Search

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.

1 Metabolic Research Laboratories, University of Cambridge, Cambridge, UK, 2 Wolfson Brain Imaging Centre, University of Cambridge, Cambridge, UK, 3 Wolfson Department of Diabetes and Endocrinology, Addenbrooke’s Hospital, Cambridge, UK 4 Department of Radiology, University of Cambridge, Cambridge, UK 5 Department of Radiology, Addenbrooke’s Hospital, Cambridge, UK 6 Department of Medicine, Addenbrooke’s Hospital, Cambridge, UK