Exercise Regulation of Glucose Homeostasis

血糖稳态的运动调节

• 批准号: 9332377
• 负责人: LAURIE J GOODYEAR
• 金额: $ 36.11万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-16 至 2018-12-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9332377
• 关键词: 1 year old; Actins; Acute; Adult Children; Award; Body fat; Calcium; Contracts; Data; Development; Diabetes Mellitus; Diabetes prevention; Diet; Dietary Intervention; Epidemiology; Epigenetic Process; Exercise; Fasting; Fatty acid glycerol esters; Funding; Gene Expression; Genomics; Glucose; Glucose Intolerance; Goals; Health; Health Benefit; Healthcare; High Fat Diet; Homeostasis; Human; Incidence; Insulin; Insulin Resistance; Intervention; Investigation; Laboratories; Life; Liver; Long-Term Effects; Mediating; Metabolic; Modification; Molecular; Mothers; Motor; Mus; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Onset of illness; Overnutrition; Phosphotransferases; Physical activity; Physiological; Population; Pregnancy; Proteins; Public Health; Risk Factors; Role; Science; Serum; Signaling Protein; Skeletal Muscle; Technology; Testing; Tissues; Training; Translational Research; Translations; United States; Weaning; Work; World Health Organization; blood glucose regulation; calmodulin-dependent protein kinase II; clinically significant; exercise intervention; exercise training; feeding; glucose disposal; glucose tolerance; glucose transport; glucose uptake; improved; insulin sensitivity; liver metabolism; maternal obesity; metabolic phenotype; mouse model; novel; offspring; prevent; public health relevance; response; skeletal muscle metabolism

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.

描述（由申请人提供）：肥胖和2型糖尿病的速度正在以惊人的速度和全世界的惊人速度增加。越来越多的证据表明，定期的体育锻炼可以预防或延迟2型糖尿病的发作，而这些运动的重要作用的至少部分机制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，包括与AMPK相关的激酶SNARK，QSK和BRSK1，肌动蛋白运动蛋白MOYO-1C和钙介导的蛋白质CAMKII。在接下来的五年中，该项目的重点是检验以下假设：在怀孕之前和期间进行运动对成人后代的全身和组织胰岛素敏感性产生深远影响。尽管孕产妇的肥胖和过度营养是肥胖症的确定危险因素和后代2型糖尿病的发展，但对产妇运动对后代健康的长期影响知之甚少。在此资助周期中产生的初步小鼠研究表明，即使母亲消耗了高脂饮食，也可以消除葡萄糖不耐症的发展，空腹胰岛素浓度升高，胰岛素抵抗和增加后代的体内脂肪。孕产妇运动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烈的理由。拟议工作的总体假设是，孕产妇运动可以改善后代的全身和组织葡萄糖稳态，并且对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作用。有四个具体的目的：1）确定母体运动对后代全身代谢稳态的影响； 2）确定训练有素的大坝后代是否对饮食和运动操作更有利； 3）确定肝脏在孕产妇运动作用中的作用，以改善后代的代谢表型； 4）确定骨骼肌在孕产妇运动作用中的作用，以改善后代的代谢表型。最先进的生理评估与最先进的基因组技术结合使用将为阐明产妇运动对后代健康的重要影响的生理机制提供强大的方法。这些研究最终将这些研究转化为人口对于全球公共卫生至关重要。