (KO) mice, which are deficient in the POMC-MC4R pathway. GLP-1 analogs were administered for 21 days to MC4R KO mice and compared their efficacy. RESULTS: The percentage of body weight reduction was 19.7 ± 4.1% for semaglutide, 31.6 ± 7.6% for tirzepatide, and 24.1 ± 5.8% for retatrutide. Body composition analysis, including fat and lean mass, was performed using the Echo-MRI system, revealing significant suppression of both fat and lean mass by all three GLP-1 analogs. Furthermore, GLP-1 analogs improved plasma insulin levels, HOMA-IR, cholesterol levels, and markers of liver damage (AST and ALT), as well as reduced liver hypertrophy. While GLP-1 analogs suppressed genes related to fatty acid synthesis, they had no significant effect on inflammation-related gene expressions. Additionally, GLP-1 analogs reduced energy expenditure, with only tirzepatide showing a significant decrease in the respiratory quotient (RQ) in MC4R KO mice. CONCLUSION: Our findings demonstrate that all three GLP-1 analogs, semaglutide, tirzepatide, and retatrutide, exhibit significant anti-obesity effects in MC4R KO mice. These results suggest that GLP-1 analogs may provide an effective treatment option for patients with MC4R-POMC pathway deficiencies. Moreover, the efficacy of these drugs in MC4R KO mice aligns with clinical studies, indicating that MC4R KO mice serve as a reliable animal model for obesity research.
2026-02-09 | Monogenic and syndromic obesity in children: Clinical recognition, genetics, and precision management
ABSTRACT 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.
gene therapies
2026-04-16 | POMC neuron METTL14/m6A/YTHDC1/YTHDF2 pathways safeguard energy balance, body weight, and metabolism.
METTL14 mediates N6-methyladenosine (m6A) RNA modification, while YTHDC1 and YTHDF2 specifically bind m6A-methylated RNA to regulate RNA fate. POMC neurons constitute the core of the central melanocortin circuit, and POMC deficiency causes obesity in both mice and humans. However, how m6A-based epitranscriptomics regulates melanocortin circuit function remains unclear. Here, we generated and characterized POMC neuron-specific knockout mice lacking Mettl14 (Mettl14ΔPOMC), Ythdc1 (Ythdc1ΔPOMC), or Ythdf2 (Ythdf2 ΔPOMC). Mettl14ΔPOMC and Ythdc1ΔPOMC mice develop hyperphagia, obesity, glucose intolerance, insulin resistance, and hepatic steatosis in both sexes under standard chow conditions, accompanied by POMC downregulation. Conversely, POMC neuron-specific overexpression of METTL14 or YTHDC1 protects against diet-induced obesity. In contrast, Ythdf2 ΔPOMC mice are resistant to obesity, revealing an m6A-dependent balance between YTHDC1 and YTHDF2. Mechanistically, the METTL14/YTHDC1 pathway is indispensable for embryonic POMC neurogenesis, while in adults YTHDC1 maintains melanocortin circuit integrity/function. METTL14 and YTHDC1 directly target POMC and ISL1 transcripts to regulate protein expression. POMC neuron-specific restoration of POMC reverses obesity and metabolic phenotypes in Mettl14ΔPOMC and Ythdc1ΔPOMC mice, defining an anti-obesity METTL14/m6A/YTHDC1/POMC axis. These findings identify METTL14 as the m6A writer for POMC/ISL1 and YTHDC1 and YTHDF2 as their readers, uncovering a critical role of m6A epitranscriptomic regulation in melanocortin circuit development and maintenance.
