Obesity is a major health problem in the U.S. However, how adipose tissue disorders cause metabolic diseases is not well understood. Study of familial lipodystrophies which are characterized by partial (familial partial lipodystrophies; FPL) or almost complete lack of body fat (congenital generalized lipodystrophy, CGL) and metabolic complications may elucidate the mechanisms involved. Recently, FPL was reported to be due to defects in lamin A/C (LMNA) and peroxisome proliferator-activated receptor-g (PPARG) genes and CGL due to mutations in 1- acylglycerol-3-phosphate O-acyltransferase 2 (AGPA T2) or Seipin genes on chromosome 9q34 and 11q13, respectively. The main aim of this proposal is to identify additional gene(s) that cause CGL and FPL. Another aim is to define the role of AGPAT2 mutations in adipose tissue biology and development by conducting functional studies and by developing a knockout Agpat2 mouse model. To accomplish these aims, we have collected a number of well-characterized CGL pedigrees, which do not harbor substantial alterations in AGPAT2 and Seipin and FPL pedigrees without alterations in LMNA and PPARG. We will carefully characterize minor changes in the phenotype by studying body fat distribution by anthropometry and whole body magnetic resonance imaging and will ascertain severity of metabolic complications by measuring insulin sensitivity, plasma lipoproteins, free fatty acids, glycerol, leptin and other metabolic variables. Additional locus (loci) for CGL and FPL will be determined by genome-wide linkage analysis. Following chromosomal localization and fine mapping, candidate genes, already mapped or identified in these regions will be examined for mutations using direct sequencing. The identification of novel genes responsible for CGL and FPL and understanding of the role of AGPATs in adipocyte biology will lead to a better understanding of how common adipose tissue disorders such as obesity cause insulin resistance and other metabolic complications.
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