MENOPAUSE, GENES AND METABOLISM AFTER WEIGHT LOSS AND EXERCISE

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。美国肥胖率继续上升，估计有三分之一的人口超重。非洲裔美国女性的肥胖率为49%，而高加索女性的肥胖率为33%。此外，非洲裔美国女性对胰岛素的抵抗力明显高于白人，2型糖尿病的患病率是高加索女性的两倍。这些种族差异的原因并不能完全用肥胖的差异来解释。假设在超重、胰岛素抵抗的绝经后妇女中，低卡路里减重(WL)和有氧运动(AEX)影响身体成分、葡萄糖、脂肪、肌肉和脂肪组织代谢的机制和幅度存在种族(非裔美国人和高加索人)和遗传差异。这将通过一项试验，比较WL和AEX+WL对超重的非裔美国人和高加索绝经后妇女的葡萄糖、脂肪、脂肪和肌肉代谢的影响，具体目的如下：1.通过测量干预前后的胰岛素敏感性、游离脂肪酸(FFA)抑制以及肌肉活检中的胰岛素信号蛋白和活性，确定WL和AEX+WL对胰岛素对葡萄糖、肌肉和脂肪代谢的影响是否存在种族(非裔美国人和高加索人)和/或遗传差异。2.通过比较WL和AEX+WL对骨骼肌中影响胰岛素作用的蛋白质(如GLUT4、IRS1和PI-3激酶)的影响(包括基因芯片技术)，以及胰岛素对脂肪细胞脂解的抑制作用，确定WL与AEX+WL对非裔美国人和高加索女性胰岛素敏感性的影响的细胞机制。3.确定减肥和运动对骨骼肌和脂肪组织的代谢反应是否存在种族差异，以及身体成分、血脂和胰岛素敏感性的变化。4.确定脂蛋白脂酶(LPL)PvuII基因的遗传变异和/或其他肥胖-糖尿病基因多态性是否影响肌肉和脂肪组织中的LPL活性和对低热量饮食的代谢反应，改变肥胖绝经后妇女长期饮食诱导的WL中总脂肪和内脏脂肪以及葡萄糖/胰岛素和脂蛋白脂下降的幅度。5.在探索性分析中确定非裔美国人和高加索女性是否存在影响胰岛素敏感性的基因-种族-环境相互作用以及对减肥和有氧运动或减肥的单独反应。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The prevalence of obesity continues to rise in the U.S. with estimates that 1/3 of the population is overweight. The incidence of obesity is 49% in African-American women compared to 33% in Caucasian women. Moreover, African-American women are significantly more insulin resistant and have twice the prevalence of type 2 diabetes than Caucasians. The reasons for these racial disparities are not entirely explained by differences in obesity. The hypotheses are that there are ethnic (African American vs. Caucasian) and genetic differences in the mechanisms and magnitude by which hypocaloric weight loss (WL) and aerobic exercise (AEX) affect body composition, glucose, lipid, muscle and adipose tissue metabolism in overweight, insulin resistant postmenopausal women. This will be tested in a trial comparing the effects of WL vs. AEX+WL on glucose, lipid, fat and muscle metabolism in overweight African American and Caucasian postmenopausal women with the following specific aims: 1. To determine whether there are racial (African American vs. Caucasian) and/or genetic differences in the effects of WL vs. AEX+WL on the metabolic actions of insulin on glucose, muscle, and fat metabolism by measuring insulin sensitivity, free fatty acid (FFA) suppression and insulin signaling proteins and activities in muscle biopsies during hyperinsulinemic-euglycemic clamps before and after the interventions. 2. To determine the cellular mechanisms by which the addition of AEX to WL affects insulin sensitivity in African American compared to Caucasian women by ascertaining the effects of WL vs. AEX+WL on proteins affecting insulin action (such as GLUT4, IRS1 and PI-3 kinase) in skeletal muscle (including micro-array technology), and insulin suppression of lipolysis in isolated adipocytes. 3. To determine whether there are racial differences in the skeletal muscle and adipose tissue metabolic responses to weight loss and exercise, and the changes in body composition, lipids and insulin sensitivity. 4. To determine whether genetic variation in the lipoprotein lipase (LPL) PvuII gene and/or other obesity-diabetes gene polymorphisms affect fasting LPL activity in muscle and adipose tissue and the metabolic responses to a hypocaloric diet, to alter the magnitude of the reduction in total and visceral fat, and glucose/insulin and lipoprotein lipids during longterm dietary-induced WL in obese postmenopausal women. 5. To determine in exploratory analyses if there are gene-race-environment interactions which affect insulin sensitivity and the response to weight loss and aerobic exercise or weight loss alone in African-American and Caucasian women.