Novel Mechanisms for Exercise Training Effects on Glucose Homeostasis

项目摘要/摘要 有规律的体育锻炼对整体健康是必不可少的，包括改善全身的有益效果 代谢动态平衡和胰岛素敏感性：对糖尿病患者至关重要的适应。而当 运动训练的这些好处已经被很好地描述了，潜在的细胞和分子机制是 不是很清楚。运动刺激组织与组织之间的沟通，从而改善整体状况 代谢健康已成为科学研究的一个重要领域。锻炼是一项复杂的工作 调节众多分子、信号网络和组织的生理刺激，我们假设 所有这些适应都有助于调节体育锻炼对健康的有益影响。 该奖项支持的研究表明，运动诱导的皮下脂肪适应 组织(ScWAT)在这一过程中发挥着基础性作用。在该项目的下一阶段，我们建议使用 研究运动和脂肪组织生物学的三个关键领域的小鼠模型，所有这些都是基于 关于我们令人信服的初步或已发表的研究。具体目标1是基于我们的发现，即 运动训练短波紫外线对新陈代谢有益作用的机制涉及分泌和 多种运动诱导脂肪因子的生物学作用。我们发现转化生长因子-β-2就是这样的一个练习- 证明转化生长因子-β-2受乳酸调节，对组织有深远的影响。 和全身新陈代谢。特定目标1的一个目标是阐明细胞信号机制。 调节这个新的运动诱导的乳酸-转化生长因子-β-2轴。鉴于其潜在的临床意义 运动调节脂肪因子，目标1的另一个目标是阐明运动调节的完整scwat 秘密的。在特定的目标2中，我们将研究CRISP1，另一种新发现的运动调节 阿迪波金。重要的是，我们的初步数据显示，CRISP1是由一种不依赖乳酸的 机制，并对组织和系统代谢有有益的影响。此外，CRISP1似乎是 在雄性小鼠中，只有随着锻炼而增加，在目标2中，我们将研究潜在的 对scwat的性别适应机制。特定目标3将调查运动规则 “脂激素类”，传递脂类的信号，这是一类新的分子，被证明具有代谢作用。我们发现 12，13-diHOME是一种新的脂肪因子，可通过运动和运动训练而增加，从棕色释放 脂肪组织，提高骨骼肌脂肪酸新陈代谢的功能。具体目标3将研究 运动调节的12，13-二HOME的代谢后果。这个创新的项目应该会带来一个新的 从脂肪组织中提取的运动刺激循环因子的功能调节 运动对健康的有益影响。这些研究有可能定义新的生物制品来帮助 治疗肥胖、2型糖尿病和其他代谢性疾病。

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.