Exercise Regulation of Glucose Homeostasis

项目总结/摘要 该项目的总体假设是，母亲定期进行体育锻炼对预防 2型糖尿病和后代代谢疾病。我们的小鼠研究表明， 在怀孕期间对雄性和雌性后代的代谢健康都有显著的有益影响。 这些发现开辟了运动生理学研究的新领域，表明运动是一种 这是治疗2型糖尿病的重要工具，并强调了科学治疗的必要性。 一项旨在确定母体运动改善代谢的分子机制的研究 后代的健康。为此，根据我们广泛发表的初步数据，我们 明确了四个具体目标。具体目标1将研究维生素D受体（VDR）和TGF β 2作为中枢神经系统的作用。 母体运动对后代肝脏、骨骼肌和其他代谢健康影响的介质 后代组织这包括以下实验：a）确定VDR在母亲运动中的功能- 诱导肝脏、骨骼肌和脂肪组织AMPK/泰特信号传导、表观遗传变化和体内 葡萄糖稳态; B）研究TGF β 2作为激活表观遗传的母体来源的运动信号 改变和改善后代表型;以及c）确定母亲锻炼是否具有广泛的影响， 改善骨骼肌和脂肪组织的功能。具体目标2将确定最佳的锻炼， 用于改善后代代谢健康的药物治疗。这包括实验， 定义：a）改善代谢健康的最佳产妇运动方案;和B）药理学激活剂 模拟母亲锻炼对后代健康的有益影响。具体目标3是确定和 确定新的运动调节胎盘蛋白的功能，改善代谢健康， 后代，因为我们的初步研究结果表明，胎盘是传递母体影响的核心 锻炼后代。目的3：a）研究新的胎盘分泌蛋白 通过母亲运动增加; B）这些蛋白质的胎儿组织目的地;和c）研究母亲运动对胎儿组织的影响。 运动对胎盘空间和单细胞转录组学的影响。我们最近做出了令人兴奋的 发现祖母运动改善了第二代（F2）后代的代谢健康， 成年具体目标4将确定祖母运动训练增强的机制。 F2后代健康。这将包括调查：a）母体运动对F1精子和卵母细胞的影响; B） 改善F2后代葡萄糖耐量的机制，包括骨骼肌葡萄糖研究 外祖母运动对骨骼肌、肝脏和脂肪的表观遗传调节的影响 F2中的组织。这一新兴的运动生理学研究领域具有促进世界健康的巨大潜力 通过了解女性生殖期锻炼的机制可以限制恶性循环， 代谢风险的增加。

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.