Genetic and Metabolic Basis of Familial Lipodystrophies

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DESCRIPTION (provided by applicant): Obesity remains a major health problem in US and causes metabolic complications such as diabetes, dyslipidemia and insulin resistance. Similar complications also occur in patients with familial lipodystrophies, monogenic disorders characterized by partial (familial partial lipodystrophy, FPL) or almost complete (congenital generalized lipodystrophy, CGL) lack of body fat. In the last few years, several genes, namely, 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) and Berardinelli-Seip Congenital Lipodystrophy 2 (BSCL2), for the autosomal recessive, CGL; lamin A/C (LMNA), peroxisome proliferator-activated receptor-D (PPARG), and v-AKT murine thymoma oncogene homolog 2 (AKT2) for the autosomal dominant FPL; and LMNA and zinc metalloproteinase (ZMPSTE24) for mandibuloacral dysplasia associated lipodystrophies have been identified. However, affected subjects from many pedigrees lack mutations in these genes suggesting additional loci. Furthermore, the genetic basis of many extremely rare varieties of lipodystrophies associated with SHORT and neonatal progeroid syndromes remains unknown. Thus, the first aim of this proposal is to identify additional gene(s) involved in adipocyte biology, development and differentiation that cause lipodystrophies. Our laboratory has also been studying the functional role of various isoforms of AGPAT (mainly AGPAT1 and 2) either in vitro or by developing knockout mouse models. The Agpat2-/- mice reproduce many features of human CGL such as extreme lack of body fat, early onset hyperglycemia, hyperinsulinemia, hypertriglyceridemia and hepatic steatosis. Interestingly, our studies reveal that in these null mice, dietary triglycerides are major contributors to hepatic steatosis. The Agpatl-/- mice also have profound lack of body fat but the detailed phenotype remains to be characterized. Furthermore, the biological function of BSCL2-encoded protein, seipin, still remains unknown and thus how BSCL2 mutations cause lipodystrophy remains puzzling. Therefore, the second aim of this proposal is to further characterize Agpat2- /- and Agpatl-/- mice and to develop Bscl2 knockout mouse model to gain insights into biological role of various genes implicated in generalized lipodystrophies and to understand molecular mechanisms involved in causation of insulin resistance and its associated morbidities.