Novel Mechanisms for Exercise Training Effects on Glucose Homeostasis

运动训练影响血糖稳态的新机制

• 批准号: 10540686
• 负责人: LAURIE J GOODYEAR
• 金额: $ 61.55万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-10 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10540686
• 关键词: Acute; Adipose tissue; Area; Attenuated; Award; Biological; Biological Products; Biology; Blood Glucose; Brown Fat; Communication; Complex; Cysteine; Data; Diabetes Mellitus; Economic Burden; Exercise; Fatty Acids; Female; Genes; Goals; Gonadal Steroid Hormones; Health; Health Promotion; Healthcare Systems; Homeostasis; Investigation; Lipids; Mediating; Metabolic; Metabolic Diseases; Metabolism; Molecular; Mus; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Obesity; PPAR alpha; Persons; Phase; Physical Exercise; Physical activity; Physiological; Play; Prevalence; Prevention; Process; Public Health; Publishing; Regulation; Research; Role; Running; SRD5A2 gene; Serum; Signal Transduction; Skeletal Muscle; Stimulus; Testosterone; Tissues; Training; Transforming Growth Factor Beta 2; Transplantation; United States; Work; adipokines; blood glucose regulation; blood lipid; clinically relevant; clinically significant; dehydroepiandrosterone; diabetes mellitus therapy; disorder prevention; elk-1 protein; exercise training; fatty acid metabolism; functional improvement; glucose disposal; glucose tolerance; improved; innovation; insulin sensitivity; male; metabolic abnormality assessment; mouse model; novel; novel therapeutics; obesity treatment; problems and exercises; receptor; response; secretory protein; sedentary; sex; skeletal muscle metabolism; subcutaneous; uptake

PROJECT SUMMARY/ABSTRACT Regular physical activity is essential for overall health, including beneficial effects to improve whole-body metabolic homeostasis and insulin sensitivity: adaptations that are critical for people with diabetes. While these benefits of exercise training are well described, the underlying cellular and molecular mechanisms are not well understood. The concept that exercise stimulates tissue-to-tissue communication to improve overall metabolic health has emerged as an important area of scientific investigation. Exercise is a complex physiological stimulus that regulates numerous molecules, signaling networks and tissues, and we hypothesize that all of these adaptations contribute to mediating the beneficial effects of physical exercise on health. Studies supported by this award have shown that exercise-induced adaptations to subcutaneous adipose tissue (scWAT) play a fundamental role in this process. In the next phase of this project we propose to use mouse models to investigate three critical areas of exercise and adipose tissue biology, all of which are based on our compelling preliminary or published studies. Specific Aim 1 is based on our findings suggesting that the mechanism for the beneficial role of exercise-trained scWAT on metabolism involves the secretion and biological actions of multiple exercise-induced adipokines. We discovered that TGF-β2 is one such exercise- specific adipokine, and demonstrated that TGF-β2 is regulated by lactate and has profound effects on tissue and systemic metabolism. One goal of Specific Aim 1 is to elucidate the cellular signaling mechanisms regulating this novel exercise-induced lactate-TGF-β2 axis. Given the potential clinical significance of exercise-regulated adipokines, another goal of Aim 1 is to elucidate the complete exercise-regulated scWAT secretome. In Specific Aim 2, we will investigate CRISP1, another newly identified exercise-regulated adipokine. Importantly, our preliminary data show that CRISP1 is regulated by a lactate-independent mechanism and has beneficial effects on tissue and systemic metabolism. In addition, CRISP1 appears to be sex-specific, only increasing with exercise in male mice, and in Aim 2 we will investigate underlying mechanisms for sex-specific adaptations to scWAT. Specific Aim 3 will investigate exercise regulation of “lipokines”, signaling lipids that are a new class of molecules shown to have metabolic effects. We discovered that 12,13-diHOME is a novel lipokine increased by both exercise and exercise training, released from brown adipose tissue, and functions to increase skeletal muscle fatty acid metabolism. Specific Aim 3 will study the metabolic consequences of exercise-regulated 12,13-diHOME. This innovative project should lead to a new paradigm in which exercise-stimulated circulating factors derived from adipose tissues function to regulate the beneficial effects of exercise on health. These studies have the potential to define novel biologics to aid in the treatment of obesity, type 2 diabetes, and other metabolic diseases.

项目摘要/摘要 定期体育锻炼对于整体健康至关重要，包括改善全身的有益效果 代谢稳态和胰岛素敏感性：对糖尿病患者至关重要的适应性。尽管 锻炼训练的这些好处是充分描述的，潜在的细胞和分子机制是 不太了解。运动刺激组织到组织的沟通以改善整体的概念 代谢健康已成为科学研究的重要领域。运动是一个复杂的 调节许多分子，信号网络和组织的物理刺激，我们假设 所有这些适应都有助于调解体育锻炼对健康的有益影响。 该奖项支持的研究表明，运动引起对皮下脂肪的适应 组织（SCWAT）在此过程中起着基本作用。在下一阶段，我们建议使用 小鼠模型研究运动和脂肪组织生物学的三个关键领域，所有这些领域均基于 关于我们引人入胜的初步或发表研究。具体目标1是基于我们的发现，表明 运动训练的SCWAT在代谢中有益作用的机制涉及分泌和 多种运动引起的脂肪因子的生物学作用。我们发现TGF-β2就是这样一种练习 特定的脂肪因子，并证明TGF-β2受缝隙调节，并对组织具有深远的影响 和系统性代谢。特定目标1的目标之一是阐明细胞信号传导机制 调节这种新型运动诱导的乳酸-TGF-β2轴。考虑到潜在的临床意义 运动调节的脂肪因子，目标1的另一个目标是阐明完整的运动调节的SCWAT 秘密。在特定的目标2中，我们将调查另一个新确定的运动调节的Crisp1 脂蛋白。重要的是，我们的初步数据表明，crisp1受鞋底无关的调节 机制，对组织和全身代谢具有有益作用。此外，crisp1似乎是 性别特异性，仅随着雄性小鼠的运动而增加，在AIM 2中，我们将调查基础 针对SCWAT的性别适应的机制。特定目标3将调查对 “ Lipopkines”，信号脂质，这些脂质是一种新的分子，这些分子显示出具有代谢作用。我们发现了 12,13-dihome是一种新颖的脂蛋白，通过锻炼和运动训练增加了，从布朗释放 脂肪组织和增加骨骼肌脂肪酸代谢的功能。特定目标3将研究 运动调节的代谢后果12,13-dihome。这个创新的项目应导致一个新的 范式刺激了从脂肪组织功能衍生出的循环因子来调节 运动对健康的有益影响。这些研究有可能定义新型生物制剂以帮助 肥胖，2型糖尿病和其他代谢疾病的治疗。