Exercise Regulation of Glucose Homeostasis Administrative Supplement

描述（由申请人提供）：在美国和全世界，肥胖和 2 型糖尿病的发病率正以惊人的速度增加。越来越多的证据表明，定期体育活动可以预防或延缓 2 型糖尿病的发病，运动产生这些重要作用的机制至少部分是运动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转运的新型信号蛋白，包括 AMPK 相关激酶 SNARK、QSK 和 BRSK1、肌动蛋白运动蛋白 Myo-1c 和钙介导蛋白 CaMKII。该项目未来五年的重点是检验以下假设：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具有深远影响。虽然母亲肥胖和营养过剩是导致后代肥胖和患 2 型糖尿病的既定危险因素，但人们对母亲运动对后代健康的长期影响知之甚少。在此资助周期内进行的初步小鼠研究表明，即使母亲食用高脂肪饮食，母亲锻炼也可以消除后代一岁时葡萄糖不耐症、空腹胰岛素浓度升高、胰岛素抵抗和体脂增加的情况。母亲锻炼对后代代谢健康的这些深远影响，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。拟议工作的总体假设是，母亲运动可以改善后代的全身和组织葡萄糖稳态，并且肝脏和骨骼肌的表观遗传修饰介导运动对葡萄糖稳态的这些重要影响。有四个具体目标：1）确定母亲运动对后代全身代谢稳态的影响； 2) 确定经过训练的母鼠的后代是否对饮食和运动控制有更有利的反应； 3）确定肝脏在母体运动改善后代代谢表型的效果中的作用； 4) 确定骨骼肌在母亲锻炼改善后代代谢表型的效果中的作用。将最先进的生理评估与尖端基因组技术相结合，将为阐明母亲锻炼对后代健康产生重要影响的生理机制提供有力的方法。这些研究最终转化为人类对于全球公共卫生至关重要。

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.