This study is designed to determine the cellular mechanisms underlying the paradoxical association of insulin resistance with decreased visceral adiposity and circulating triglyceride (TG) levels in African-American (AA) compared to Caucasian (CAU) postmenopausal women. This will provide insight into mechanisms underlying racial differences in obesity and its associated metabolic dysfunction (insulin resistance, type 2 diabetes, dyslipidemia, hypertension). The hypothesis is that postmenopausal AA women have a higher skeletal muscle lipoprotein lipase (SM-LPL) and a lower adipose tissue LPL (AT-LPL) activity that leads to the preferential accumulation of TG in muscle (SM-TG), while the converse exists in CAU women. We also postulate that a weight loss (WL) intervention, by preferentially decreasing SM-LPL activity in AA and AT-LPL activity in CAU, will promote reductions of SM-TG in AA and of visceral adiposity in CAU to improve lipoprotein lipid profiles and insulin sensitivity.
Specific aims determine whether: 1) decreased visceral (omental and mesenteric) and subcutaneous abdominal (SAT) AT-LPL activity and increased skeletal muscle LPL activity in rectus abdominis and vastus lateralis are the cellular mechanisms underlying racial differences in visceral obesity and SM-TG accumulation in AA compared to CAU postmenopausal women using tissue obtained during elective abdominal surgery and by needle biopsy, and 2) WL, by reducing SM (vastus lateralis - and SAT-LPL activity, is associated with a decrease in SM and visceral fat accumulation to increase in vivo insulin action (hyperinsulinemic euglycemic clamp) and the in vitro antilipolytic response to insulin in a homogeneous population of healthy obese AA and CAU postmenopausal women. We will study healthy, obese (BMI = 30-40 kg/m2), sedentary 50-65 year old postmenopausal women not on hormone-replacement therapy. We will measure AT- and SM-LPL activity, SM-TG content, visceral fat and mid-thigh low density lean tissue area (CT scans) insulin sensitivity in abdominal adipocytes as insulin suppression of lipolysis and in whole body estimated by hyperinsulinemic euglycemic clamps and using the Homeostasis Model Assessment of Insulin Resistance (HOMA IR), total body fat (DXA), lipoprotein lipids, oral glucose tolerance and obesity-related hormones (leptin, insulin, SHBG, free testosterone). Collectively, these results will determine whether racial differences in the tissue-specific LPL activity, the key enzyme for hydrolysis and the ensuing storage of circulating TGs, establish a metabolic setting in obese AA of increased SM-TG (due to increased SM-LPL and decreased visceral fat) and in obese CAU of increased visceral fat (due to increased AT-LPL) that predisposes them to insulin resistance and risk for type 2 diabetes.
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