Lipodystrophy: metabolic insights from a rare disorder

Abstract

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.

Ubiquitin ligase Cbl-b and obesity-induced insulin resistance [Review]

“…Although adiposity causes the development of insulin resistance and inflammation, it remains unclear whether adiposity and hyperlipidemia are necessary for insulin resistance. In fact, lipodystrophy causes severe inflammation in adipose tissue without adiposity [61,62]. Finally, we investigated the importance of TLR4 in the development of insulin resistance in Cbl-b -/-mice fed a HFD for 5 weeks by using Eritoran, a TLR4 antagonist [63].…”

Human Immunodeficiency Virus infection and cardiovascular disease

“…It is well established that increased truncal adiposity confers heightened risk of cardiovascular complications in the general population. Intraabdominal fat delivers excess free fatty acids directly into the portal blood system and secretes cytokines and other factors that contribute to insulin resistance, impaired fibrinolysis, and endothelial dysfunction (Huang-Doran et al, 2010;Wohl et al, 2008)). Significant evidence suggests that markers of impaired fibrinolysis are increased in HIV in association with insulin resistance and various altered metabolic pathways.…”

Definitive diagnosis of mandibular hypoplasia, deafness, progeroid features and lipodystrophy (MDPL) syndrome caused by a recurrent <i>de novo</i> mutation in the <i>POLD1</i> gene

“…, Kumiko Yanagi 3) *, Satoshi Ugi 4) , Kunihisa Kobayashi 1) , Kumiko Ohkubo 5) , Yuji Tajiri 6) , Hiroshi Maegawa 4) , Atsunori Kashiwagi 7) and Tadashi Kaname 3) resulting in lipodystrophy and progeroid features caused by mutations of the lamin A/C gene (LMNA) in type A and the zinc metalloprotease (ZNPTSTE24) gene in type B [8,9]. However, many others remain to be elucidated [1][2][3][4].…”

“…However, many others remain to be elucidated [1][2][3][4]. Currently, the comprehensive definition and classification of lipodystrophy is a work in progress with up to 20 loci described as being associated with infrequent lipodystrophy syndromes [2,4,5] (Table 1).…”