Exercise Regulation of Glucose Homeostasis

血糖稳态的运动调节

• 批准号: 10587516
• 负责人: LAURIE J GOODYEAR
• 金额: $ 72.46万
• 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 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587516
• 关键词: Adipose tissue; Adult; Affect; Animals; Area; Brown Fat; Cells; Clinical; Consensus; Data; Destinations; Development; Diabetes prevention; Epigenetic Process; Exercise; Exercise Physiology; Female; Female of child bearing age; Fetal Liver; Fetal Tissues; Foundations; Funding; Generations; Genes; Genetic Transcription; Goals; Health; Health Benefit; Healthcare; Hepatic Tissue; High Fat Diet; Homeostasis; Incidence; Intervention; Investigation; Life Style; Literature; Liver; Mediating; Mediator; Metabolic; Metabolic Diseases; Molecular; Mothers; Mus; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity Epidemic; Onset of illness; Oocytes; Pharmacological Treatment; Phenotype; Physical Exercise; Physical activity; Placenta; Pregnancy; Pregnancy Proteins; Prevention; Proteins; Protocols documentation; Publishing; Research; Research Project Grants; Risk; Role; Serum; Signal Transduction; Skeletal Muscle; Superoxide Dismutase; Tissues; Training; Transforming Growth Factor beta; Vitamin D; Vitamin D3 Receptor; Woman; Work; World Health; blood glucose regulation; clinical translation; combat; epigenetic regulation; exercise training; experimental study; functional improvement; glucose tolerance; glucose uptake; improved; in vivo; innovation; insulin sensitivity; male; maternal obesity; novel; novel therapeutics; nutrition; offspring; optimal treatments; pharmacologic; pregnant; prevent; protein function; reproductive; secretory protein; sedentary; skeletal tissue; sperm cell; tool; transcriptome sequencing; transcriptomics; transmission process

PROJECT SUMMARY/ABSTRACT The overall hypothesis of this project is that regular physical exercise in mothers is critical for the prevention of type 2 diabetes and metabolic disease in offspring. Our mouse studies establish that maternal exercise before and during pregnancy has striking beneficial effects on the metabolic health of both male and female offspring. These findings have opened a new area of exercise physiology research, suggesting that exercise is an important tool to combat the development of type 2 diabetes, and underscores the need for scientific investigation aimed at determining the molecular mechanisms by which maternal exercise improves metabolic health of offspring. For this purpose, and based on our extensive published and preliminary data, we have defined four Specific Aims. Specific Aim 1 will investigate the vitamin D receptor (VDR) and TGF2 as central mediators of maternal exercise effects on offspring metabolic health in liver, skeletal muscle, and other offspring tissues. This includes experiments that will: a) determine the function of VDR in maternal exercise- induced hepatic, skeletal muscle, and adipose tissue AMPK/TET signaling, epigenetic changes, and in vivo glucose homeostasis; b) investigate TGF2 as a maternally derived exercise signal that activates epigenetic changes and improves offspring phenotype; and c) determine if maternal exercise has wide ranging effects to improve the function of skeletal muscle and adipose tissues. Specific Aim 2 will determine optimal exercise and pharmacologic treatments for the improvement of offspring metabolic health. This includes experiments to define: a) optimal maternal exercise protocols to improve metabolic health; and b) pharmacologic activators that mimic the beneficial effects of maternal exercise on offspring health. Specific Aim 3 is to identify and determine the function of novel exercise regulated placental proteins that improve the metabolic health of offspring, as our initial findings established that placenta is central to transmitting the effects of maternal exercise to offspring. Aim 3 experiments include: a) investigation of novel placental secretory proteins increased by maternal exercise; b) fetal tissue destination of these proteins; and c) investigating maternal exercise effects on placenta spatial and single cell transcriptomics. We have recently made the exciting discovery that grandmaternal exercise improves the metabolic health of second generation (F2) offspring in adulthood. Specific Aim 4 will determine the mechanisms by which grandmaternal exercise training enhances F2 offspring health. This will include investigating: a) maternal exercise effects on F1 sperm and oocytes; b) mechanisms for improved glucose tolerance in F2 offspring, including studies of skeletal muscle glucose uptake; and c) effects of grandmaternal exercise on epigenetic regulation of skeletal muscle, liver, and adipose tissue in F2. This emerging area of exercise physiology research has great potential to advance world health by understanding mechanisms by which exercise during female reproductive years may limit the vicious cycles of increased metabolic risk across multiple generations.

项目摘要/摘要 该项目的总体假设是，母亲的定期体育锻炼对于预防至关重要 后代2型糖尿病和代谢疾病。我们的鼠标研究确定了之前的运动 在怀孕期间，对男性和女性后代的代谢健康产生了惊人的有益影响。 这些发现开辟了一个新的运动生理研究领域，表明运动是一种 对抗2型糖尿病发展的重要工具，并强调了科学的需求 旨在确定Mater运动改善代谢的分子机制的研究 后代的健康。为此目的，并基于我们广泛的发布和初步数据，我们有 定义了四个特定目标。特定的目标1将研究维生素D受体（VDR）和TGF2作为中心 孕产妇运动对后代代谢健康的介体对肝脏，骨骼肌和其他 后代组织。这包括将：a）确定VDR在母体运动中的功能的实验 - 诱导肝肌，骨骼肌和脂肪组织AMPK/TET信号传导，表观遗传变化和体内 葡萄糖稳态； b）研究TGF2作为激活表观遗传学的主要衍生运动信号 变化并改善后代表型； c）确定孕产妇运动是否具有广泛的影响 具体目标2将决定最佳练习和 改善后代代谢健康的药理治疗方法。这包括实验 定义：a）最佳孕产妇运动方案以改善代谢健康； b）药学激活剂 模仿孕产妇运动对后代健康的有益影响。特定目标3是识别和 确定新型运动调节的斑点蛋白的功能，以改善 后代，正如我们的初步发现确定plapeta是传播母体影响的核心 锻炼后代。 AIM 3实验包括：a）研究新型斑点秘密蛋白 通过孕产妇运动增加； b）这些蛋白质的胎儿组织目的地； c）调查母亲 运动对PLACETA空间和单细胞转录组学的影响。我们最近使这令人兴奋 发现宏伟的运动改善了第二代的代谢健康（F2）后代 成年。特定目标4将确定宏伟的运动训练的机制 F2后代健康。这将包括研究：a）孕产妇对F1精子和卵母细胞的影响； b） 提高F2后代葡萄糖耐量的机制，包括骨骼肌葡萄糖的研究 吸收c）宏伟运动对骨骼肌，肝脏和脂肪的表观遗传调节的影响 F2中的组织。这种新兴运动生理学研究具有巨大的潜力，可以提高世界卫生 通过理解在女性生殖年中锻炼的机制，可能会限制恶性周期 多代新陈代谢风险的增加。