and specific aims): Cardiovascular disease (CVD) is associated with a cluster of risk factors including obesity, insulin resistance (IR), hyperlipidemia and hypertension. These risk factors are directly associated with high dietary fat, weight gain and increased sympathetic nervous system (SNS) activity in males. There appears to be a sexual dimorphism in the development of these risk factors wherein women are resistant until menopause. Androgen-related deposition of fat in the abdominal region is associated with higher CVD risk in both men and women. Moreover, women become more susceptible to CVD postmenopause as weight gain occurs. It is unclear whether estrogen is protective or androgens deleterious and how these interact with SNS mediators in this differential development. The objective of the proposed studies is to determine the effect of gender on the development of risk factors in dietary-induced obesity, IR and hypertension. 96 Gonadectomized or sham-operated male and female rats will be fed 12 or 48% energy as saturated fat diet for 10 weeks to induce obesity. Food intake and body weight will be recorded weekly. Chronic femoral catheters will be implanted for conscious, unrestrained, 24-hour blood pressure measurements at the end of the feeding period. Hyperinsulinemic-euglycemic clamp will be performed to assess insulin sensitivity. In addition, fasting blood samples will be analyzed for glucose, insulin, triglyceride, total cholesterol, high-density lipoprotein, and steroid hormones. Adipose depots, liver and kidney weights will be obtained and tissues saved for associated histological and molecular analyses. Carcass analysis will be used to estimate body composition. Adrenergic receptor and hormone-sensitive lipoprotein lipase density and activity will be assessed in adipose tissue from the above animals and in cultured adipocytes exposed to various media concentrations and combinations of steroid hormones. The results of the proposed studies will contribute to the understanding of basic mechanisms and therapeutic (dietary/pharmacological) intervention in the development of obesity-induced IR syndrome with a novel focus on gender.
