"Apolipoproteins and lipoprotein modifying enzymes are responsible for the maintenance of lipid homeostasis in the circulation. Mutations in these proteins may affect the lipoproteins present in plasma and may result in dyslipidemia. Obesity plays a central role in the development of the metabolic syndrome. Our data indicate that apoE promotes diet-induced obesity. Based on this, we hypothesize that components of the lipoprotein system that promote direct delivery of lipids to the peripheral tissues will contribute to the development of obesity and insulin resistance; in contrast, components that promote reverse lipid transport may prevent these conditions. Thus, we propose to investigate the role of the chylomicron and HDL pathways in the development of obesity and insulin resistance. Our objectives are: 1) To determine how expression or lack of expression of apolipoproteins or lipoprotein modifying enzymes in transgenic and knock-out mice affect diet-induced obesity, and type II diabetes. In this objective, mice deficient or transgenic for proteins of the chylomicron and HDL pathways will be placed on western-type diet and their weight, body composition, and sensitivity to insulin will be determined over time. 2) To identify cellular genes and pathways that are affected by apoE and other components of the lipoprotein transport system and may promote or prevent adopigenesis. In this objective we propose to use microarray analysis, to identify signaling pathways affected by apoE and other proteins of the lipoprotein system. Select target genes that will be identified from this analysis will be expressed in cultured preadipocytes using adenoviral vectors, to validate their functional role in preadipocyte differentiation, lipid deposition, and the development of insulin resistance. This study may provide novel insights in the mechanisms that result to obesity, and may reveal new therapeutic targets for the treatment of the metabolic syndrome."