MC4R: A Genetic Key to Metabolic and Cardiovascular Disorders
Keywords:
melanocortin-4 receptor, metabolic disorders, cardiovascular disorders, obesity, MC4R mutationsAbstract
The melanocortin-4 receptor (MC4R) is a critical regulator of energy homeo-stasis, lipid metabolism, and cardiovascular risk factors. First cloned in 1993, MC4R’s role in appetite regulation was confirmed through animal studies, and its genetic mutations were later identified as major contribu-tors to monogenic obesity. This review synthesizes current research on MC4R’s genetic variations and their implications for obesity, metabolic disorders, and cardiovascular health. A systematic literature review was conducted, adhering to PRISMA guidelines, with data extracted from PubMed, Scopus, Web of Science, and Google Scholar. Studies from 1992 to 2025 focusing on MC4R mutations, their effects on obesity, type 2 diabetes, dyslipidemia, and hypertension, as well as their contribution to cardiovascular risk were included. Recent insights highlight rare MC4R variants, such as p.Ser36Thr and p.Ala175Thr which are associated with severe obesity, and novel structural variants, e.g., p.Ser85Gly, which destabilize signaling pathways. Loss-of-function MC4R variants cause hyperphagia and early-onset obesity, whereas gain-of-function variants enhance satiety, providing protection against obesity. MC4R dysfunction also impacts glucose homeostasis and lipid metabolism, thereby increasing the risk of type 2 diabetes, dyslipidemia, and hypertension. Additionally, alterations in MC4R increase cardiovascular risk via pathways involving energy imbalance, sympathetic activation, and endothelial dysfunction. This review highlights the genetic underpinnings of MC4R in metabolic and cardiovascular diseases and underscores the need for developing targeted therapeutic strategies.
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