Qamar Sulmaaz, Mallik Ritwika, Makaronidis Janine
Centre for Obesity Research, Rayne Institute, Department of Medicine, University College London, London, UK.
UCLH Bariatric Centre for Weight Management and Metabolic Surgery, University College London Hospital, London, UK.
touchREV Endocrinol. 2024 Oct;20(2):62-71. doi: 10.17925/EE.2024.20.2.9. Epub 2024 Feb 9.
Obesity is a silent global pandemic. It is a condition associated with multiple risk factors and adverse outcomes that arise from the intertwined relationship between environmental factors and genetics. The genetic factors that cause phenotypic expression are variable. Monogenic obesity is a severe early-onset and rarer form of obesity, which presents with co-morbidities such as abnormal feeding behaviour. Monogenic obesity causes impaired weight regulation in the hypothalamus due to defects in the leptin-melanocortin signalling pathway. The emergence of a new therapeutic treatment, the melanocortin-4 receptor agonist setmelanotide (originally RM-493), has represented a breakthrough in the management of monogenic obesity and has raised hope in managing complex obesity. This review provides an overview of the setmelanotide trials that have taken place, as well as its mechanism of action, side effects and weight loss outcomes that led to its approval in the treatment of pro-opiomelanocortin (POMC) deficiency and proprotein convertase subtilisin/kexin type 1 (PCSK1) deficiency. It also explores setmelanotide's role in other genetic forms of obesity, such as hypothalamic obesity, Prader-Willi syndrome, Alström syndrome and other rare genetic conditions that are being investigated. This review aims to help to understand the pathophysiology of genetic obesity and aid in future treatment options for people with severe, complex genetic obesity.
肥胖是一种悄无声息的全球流行病。它是一种与多种风险因素及不良后果相关的病症，这些风险因素和不良后果源于环境因素与基因之间的相互交织关系。导致表型表达的基因因素各不相同。单基因肥胖是一种严重的早发性且较为罕见的肥胖形式，伴有诸如异常进食行为等合并症。单基因肥胖由于瘦素 - 黑皮质素信号通路缺陷导致下丘脑体重调节受损。一种新的治疗方法——黑皮质素 - 4 受体激动剂setmelanotide（最初为RM - 493）的出现，代表了单基因肥胖治疗方面的一项突破，并为治疗复杂肥胖带来了希望。本综述概述了已开展的setmelanotide试验，以及其作用机制、副作用和减肥效果，正是这些因素促使其获批用于治疗阿片 - 促黑素细胞皮质素原（POMC）缺乏症和前蛋白转化酶枯草溶菌素/kexin 1型（PCSK1）缺乏症。它还探讨了setmelanotide在其他遗传性肥胖形式中的作用，如下丘脑性肥胖、普拉德 - 威利综合征、阿尔斯特伦综合征以及其他正在研究的罕见遗传病症。本综述旨在帮助理解遗传性肥胖的病理生理学，并为患有严重复杂遗传性肥胖的患者提供未来的治疗选择。
