Sridhar Gumpeny R, Gumpeny Lakshmi
Department of Endocrinology and Diabetes, Endocrine and Diabetes Centre, Visakhapatnam 530002, Andhra Pradesh, India.
Department of Internal Medicine, Gayatri Vidya Parishad Institute of Healthcare and Medical Technology, Visakhapatnam 530048, Andhra Pradesh, India.
World J Exp Med. 2024 Dec 20;14(4):99239. doi: 10.5493/wjem.v14.i4.99239.
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: 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.
肥胖在全球范围内日益普遍，遗传因素在其发展过程中发挥作用。下丘脑瘦素 - 促黑素细胞激素途径对食欲和体重调节至关重要；瘦素激活阿黑皮素原神经元，导致促黑素细胞激素肽的产生；这些肽反过来作用于促黑素细胞激素4受体（MC4R），从而抑制食欲并增加能量消耗。MC4R突变导致综合征性和非综合征性肥胖。这些突变根据其对受体生命周期的影响进行分类：无效突变、细胞内滞留、结合缺陷、信号传导缺陷以及功能未知的变体。MC4R突变的临床表现包括早发性肥胖、食欲亢进以及代谢异常，如高胰岛素血症和血脂异常。随着靶向治疗的发展，如MC4R激动剂Setmelanotide，因MC4R突变导致的肥胖管理策略也在不断演变，Setmelanotide可减轻体重并控制症状，且无不良心血管影响。未来的研究方向必须包括扩大人群研究以更好地了解MC4R突变的流行病学，探索MC4R信号传导的分子机制，以及开发新的治疗药物。了解MC4R与其他遗传和环境因素之间的相互作用将是推进肥胖预防和治疗的关键。
