Novel Mechanisms for Exercise Training Effects on Glucose Homeostasis

项目总结/摘要 定期的身体活动对整体健康至关重要，包括改善全身的有益效果 代谢稳态和胰岛素敏感性：适应性对糖尿病患者至关重要。而 运动训练的这些益处已经被很好地描述了，基本的细胞和分子机制也被 没有很好地理解。运动可以刺激组织间的交流， 代谢健康已经成为科学研究的一个重要领域。运动是一种复杂的 生理刺激调节许多分子，信号网络和组织，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性 组织（scWAT）在这一过程中发挥着重要作用。在本项目的下一阶段，我们建议使用 小鼠模型来研究运动和脂肪组织生物学的三个关键领域，所有这些都是基于 我们引人注目的初步或已发表的研究。具体目标1是基于我们的研究结果表明， 运动训练的scWAT对代谢的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TGF-β2就是这样一种运动- 特异性脂肪因子，并证明TGF-β2受乳酸调节，对组织有深远的影响 和全身代谢。具体目标1的一个目标是阐明细胞信号传导机制 调节这种新的运动诱导的乳酸-TGF-β2轴。考虑到潜在的临床意义， 运动调节的脂肪因子，目的1的另一个目标是阐明完整的运动调节的scWAT 分泌蛋白在具体目标2中，我们将研究CRISP 1，另一种新发现的运动调节蛋白， 脂肪因子重要的是，我们的初步数据表明，CRISP 1是由一种不依赖乳酸盐的 机制，并对组织和全身代谢具有有益作用。此外，CRISP 1似乎是 性别特异性，仅在雄性小鼠中随着运动而增加，在目标2中，我们将研究潜在的 对scWAT的性别特异性适应机制。具体目标3将研究运动调节 “脂因子”，信号脂质是一类新的分子，显示具有代谢作用。我们发现 12，13-diHOME是布朗释放的一种新型脂因子，可通过运动和运动训练增加 脂肪组织，并具有增加骨骼肌脂肪酸代谢的功能。具体目标3将研究 运动调节的12，13-diHOME的代谢后果。这一创新项目将带来一个新的 一个范例，其中来自脂肪组织的运动刺激的循环因子起调节 运动对健康的有益影响。这些研究有可能定义新的生物制剂，以帮助 治疗肥胖症、2型糖尿病和其他代谢疾病。

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.