2024-03-06 | Hypothalamic POMC neuron-specific knockout of MC4R affects insulin sensitivity by regulating Kir2.1
Abstract Background Imbalance in energy regulation is a major cause of insulin resistance and diabetes. Melanocortin-4 receptor (MC4R) signaling at specific sites in the central nervous system has synergistic but non-overlapping functions. However, the mechanism by which MC4R in the arcuate nucleus (ARC) region regulates energy balance and insulin resistance remains unclear. Methods The MC4R flox/flox mice with proopiomelanocortin (POMC) -Cre mice were crossed to generate the POMC-MC4R flox/+ mice. Then POMC-MC4R flox/+ mice were further mated with MC4R flox/flox mice to generate the POMC-MC4R flox/flox mice in which MC4R is selectively deleted in POMC neurons. Bilateral injections of 200 nl of AAV-sh-Kir2.1 (AAV-sh-NC was used as control) were made into the ARC of the hypothalamus. Oxygen consumption, carbon dioxide production, respiratory exchange ratio and energy expenditure were measured by using the CLAMS; Total, visceral and subcutaneous fat was analyzed using micro-CT. Co-immunoprecipitation assays (Co-IP) were used to analyze the interaction between MC4R and Kir2.1 in GT1-7 cells. Results POMC neuron-specific ablation of MC4R in the ARC region promoted food intake, impaired energy expenditure, leading to increased weight gain and impaired systemic glucose homeostasis. Additionally, MC4R ablation reduced the activation of POMC neuron, and is not tissue-specific for peripheral regulation, suggesting the importance of its central regulation. Mechanistically, sequencing analysis and Co-IP assay demonstrated a direct interaction of MC4R with Kir2.1. Knockdown of Kir2.1 in POMC neuron-specific ablation of MC4R restored the effect of MC4R ablation on energy expenditure and systemic glucose homeostasis, indicating by reduced body weight and ameliorated insulin resistance. Conclusion Hypothalamic POMC neuron-specific knockout of MC4R affects energy balance and insulin sensitivity by regulating Kir2.1. Kir2.1 represents a new target and pathway that could be targeted in obesity.
2023-11-29 | CerS6-dependent ceramide synthesis in hypothalamic neurons promotes ER/mitochondrial stress and impairs glucose homeostasis in obese mice
Dysregulation of hypothalamic ceramides has been associated with disrupted neuronal pathways in control of energy and glucose homeostasis. However, the specific ceramide species promoting neuronal lipotoxicity in obesity have remained obscure. Here, we find increased expression of the C16:0 ceramide-producing ceramide synthase (CerS)6 in cultured hypothalamic neurons exposed to palmitate in vitro and in the hypothalamus of obese mice. Conditional deletion of CerS6 in hypothalamic neurons attenuates high-fat diet (HFD)-dependent weight gain and improves glucose metabolism. Specifically, CerS6 deficiency in neurons expressing pro-opiomelanocortin (POMC) or steroidogenic factor 1 (SF-1) alters feeding behavior and alleviates the adverse metabolic effects of HFD feeding on insulin sensitivity and glucose tolerance. POMC-expressing cell-selective deletion of CerS6 prevents the diet-induced alterations of mitochondrial morphology and improves cellular leptin sensitivity. Our experiments reveal functions of CerS6-derived ceramides in hypothalamic lipotoxicity, altered mitochondrial dynamics, and ER/mitochondrial stress in the deregulation of food intake and glucose metabolism in obesity.
2023-06-09 | Agrp-negative arcuate NPY neurons drive feeding under positive energy balance via altering leptin responsiveness in POMC neurons.
Neuropeptide Y (NPY) in the arcuate nucleus (ARC) is known as one of the most critical regulators of feeding. However, how NPY promotes feeding under obese conditions is unclear. Here, we show that positive energy balance, induced by high-fat diet (HFD) or in genetically obese leptin-receptor-deficient mice, leads to elevated Npy2r expression especially on proopiomelanocortin (POMC) neurons, which also alters leptin responsiveness. Circuit mapping identified a subset of ARC agouti-related peptide (Agrp)-negative NPY neurons that control these Npy2r expressing POMC neurons. Chemogenetic activation of this newly discovered circuitry strongly drives feeding, while optogenetic inhibition reduces feeding. Consistent with that, lack of Npy2r on POMC neurons leads to reduced food intake and fat mass. This suggests that under energy surplus conditions, when ARC NPY levels generally drop, high-affinity NPY2R on POMC neurons is still able to drive food intake and enhance obesity development via NPY released predominantly from Agrp-negative NPY neurons.
