Exercise Regulation of Glucose Homeostasis

项目摘要 肥胖和2型糖尿病的发病率在美国和全世界以惊人的速度增长。 世界越来越多的证据表明，定期的体育活动可以预防或延迟2型糖尿病的发作。 糖尿病，至少部分的机制，这些重要的影响，运动是有益的作用， 运动对全身和组织葡萄糖稳态的影响。这个项目的长期目标是了解 运动对葡萄糖稳态和代谢产生有益影响的分子机制 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型信号蛋白 SNARK、QSK和BRSK 1、肌动蛋白马达蛋白Myo-1c和钙介导蛋白CaMKII。的 未来五年，本项目的重点是验证运动训练之前和期间 妊娠对成年后代的全身和组织胰岛素敏感性具有深远的影响。而产妇 肥胖和营养过剩是肥胖和2型糖尿病发展的既定危险因素， 然而，对于母亲锻炼对后代健康的长期影响，人们知之甚少。初步 在这一供资周期内进行的小鼠研究表明，产妇锻炼可以消除 葡萄糖耐受不良的发展，空腹胰岛素浓度增加，胰岛素抵抗， 即使母亲食用高脂肪饮食，也会在一岁时增加后代的体脂。这些深刻的影响 母亲运动对后代代谢健康的影响，沿着这些发现的潜在临床意义 对人类健康的影响，为拟议的研究提供有力的理由。提出的总体假设 母亲的锻炼可以改善后代的全身和组织葡萄糖稳态， 肝脏和骨骼肌的表观遗传修饰介导了运动对葡萄糖的重要影响 体内平衡具体目的有四：1）确定孕妇运动对全身的影响 后代的代谢稳态; 2）为了确定受过训练的母鼠的后代是否具有更有利的代谢平衡， 对饮食和运动的反应; 3）确定肝脏在母亲的影响中的作用。 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 生理评估与尖端基因组技术相结合，将提供一个强大的 一种阐明母亲运动对胎儿重要影响的生理机制的方法 后代健康这些研究最终转化为人类群体将是重要的， 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.