Sridhar GR, Gumpeny L. Melanocortin 4 receptor mutation in obesity. World J Exp Med 2024; 14(4): 99239 [DOI: 10.5493/wjem.v14.i4.99239]
Corresponding Author of This Article
Gumpeny R Sridhar, FRCP (Hon), Adjunct Professor, Department of Endocrinology and Diabetes, Endocrine and Diabetes Centre, 15-12-15 Krishnanagar, Visakhapatnam 530002, Andhra Pradesh, India. sridharvizag@gmail.com
Research Domain of This Article
Endocrinology & Metabolism
Article-Type of This Article
Minireviews
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This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Exp Med. Dec 20, 2024; 14(4): 99239 Published online Dec 20, 2024. doi: 10.5493/wjem.v14.i4.99239
Melanocortin 4 receptor mutation in obesity
Gumpeny R Sridhar, Lakshmi Gumpeny
Gumpeny R Sridhar, Department of Endocrinology and Diabetes, Endocrine and Diabetes Centre, Visakhapatnam 530002, Andhra Pradesh, India
Lakshmi Gumpeny, Department of Internal Medicine, Gayatri Vidya Parishad Institute of Healthcare and Medical Technology, Visakhapatnam 530048, Andhra Pradesh, India
Author contributions: Both authors contributed to this manuscript. Sridhar GR designed the concept and outline; Lakshmi G contributed to the writing and editing of the manuscript.
Conflict-of-interest statement: Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Gumpeny R Sridhar, FRCP (Hon), Adjunct Professor, Department of Endocrinology and Diabetes, Endocrine and Diabetes Centre, 15-12-15 Krishnanagar, Visakhapatnam 530002, Andhra Pradesh, India. sridharvizag@gmail.com
Received: July 18, 2024 Revised: August 22, 2024 Accepted: August 27, 2024 Published online: December 20, 2024 Processing time: 104 Days and 16.9 Hours
Abstract
Obesity is increasingly prevalent worldwide, with genetic factors contributing to its development. The hypothalamic leptin-melanocortin pathway is central to the regulation of appetite and weight; leptin activates the proopiomelanocortin neurons, leading to the production of melanocortin peptides; these in turn act on melanocortin 4 receptors (MC4R) which suppress appetite and increase energy expenditure. MC4R mutations are responsible for syndromic and non-syndromic obesity. These mutations are classified based on their impact on the receptor's life cycle: i.e. null mutations, intracellular retention, binding defects, signaling defects, and variants of unknown function. Clinical manifestations of MC4R mutations include early-onset obesity, hyperphagia, and metabolic abnormalities such as hyperinsulinemia and dyslipidemia. Management strategies for obesity due to MC4R mutations have evolved with the development of targeted therapies such as Setmelanotide, an MC4R agonist which can reduce weight and manage symptoms without adverse cardiovascular effects. Future research directions must include expansion of population studies to better understand the epidemiology of MC4R mutations, exploration of the molecular mechanisms underlying MC4R signaling, and development of new therapeutic agents. Understanding the interaction between MC4R and other genetic and environmental factors will be key to advancing both the prevention and treatment of obesity.
Core Tip: The leptin-melanocortin pathway regulates energy balance and body weight. Melanocortin-4 receptor (MC4R) plays a key role in this pathway by reducing hunger, inducing satiety and increasing energy expenditure. Mutations of MC4R result in obesity and hyperphagia in childhood. Setmelanotide is an MC4R agonist approved for use in obesity caused by leptin-melanocortin pathway dysfunction.