2023-04-06 | TLR4 in POMC neurons regulates thermogenesis in a sex-dependent manner
The rising prevalence of obesity has become a worldwide health concern. Obesity usually occurs when there is an imbalance between energy intake and energy expenditure. However, energy expenditure consists of several components, including metabolism, physical activity, and thermogenesis. Toll-like receptor 4 (TLR4) is a transmembrane pattern recognition receptor, and it is abundantly expressed in the brain. Here, we showed that pro-opiomelanocortin (POMC)-specific deficiency of TLR4 directly modulates brown adipose tissue thermogenesis and lipid homeostasis in a sex-dependent manner. Deleting TLR4 in POMC neurons is sufficient to increase energy expenditure and thermogenesis resulting in reduced body weight in male mice. POMC neuron is a subpopulation of tyrosine hydroxylase neurons and projects into brown adipose tissue, which regulates the activity of sympathetic nervous system and contributes to thermogenesis in POMC-TLR4-KO male mice. By contrast, deleting TLR4 in POMC neurons decreases energy expenditure and increases body weight in female mice, which affects lipolysis of white adipose tissue (WAT). Mechanistically, TLR4 KO decreases the expression of the adipose triglyceride lipase and lipolytic enzyme hormone-sensitive lipase in WAT in female mice. Furthermore, the function of immune-related signaling pathway in WAT is inhibited because of obesity, which exacerbates the development of obesity reversely. Together, these results demonstrate that TLR4 in POMC neurons regulates thermogenesis and lipid balance in a sex-dependent manner.
oligonucleotides
2023-03-22 | miRNA-383 and miRNA-384 Suppress Proopiomelanocortin Gene Expression in the Hypothalamus: Effects of Early Life Ethanol Exposure
Introduction: Early life ethanol exposure is known to program hypothalamic proopiomelanocortin (POMC) neurons to express a reduced level of POMC and its control of stress axis functions throughout the life span. In this study, we tested whether miRNAs contribute to the ethanol-induced suppression of Pomc gene expression during the developmental period. Methods: In in vivo studies, POMC-EGFP male mice were fed with 2.5 g/kg ethanol using milk formula (AF), pair-fed isocaloric milk formula, or left in the litter during postnatal days (PNDs) 2–6. In in vitro studies, mHypoA-POMC/GFP cells were treated with ethanol (50 m<sc>M</sc>) for a 24-h period. Hypothalamic tissues or cell extracts were used for measurement of miRNAs and POMC mRNA. Results: Determination of genome-wide microRNA expression profile identified 40 miRNAs significantly altered in hypothalamic tissues of AF mice. In silico analysis further identified miRNA-383, -384, and -488 have putative binding sites at the POMC 3′UTR. However, only miR-383 and miR-384 are identified to be responsive to ethanol. Administration of miR-383 or -384 inhibitor oligos suppressed ethanol-stimulated miR-383 or -384 expression and restored Pomc mRNA and protein expression in AF mice. mHypoA-POMC/GFP cells when treated with ethanol showed elevated levels of miR-383 and miR-384 and reduced level of Pomc mRNA. Treatment with miR-383 or -384 mimic oligos reduced the level of Pomc mRNA, while treatment with miR-383 or -384 inhibitor oligos increased the level of Pomc mRNA. Reporter assay further confirms the binding specificity of miR-383 and miR-384 to Pomc 3’UTR. Conclusion: These data suggest that miR-383 and miR-384 suppress Pomc gene expression and may contribute to the ethanol-induced alteration of the stress axis functions.
2022-09-29 | MicroRNA-7 regulates melanocortin circuits involved in mammalian energy homeostasis
MicroRNAs (miRNAs) modulate physiological responses by repressing the expression of gene networks. We found that global deletion of microRNA-7 (miR-7), the most enriched miRNA in the hypothalamus, causes obesity in mice. Targeted deletion of miR-7 in Single-minded homolog 1 (Sim1) neurons, a critical component of the hypothalamic melanocortin pathway, causes hyperphagia, obesity and increased linear growth, mirroring Sim1 and Melanocortin-4 receptor (MC4R) haplo-insufficiency in mice and humans. We identified Snca (α-Synuclein) and Igsf8 (Immunoglobulin Superfamily Member 8) as miR-7 target genes that act in Sim1 neurons to regulate body weight and endocrine axes. In humans, MIR-7-1 is located in the last intron of HNRNPK, whose promoter drives the expression of both genes. Genetic variants at the HNRNPK locus that reduce its expression are associated with increased height and truncal fat mass. These findings demonstrate that miR-7 suppresses gene networks involved in the hypothalamic melanocortin pathway to regulate mammalian energy homeostasis.
2022-08-25 | Magel2 knockdown in hypothalamic POMC neurons innervating the medial amygdala reduces susceptibility to diet-induced obesity.
