MENOPAUSE, GENES AND METABOLISM AFTER WEIGHT LOSS AND EXERCISE

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 肥胖症的患病率在美国继续上升，估计有1/3的人口超重。非裔美国女性的肥胖发生率为49%，而白人女性为33%。此外，非洲裔美国妇女的胰岛素抵抗明显更强，2型糖尿病的患病率是白人的两倍。这些种族差异的原因并不能完全用肥胖的差异来解释。这些假设是，低热量减肥（WL）和有氧运动（AEX）影响超重、胰岛素抵抗的绝经后妇女的身体组成、葡萄糖、脂质、肌肉和脂肪组织代谢的机制和程度存在种族（非裔美国人vs.高加索人）和遗传差异。这将在一项试验中进行测试，该试验比较WL与AEX+WL对超重的非裔美国人和白人绝经后妇女的葡萄糖、脂质、脂肪和肌肉代谢的影响，具体目的如下：通过测量干预前后高胰岛素-正常血糖钳夹期间肌肉活检中的胰岛素敏感性、游离脂肪酸（FFA）抑制和胰岛素信号蛋白和活性，确定WL与AEX+WL对胰岛素对葡萄糖、肌肉和脂肪代谢的代谢作用的影响是否存在种族（非洲裔美国人vs.高加索人）和/或遗传差异。2.通过确定WL vs. AEX +WL对影响骨骼肌中胰岛素作用的蛋白质（如GLUT 4、IRS 1和PI-3激酶）的影响（包括微阵列技术）以及胰岛素对分离脂肪细胞中脂解的抑制，确定与高加索女性相比，在WL中添加AEX影响非裔美国人胰岛素敏感性的细胞机制。3.确定骨骼肌和脂肪组织对减肥和运动的代谢反应以及身体成分、脂质和胰岛素敏感性的变化是否存在种族差异。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空腹LPL活性以及对低热量饮食的代谢反应，以改变肥胖绝经后女性长期饮食诱导WL期间总脂肪和内脏脂肪、葡萄糖/胰岛素和脂蛋白脂质的减少幅度。5.在探索性分析中确定是否存在基因-种族-环境相互作用影响非裔美国人和白人女性的胰岛素敏感性以及对减肥和有氧运动或单独减肥的反应。

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.