Exercise Regulation of Glucose Homeostasis

项目总结 肥胖率和2型糖尿病的发病率在美国和整个国家都在以惊人的速度增长 整个世界。越来越多的证据表明，有规律的体力活动可以预防或延缓2型糖尿病的发病。 糖尿病，而运动的这些重要作用的至少部分机制是有益的作用 运动对全身和组织的葡萄糖动态平衡。这个项目的长期目标是了解 运动对葡萄糖动态平衡和代谢有益的分子机制 健康。该奖项当前资助周期的研究使用了各种小鼠模型来阐明 包括AMPK相关激酶在内的参与运动刺激葡萄糖转运的新信号蛋白 Snark、QSK和BRSK1，肌动蛋白马达蛋白Myo-1c，以及钙介导的蛋白CaMKII。这个 该项目未来五年的重点是检验运动训练之前和期间的假设 怀孕对成年后代的全身和组织胰岛素敏感性有深远的影响。而母性的 肥胖和过度营养是肥胖和发展为2型糖尿病的既定危险因素。 对于孩子来说，母亲锻炼对孩子健康的长期影响知之甚少。初步 在这一资助周期中产生的小鼠研究表明，母体锻炼可以消除 发展为糖耐量低减、空腹胰岛素浓度升高、胰岛素抵抗和 即使母亲食用高脂肪的饮食，一岁大的后代体内也会出现脂肪。这些深刻的影响 母体运动对子代代谢健康的影响及其潜在的临床意义 为了人类健康，为拟议的研究提供了强有力的理由。建议的总体假设 研究工作是母体运动改善子代全身和组织的葡萄糖动态平衡 肝脏和骨骼肌的表观遗传修饰介导了运动对血糖的这些重要影响 动态平衡。它有四个具体目标：1)确定母体运动对全身的影响 后代的代谢动态平衡；2)确定训练过的母鸡的后代是否有更有利的 对饮食和运动操作的反应；3)确定肝脏在母体影响中的作用 运动以改善后代的代谢表型；以及4)确定骨骼肌在 母体运动对改善子代代谢表型的影响。使用最先进的技术 生理评估与尖端基因组技术相结合将提供强大的 阐明母体运动对健康的重要影响的生理机制 后代健康。最终将这些研究转化为人类人口将对世界各地的 公共卫生。

PROJECT SUMMARY The rates of obesity and type 2 diabetes are increasing at alarming rates in the United States and throughout the world. There is increasing evidence that regular physical activity can prevent or delay the onset of type 2 diabetes, and at least part of the mechanism for these important effects of exercise is the beneficial role of exercise on whole body and tissue glucose homeostasis. The long-term goal of this project is to understand the molecular mechanisms by which exercise exerts beneficial effects on glucose homeostasis and metabolic health. Studies from the current funding cycle of this award have used various mouse models to elucidate novel signaling proteins involved in exercise-stimulated glucose transport including the AMPK-related kinases SNARK, QSK, and BRSK1, the actin motor protein Myo-1c, and the calcium mediated protein CaMKII. The focus of this project for the coming five years is to test the hypothesis that exercise-training before and during pregnancy has profound effects on whole body and tissue insulin sensitivity in adult offspring. While maternal obesity and over-nutrition are established risk factors for obesity and the development of type 2 diabetes in offspring, little is known about the long-term effects of maternal exercise on offspring health. Preliminary mouse studies generated during this funding cycle have shown that maternal exercise can abolish the development of glucose intolerance, increased fasting insulin concentrations, insulin resistance, and increased body fat in offspring at one year of age, even if the mother consumed a high-fat diet. These profound effects of maternal exercise on offspring metabolic health, along with the potential clinical significance of these findings for human health, provide strong rationale for the proposed studies. The overall hypotheses of the proposed work are that maternal exercise improves whole body and tissue glucose homeostasis in offspring and that epigenetic modifications to liver and skeletal muscle mediate these important effects of exercise on glucose homeostasis. There are four specific aims: 1) To determine the effects of maternal exercise on whole body metabolic homeostasis in offspring; 2) To determine if offspring of trained dams have a more advantageous response to dietary and exercise manipulations; 3) To determine the role of the liver in the effects of maternal exercise to improve the metabolic phenotype of offspring; and 4) To determine the role of skeletal muscle in the effects of maternal exercise to improve the metabolic phenotype of offspring. The use of state-of-the art physiological assessments in combination with cutting-edge genomic technologies will provide a powerful approach for elucidation of physiological mechanisms underlying the important effects of maternal exercise on offspring health. Eventual translation of these studies to the human population will be important for worldwide public health.