The application of GLP-1 receptor agonists in obesity due to MC4R deficiency

Abstract

Although the pathogenesis of genetic obesity is becoming increasingly clear, effective treatments remain lacking, particularly for obesity caused by melanocortin 4 receptor (MC4R) deficiency. The activity of MC4R is strictly regulated by its endogenous ligands: α-melanocyte-stimulating hormone (α-MSH) binds to MC4R and transmits anorexigenic and energy-expenditure signals, whereas agouti-related protein (AgRP) exerts an antagonistic effect by binding to the receptor, competitively inhibiting α-MSH action and promoting appetite. Current options, such as lifestyle modifications and bariatric surgery, have limited efficacy, highlighting the need for accessible pharmacological interventions. This review evaluates glucagon-like peptide-1 (GLP-1) receptor agonists in MC4R-deficient obesity. We conducted a comprehensive literature search across databases, including PubMed and Web of Science, compiling data from clinical trials, case reports, and basic research studies published up to 2025, with a focus on the efficacy, safety, and mechanism of action of drugs such as liraglutide, semaglutide, and tirzepatide in patients with MC4R deficiency. Evidence indicates these agents induce significant weight loss, appetite suppression, and metabolic improvements via mechanisms independent of intact MC4R signaling. Their weight-loss effects are comparable to those seen in common obesity, with additional benefits for comorbidities like insulin resistance and dyslipidemia. These findings support the GLP-1 pathway as an alternative to impaired MC4R, offering a viable treatment. Understanding their efficacy and mechanisms provides new treatment options for this rare condition and offers evidence for genetically specific personalized weight management.

Keywords

MC4R deficiency / genetic obesity / GLP-1 receptor agonists / leptin-melanocortin pathway / weight management

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