Human Lipodystrophies: Genetic and Acquired Diseases of Adipose Tissue

Abstract

Human lipodystrophies represent a heterogeneous group of diseases characterized by generalized or partial fat loss, with fat hypertrophy in other depots when partial. Insulin resistance, dyslipidemia and diabetes are generally associated, leading to early complications. Genetic forms are uncommon: recessive generalized congenital lipodystrophies result in most cases from mutations in the genes encoding seipin or the 1-acyl-glycerol-3-phosphate-acyltransferase 2(AGPAT2). Dominant partial familial lipodystrophies result from mutations in genes encoding the nuclear protein lamin A/C or the adipose transcription factor PPARgamma. Importantly, lamin A/Cmutations are also responsible for metabolic laminopathies, resembling the metabolic syndrome and progeria, a syndrome of premature aging. A number of lipodystrophic patients remain undiagnosed at the genetic level. Acquired lipodystrophy can be generalized, resembling congenital forms, or partial, as the Barraquer-Simons syndrome, with loss of fat in the upper part of the body contrasting with accumulation in the lower part. Although their etiology is generally unknown, they could be associated with signs of autoimmunity. The most common forms of lipodystrophies are iatrogenic. In human immunodeficiency virus-infected patients, some first-generation antiretroviral drugs were strongly related with peripheral lipoatrophy and metabolic alterations. Partial lipodystrophy also characterize patients with endogenous or exogenous long-term corticoid excess. Treatment of fat redistribution can sometimes benefit from plastic surgery. Lipid and glucose alterations are difficult to control leading to early occurrence of diabetic, cardiovascular and hepatic complications.

Thiazolidinediones partially reverse the metabolic disturbances observed in Bscl2/seipin-deficient mice

“…In addition, lipid metabolism in these two models raises several questions. First, in contrast to the human phenotype [1], Bscl2 −/− mice do not display fasting hypertriglyceridaemia.…”

“…The expansion of adipose tissue leads to obesity and related metabolic complications; lipodystrophies (disorders characterised by a partial or complete lack of adipose tissue) are also associated with severe metabolic disturbances. Among the lipodystrophies, Bernardinelli-Seip congenital lipodystrophy (BSCL) displays the most severe phenotype with a combination of insulin resistance, liver steatosis and hypertriglyceridaemia [1]. BSCL is an autosomal recessive disease linked to mutations in either BSCL2, encoding seipin [2], or AGPAT2, encoding 1-acylglycerol-3-phosphate O-acyltransferase-β [3].…”

Adipokines and Aging

“…Patients with familial partial lipodystrophic syndromes (FPLDs) exhibit peripheral subcutaneous lipodystrophy and central fat accumulation, together with metabolic dysregulation, including insulin resistance, diabetes, and early atherosclerosis 22) . FPLDs are caused by mutations in LMNA (FPLD2), which encodes the nuclear protein lamin A/C, or in PPAR-(FPLD3), which plays a key role in adipocyte differentiation 23) . Cultured skin fibroblasts from FPLD patients with LMNA mutations are reported to exhibit prelamin A accumulation, increased oxidative stress, and cellular senescence 24) .…”

Lipodystrophy: The Metabolic Link of HIV Infection with Insulin-Resistance Syndrome

“…Lipodystrophies can be genetic, which is usually uncommon, or acquired. Genetic lipodystrophy is generally related to severe metabolic alterations including insulin resistance (IR) and its associated complications, such as glucose intolerance and diabetes, dyslipidemia, hepatic steatosis, polycystic ovaries, acanthosis nigricans and early cardiovascular (CV) complications [1,2]. The autosomal recessive congenital generalized lipodystrophy (CGL) and autosomal dominant familiar partial lipodystrophy (FPL) are the two most common types of genetic lipodystrophy [2].…”