ArticleThe Journal of clinical endocrinology and metabolism2018
Melanocortin 4 Receptor Pathway Dysfunction in Obesity: Patient Stratification Aimed at MC4R Agonist Treatment.
Article in The Journal of clinical endocrinology and metabolism, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
47 citing papers in PubMed, 1 synthesis or guideline pooled it, 82 citations in OpenAlex.
- Pharmacogenetic interactions of medications administered for weight loss in adults: a systematic review and meta-analysis.Pharmacogenomics · 2023Pooled it
- Measuring Hunger Severity in Rare MC4R Pathway Diseases: Development and Psychometric Evaluation of the Most Hunger Item.Advances in therapy · 2026Article
- Variants in the leptin-MC4R pathway and ciliopathy-related genes in youths with obesity beyond hyperphagia and early onset.Journal of endocrinological investigation · 2026Article
- Rationale of renewed efforts in developing MC4R modulators to treat metabolic disorders.Acta pharmaceutica Sinica. B · 2026Review
- Review
- Melanocortin receptor 4 agonist setmelanotide treats opioid-induced respiratory depression.bioRxiv : the preprint server for biology · 2026Article
- Genetic distribution of selected obesity-related SNVs in theFrontiers in genetics · 2026Article
- Leptin and leptin resistance in obesity: current evidence, mechanisms and future directions.Endocrine connections · 2025Review
- Improving the diagnosis of hyperphagia in melanocortin-4 receptor pathway diseases.Obesity (Silver Spring, Md.) · 2025Review
- Unraveling the Genetic Architecture of Obesity: A Path to Personalized Medicine.Diagnostics (Basel, Switzerland) · 2025Review
- Current and Emerging Parenteral and Peroral Medications for Weight Loss: A Narrative Review.Diseases (Basel, Switzerland) · 2025Review
- A Complex Network of Obesity-Risk Genes Revealed by Systematic Bioinformatics and Single-Cell Transcriptomic Analyses.Journal of obesity · 2025Article
- Melanocortin 4 receptor mutation in obesity.World journal of experimental medicine · 2024Review
- The melanocortin receptor genes are linked to and associated with the risk of polycystic ovary syndrome in Italian families.Journal of ovarian research · 2024Article
- MC4R Variants Modulate α-MSH and Setmelanotide Induced Cellular Signaling at Multiple Levels.The Journal of clinical endocrinology and metabolism · 2024Article
- Differentiating monogenic and syndromic obesities from polygenic obesity: Assessment, diagnosis, and management.Obesity pillars · 2024Review
- New insights into the hypothalamic-pituitary-thyroid axis: a transcriptome- and proteome-wide association study.European thyroid journal · 2024Article
- Leptin-Melanocortin pathway variants and gastric emptying in patients with obesity.Neurogastroenterology and motility · 2024Article
- Exploring the therapeutic potential of precision medicine in rare genetic obesity disorders: a scientific perspective.Frontiers in nutrition · 2024Review
- Understanding the Genetics of Early-Onset Obesity in a Cohort of Children From Qatar.The Journal of clinical endocrinology and metabolism · 2023Article
Corrections and comments
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Authors and funding
18 authors at 6 institutions in 1 country.
Funding
Abstract
Context: The hypothalamic melanocortin 4 receptor (MC4R) pathway serves a critical role in regulating body weight. Loss of function (LoF) mutations in the MC4R pathway, including mutations in the pro-opiomelanocortin (POMC), prohormone convertase 1 (PCSK1), leptin receptor (LEPR), or MC4R genes, have been shown to cause early-onset severe obesity. Methods: Through a comprehensive epidemiological analysis of known and predicted LoF variants in the POMC, PCSK1, and LEPR genes, we sought to estimate the number of US individuals with biallelic MC4R pathway LoF variants. Results: We predict ~650 α-melanocyte-stimulating hormone (MSH)/POMC, 8500 PCSK1, and 3600 LEPR homozygous and compound heterozygous individuals in the United States, cumulatively enumerating >12,800 MC4R pathway-deficient obese patients. Few of these variants have been genetically diagnosed to date. These estimates increase when we include a small subset of less rare variants: β-MSH/POMC,PCSK1 N221D, and a PCSK1 LoF variant (T640A). To further define the MC4R pathway and its potential impact on obesity, we tested associations between body mass index (BMI) and LoF mutation burden in the POMC, PCSK1, and LEPR genes in various populations. We show that the cumulative allele burden in individuals with two or more LoF alleles in one or more genes in the MC4R pathway are predisposed to a higher BMI than noncarriers or heterozygous LoF carriers with a defect in only one gene. Conclusions: Our analysis represents a genetically rationalized study of the hypothalamic MC4R pathway aimed at genetic patient stratification to determine which obese subpopulations should be studied to elucidate MC4R agonist (e.g., setmelanotide) treatment responsiveness.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.