Hyperphagia and obesity profoundly affect the health of children with Prader–Willi syndrome (PWS). The Magel2 gene among the genes in the Prader–Willi syndrome deletion region is expressed in proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARC). Knockout of the Magel2 gene disrupts POMC neuronal circuits and functions. Here, we report that loss of the Magel2 gene exclusively in ARC POMC neurons innervating the medial amygdala (MeA) causes a reduction in body weight in both male and female mice fed with a high-fat diet. This anti-obesity effect is associated with an increased locomotor activity. There are no significant differences in glucose and insulin tolerance in mice without the Magel2 gene in ARC POMC neurons innervating the MeA. Plasma estrogen levels are higher in female mutant mice than in controls. Blockade of the G protein–coupled estrogen receptor (GPER), but not estrogen receptor-α (ER-α), reduces locomotor activity in female mutant mice. Hence, our study provides evidence that knockdown of the Magel2 gene in ARC POMC neurons innervating the MeA reduces susceptibility to diet-induced obesity with increased locomotor activity through activation of central GPER.
2019-05-18 | A Novel lnc-RNA, Named lnc-ORA, Is Identified by RNA-Seq Analysis, and Its Knockdown Inhibits Adipogenesis by Regulating the PI3K/AKT/mTOR Signaling Pathway
Obesity is closely associated with numerous adipogenic regulatory factors, including coding and non-coding genes. Long noncoding RNAs (lncRNAs) play a major role in adipogenesis. However, differential expression profiles of lncRNAs in inguinal white adipose tissue (iWAT) between wild-type (WT) and ob/ob mice, as well as their roles in adipogenesis, are not well understood. Here, a total of 2809 lncRNAs were detected in the iWAT of WT and ob/ob mice by RNA-Sequencing (RNA-Seq), including 248 novel lncRNAs. Of them, 46 lncRNAs were expressed differentially in WT and ob/ob mice and were enriched in adipogenesis signaling pathways as determined by KEGG enrichment analysis, including the PI3K/AKT/mTOR and cytokine-cytokine receptor interaction signaling pathways. Furthermore, we focused on one novel lncRNA, which we named lnc-ORA (obesity-related lncRNA), which had a seven-fold higher expression in ob/ob mice than in WT mice. Knockdown of lnc-ORA inhibited preadipocyte proliferation by decreasing the mRNA and protein expression levels of cell cycle markers. Interestingly, lnc-ORA knockdown inhibited adipocyte differentiation by regulating the PI3K/AKT/mTOR signaling pathway. In summary, these findings contribute to a better understanding of adipogenesis in relation to lncRNAs and provide novel potential therapeutic targets for obesity-related metabolic diseases.
2018-11-02 | MicroRNAs are involved in the hypothalamic leptin sensitivity
The central nervous system monitors modifications in metabolic parameters or hormone levels (leptin) and elicits adaptive responses such as food intake and glucose homeostasis regulation. Particularly, within the hypothalamus, pro-opiomelanocortin (POMC) neurons are crucial regulators of energy balance. Consistent with a pivotal role of the melanocortin system in the control of energy homeostasis, disruption of the Pomc gene causes hyperphagia and obesity. Pomc gene expression is tightly controlled by different mechanisms. Interestingly, recent studies pointed to a key role for micro ribonucleic acid (miRNAs) in the regulation of gene expression. However, the role of miRNAs in the leptin sensitivity in hypothalamic melanocortin system has never been assessed. We developed a transgenic mouse model (PDKO) with a partial deletion of the miRNA processing enzyme DICER specifically in POMC neurons. PDKO mice exhibited a normal body weight but a decrease of food intake. Interestingly, PDKO mice had decreased metabolic rate by reduction of VO2 consumption and CO2 production which could explain that PDKO mice have normal weight while eating less. Interestingly, we observed an increase of leptin sensitivity in the POMC neurons of PDKO mice which could explain the decrease of food intake in this model. We also observed an increase in the expression of genes involved in the function of brown adipose tissue that is in polysynaptic contact with the POMC neurons. In summary, these results support the hypothesis that Dicer-derived miRNAs may be involved in the effect of leptin on POMC neurons activity.
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2022-03-23 | Adult-born proopiomelanocortin neurons derived from Rax-expressing precursors mitigate the metabolic effects of congenital hypothalamic proopiomelanocortin deficiency.
Proopiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus are essential regulators of energy balance. Selective loss of POMC production in these cells results in extreme obesity and metabolic comorbidities. Neurogenesis occurs in the adult hypothalamus, but it remains uncertain whether functional POMC neurons emerge in physiologically significant numbers during adulthood. Here, we tested whether Rax-expressing precursors generate POMC neurons in adult mice and rescue the metabolic phenotype caused by congenital hypothalamic POMC deficiency. Initially, we identified hypothalamic Rax-expressing cell types using wild-type and Rax-CreERT2:Ai34D mice. Then we generated compound Rax-CreERT2:ArcPomcloxTB/loxTB mice in which endogenous hypothalamic Pomc expression is silenced, but can be restored by tamoxifen administration selectively in neurons derived from Rax+ progenitors. The number of POMC neurons generated by Rax+ progenitors in adult mice and their axonal projections was determined. The metabolic effects of these neurons were assessed by measuring food intake, bodyweight, and body composition, along with glucose and insulin levels. We found that Rax is expressed by tanycytes and a previously unrecognized cell type in the hypothalamic parenchyma of adult mice. Rax+ progenitors generated ~10% of the normal adult hypothalamic POMC neuron population within two weeks of tamoxifen treatment. The same rate and steady state of POMC neurogenesis persisted from young adult to aged mice. These new POMC neurons established terminal projections to brain regions that were involved in energy homeostasis. Mice with Rax+ progenitor-derived POMC neurons had reduced body fat mass, improved glucose tolerance, increased insulin sensitivity, and decreased bodyweight in proportion to the number of new POMC neurons. These data demonstrate that Rax+ progenitors generate POMC neurons in sufficient numbers during adulthood to mitigate the metabolic abnormalities of hypothalamic POMC-deficient mice. The findings suggest that adult hypothalamic neurogenesis is a robust phenomenon in mice that can significantly impact energy homeostasis.
2018-08-10 | Faculty Opinions recommendation of Genetic identification of leptin neural circuits in energy and glucose homeostases.
Leptin, a hormone produced in white adipose tissue, acts in the brain to communicate fuel status, suppress appetite following a meal, promote energy expenditure and maintain blood glucose stability1,2. Dysregulation of leptin or its receptors (LEPR) results in severe obesity and diabetes3-5. Although intensive studies on leptin have transformed obesity and diabetes research2,6, clinical applications of the molecule are still limited 7 , at least in part owing to the complexity and our incomplete understanding of the underlying neural circuits. The hypothalamic neurons that express agouti-related peptide (AGRP) and pro-opiomelanocortin (POMC) have been hypothesized to be the main first-order, leptin-responsive neurons. Selective deletion of LEPR in these neurons with the Cre-loxP system, however, has previously failed to recapitulate, or only marginally recapitulated, the obesity and diabetes that are seen in LEPR-deficient Lepr db/db mice, suggesting that AGRP or POMC neurons are not directly required for the effects of leptin in vivo8-10. The primary neural targets of leptin are therefore still unclear. Here we conduct a systematic, unbiased survey of leptin-responsive neurons in streptozotocin-induced diabetic mice and exploit CRISPR-Cas9-mediated genetic ablation of LEPR in vivo. Unexpectedly, we find that AGRP neurons but not POMC neurons are required for the primary action of leptin to regulate both energy balance and glucose homeostasis. Leptin deficiency disinhibits AGRP neurons, and chemogenetic inhibition of these neurons reverses both diabetic hyperphagia and hyperglycaemia. In sharp contrast to previous studies, we show that CRISPR-mediated deletion of LEPR in AGRP neurons causes severe obesity and diabetes, faithfully replicating the phenotype of Lepr db/db mice. We also uncover divergent mechanisms of acute and chronic inhibition of AGRP neurons by leptin (presynaptic potentiation of GABA (γ-aminobutyric acid) neurotransmission and postsynaptic activation of ATP-sensitive potassium channels, respectively). Our findings identify the underlying basis of the neurobiological effects of leptin and associated metabolic disorders. PMID: 29670283 Funding information This work was supported by: NINDS NIH HHS, United States Grant ID: T32 NS061764 NINDS NIH HHS, United States Grant ID: P30 NS047243 NIDDK NIH HHS, United States Grant ID: R01 DK108797 NEI NIH HHS, United States Grant ID: P30 EY012196 NIDDK NIH HHS, United States Grant ID: P30 DK046200 NIDDK NIH HHS, United States Grant ID: K01 DK094943 NINDS NIH HHS, United States Grant ID: R21 NS097922 More Less keyboard_arrow_down
