Genetic and Acquired Lipodystrophic Syndromes

Abstract

Lipodystrophic syndromes are rare conditions of genetic or acquired origin in which total or partial fat loss is associated with severe hypertriglyceridemia and insulin resistance leading to early diabetes, cardiovascular, and hepatic complications. Recent advances in genetics have shown that, although genetic lipodystrophies are heterogeneous, most of them result from primary alterations in genes involved in adipogenesis, triglyceride fat storage, and/or formation of the unique adipocyte lipid droplet. Acquired forms could be iatrogenic or linked to immune and/or endocrine factors. The most common are secondary to treatment with some human immunodeficiency virus (HIV)-antiretrovirals or to endogenous or exogenous excess of cortisol. Overall, the reduced adipose tissue amount and expandability alters its capacity to buffer excess caloric intake, leading to ectopic lipid accumulation responsible for insulin resistance and cellular dysfunctions. Increased lipolysis and production of inflammatory mediators also participate to this “lipotoxicity” phenotype with increased oxidative stress, insulin resistance, and fat remodeling. The treatment of lipodystrophic syndromes is difficult. Lifestyle modifications, insulin sensitizers, and lipid-lowering molecules are generally insufficient. Very high doses of insulin are frequently needed. New therapeutic options as recombinant human leptin substitution could be helpful in patients with severe metabolic complications.