Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Hills Road, Cambridge CB2 0QQ, UK.
J Endocrinol. 2010 Dec;207(3):245-55. doi: 10.1677/JOE-10-0272. Epub 2010 Sep 24.
Obesity, insulin resistance and their attendant complications are among the leading causes of morbidity and premature mortality today, yet we are only in the early stages of understanding the molecular pathogenesis of these aberrant phenotypes. A powerful approach has been the study of rare patients with monogenic syndromes that manifest as extreme phenotypes. For example, there are striking similarities between the biochemical and clinical profiles of individuals with excess fat (obesity) and those with an abnormal paucity of fat (lipodystrophy), including severe insulin resistance, dyslipidaemia, hepatic steatosis and features of hyperandrogenism. Rare lipodystrophy patients therefore provide a tractable genetically defined model for the study of a prevalent human disease phenotype. Indeed, as we review herein, detailed study of these syndromes is beginning to yield valuable insights into the molecular genetics underlying different forms of lipodystrophy, the essential components of normal adipose tissue development and the mechanisms by which disturbances in adipose tissue function can lead to almost all the features of the metabolic syndrome.
肥胖、胰岛素抵抗及其伴随的并发症是当今导致发病率和过早死亡率的主要原因之一，但我们仍处于理解这些异常表型的分子发病机制的早期阶段。一种有力的方法是研究表现出极端表型的罕见单基因综合征患者。例如，脂肪过多（肥胖）和脂肪异常缺乏（脂肪营养不良）个体的生化和临床特征存在显著相似性，包括严重的胰岛素抵抗、血脂异常、肝脂肪变性和高雄激素血症特征。因此，罕见的脂肪营养不良患者为研究普遍存在的人类疾病表型提供了一种易于处理的基因定义模型。事实上，正如我们在此综述中所回顾的那样，对这些综合征的详细研究开始为不同形式的脂肪营养不良的分子遗传学、正常脂肪组织发育的基本成分以及脂肪组织功能障碍如何导致代谢综合征的几乎所有特征提供有价值的见解。
