| The studies presented in this dissertation describe the development and characterization of a murine model of obesity and insulin resistance that has allowed for the elucidation of relevant mechanisms linking insulin resistance with its associated dyslipidemia. Mice lacking brown adipose tissue (BATless) were bred with mice expressing human apolipoprotein B (apoB) and reared on a high-fat diet. Compared to apoB controls, the resultant mouse (designated apoBBATless) was hypertriglyceridemic, hypercholesterolemic and insulin resistant with no consistent differences in plasma glucose or free fatty acid (FFA) levels.; Male apoB/BATless mice secreted triglyceride (TG) and apoB at increased rates compared to controls, a finding that was associated with the appearance of more newly synthesized TG in very low density lipoprotein. The apoBBATless phenotype was associated with no change in apoB and microsomal triglyceride transfer protein mRNA and modestly increased low density lipoprotein receptor mRNA. ApoBBATless mice also exhibited hepatic steatosis associated with increased mRNA levels of the lipogenic enzyme, fatty acid synthase, but no change in the mRNA of the transcription factor, sterol regulatory element binding protein-1c. Increased FFA flux to the liver may also have contributed to the increased secretion of apoB-containing lipoproteins in this mouse model.; Gender-related differences in parameters of both insulin sensitivity and lipid metabolism were observed. Female apoBBATless mice were less insulin resistant relative to their apoB controls than were male apoBBATless mice. Compared to males, absolute levels of plasma TG were lower, presumably due to improved clearance pathways, since TG secretion rates were comparable. ApoB secretion rates in female apoB and apoBBATless mice were similar, suggesting that females secreted larger, more TG-enriched particles. Furthermore, estrogen was found to be a relevant modulator of insulin sensitivity. Ovariectomy was associated with increased weight gain and decreased insulin sensitivity. Estrogen replacement appeared to improve insulin sensitivity, but plasma TG levels were also increased significantly, indicative of the pleiotropic effects of the hormone.; Exploitation of this murine model may lend insight into the etiology of the dyslipidemia that accompanies insulin resistance. |
