Exercise Regulation of Glucose Homeostasis

描述(申请人提供)：肥胖率和2型糖尿病在美国和全世界正以惊人的速度增长。越来越多的证据表明，有规律的体育锻炼可以预防或延缓2型糖尿病的发病，而锻炼产生这些重要作用的机制至少有一部分是锻炼对全身和组织葡萄糖稳态的有益作用。该项目的长期目标是了解运动对葡萄糖稳态和代谢健康产生有益影响的分子机制。该奖项当前资助周期的研究使用了各种小鼠模型来阐明参与运动刺激的葡萄糖运输的新的信号蛋白，包括AMPK相关的激酶snark、QSK和BRSK1，肌动蛋白Myo-1c，以及钙介导的蛋白CaMKII。该项目未来五年的重点是验证这样一个假设，即怀孕前和怀孕期间的运动训练对成年后代的全身和组织胰岛素敏感性有深远影响。虽然母亲肥胖和过度营养是肥胖和子女患2型糖尿病的既定风险因素，但关于母亲锻炼对子女健康的长期影响，人们知之甚少。在这一资助周期中产生的初步小鼠研究表明，即使母亲食用高脂肪饮食，母体锻炼也可以消除一岁大时出现的葡萄糖不耐受、提高空腹胰岛素浓度、胰岛素抵抗和增加体脂。母体运动对子代代谢健康的深刻影响，以及这些发现对人类健康的潜在临床意义，为拟议的研究提供了强有力的理由。这项拟议工作的总体假设是，母体运动改善了子代全身和组织的葡萄糖稳态，肝脏和骨骼肌的表观遗传修饰介导了运动对葡萄糖稳态的这些重要影响。有四个具体目标：1)确定母体运动对子代全身代谢稳态的影响；2)确定训练母鼠的后代是否对饮食和运动操作有更有利的反应；3)确定肝脏在母体运动改善子代代谢表型的影响中的作用；4)确定骨骼肌在母体运动改善子代代谢表型的影响中的作用。将最先进的生理评估与尖端基因组技术相结合，将为阐明母体锻炼对后代健康的重要影响提供强有力的生理机制。最终将这些研究转化为人类群体，将对世界公共卫生具有重要意义。

DESCRIPTION (provided by applicant): 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.