2016-11-21 | A rapidly acting glutamatergic ARC→PVH satiety circuit postsynaptically regulated by α-MSH
Hunger-promoting AgRP neurons and satiety-promoting POMC neurons in the arcuate nucleus mediate homeostatic regulation of hunger. Yet a rapidly acting satiety component analogous to rapidly hunger-promoting AgRP neurons has been missing. The authors identify this missing satiety signal and show that it is carried by a novel subset of arcuate glutamatergic neurons. Arcuate nucleus (ARC) neurons sense the fed or fasted state and regulate hunger. Agouti-related protein (AgRP) neurons in the ARC (ARCAgRP neurons) are stimulated by fasting and, once activated, they rapidly (within minutes) drive hunger. Pro-opiomelanocortin (ARCPOMC) neurons are viewed as the counterpoint to ARCAgRP neurons. They are regulated in an opposite fashion and decrease hunger. However, unlike ARCAgRP neurons, ARCPOMC neurons are extremely slow in affecting hunger (many hours). Thus, a temporally analogous, rapid ARC satiety pathway does not exist or is presently unidentified. Here we show that glutamate-releasing ARC neurons expressing oxytocin receptor, unlike ARCPOMC neurons, rapidly cause satiety when chemo- or optogenetically manipulated. These glutamatergic ARC projections synaptically converge with GABAergic ARCAgRP projections on melanocortin-4 receptor (MC4R)-expressing satiety neurons in the paraventricular hypothalamus (PVHMC4R neurons). Transmission across the ARCGlutamatergic→PVHMC4R synapse is potentiated by the ARCPOMC neuron-derived MC4R agonist, α-melanocyte stimulating hormone (α-MSH). This excitatory ARC→PVH satiety circuit, and its modulation by α-MSH, provides insight into regulation of hunger and satiety.
2007-03-21 | Transgenic MSH overexpression attenuates the metabolic effects of a high-fat diet
To determine whether long-term melanocortinergic activation can attenuate the metabolic effects of a high fat diet, mice overexpressing an NH 2 -terminal POMC transgene that includes α- and γ 3 -MSH were studied on either a 10% low-fat diet (LFD) or 45% high-fat diet (HFD). Weight gain was modestly reduced in transgenic (Tg-MSH) male and female mice vs. wild type (WT) on HFD ( P < 0.05) but not LFD. Substantial reductions in body fat percentage were found in both male and female Tg-MSH mice on LFD ( P < 0.05) and were more pronounced on HFD ( P < 0.001). These changes occurred in the absence of significant feeding differences in most groups, consistent with effects of Tg-MSH on energy expenditure and partitioning. This is supported by indirect calorimetry studies demonstrating higher resting oxygen consumption and lower RQ in Tg-MSH mice on the HFD. Tg-MSH mice had lower fasting insulin levels and improved glucose tolerance on both diets. Histological and biochemical analyses revealed that hepatic fat accumulation was markedly reduced in Tg-MSH mice on the HFD. Tg-MSH also attenuated the increase in corticosterone induced by the HFD. Higher levels of Agrp mRNA, which might counteract effects of the transgene, were measured in Tg-MSH mice on LFD ( P = 0.02) but not HFD. These data show that long-term melanocortin activation reduces body weight, adiposity, and hepatic fat accumulation and improves glucose metabolism, particularly in the setting of diet-induced obesity. Our results suggest that long-term melanocortinergic activation could serve as a potential strategy for the treatment of obesity and its deleterious metabolic consequences.
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Drug Discovery Landscape
3 orphan drug designations for Obesity due to pro-opiomelanocortin deficiency, including 2 approved therapies.
3 orphan drug designations for Obesity due to pro-opiomelanocortin deficiency, including 2 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
oral melanocortin 4 receptor agonist | small molecules | FDA | 2022-06-06 | — | Rhythm Pharmaceuticals, Inc. |
Setmelanotide [Imcivree] | peptides | EMA | 2016-07-14 | 2021-07-19 | Rhythm Pharmaceuticals Netherlands B.V. |
setmelanotide [Imcivree] | peptides | FDA | 2016-04-04 | 2020-11-25 | Rhythm Pharmaceuticals, Inc. |
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