Novel Mechanisms for Exercise Training Effects on Glucose Homeostasis

描述（由申请人提供）：长期运动训练，包括持续一段时间的反复运动，对改善全身葡萄糖稳态和胰岛素敏感性具有无可争议的影响，这对糖尿病患者至关重要。虽然这些对训练的有益适应已被很好地描述，但潜在的细胞和分子机制尚未完全了解。尽管运动训练对骨骼肌适应性的影响已被广泛研究，但对其他组织在运动训练对葡萄糖稳态的调节中可能发挥的作用的研究却很少。为该应用产生的初步数据表明，将经过运动训练的小鼠皮下白色脂肪组织移植到久坐不动的受体中，显著提高了葡萄糖耐量，远高于未经训练的动物的脂肪组织移植。这种效果是短暂的，在移植后9天出现，4周后消失。此外，葡萄糖耐量的增加与骨骼肌葡萄糖摄取的增加有关。基于这些发现，本项目旨在测试一种新的假设，即运动训练导致皮下脂肪组织的适应，从而导致脂肪因子的分泌，脂肪因子反过来以旁分泌或内分泌的方式起作用，以改善全身和骨骼肌葡萄糖稳态。有两个具体目的：1)确定运动训练小鼠皮下脂肪组织是否具有旁分泌或内分泌作用，以增加全身代谢稳态，增加骨骼肌葡萄糖摄取，增加胰岛素信号；2)从运动训练小鼠皮下脂肪组织中鉴定具有改善全身和骨骼肌葡萄糖代谢功能的脂肪因子。该项目应确定新的脂肪细胞衍生因子，其功能是介导运动训练对全身和骨骼肌葡萄糖稳态的有益影响。这些研究有可能对肥胖和2型糖尿病的治疗产生重大影响。

DESCRIPTION (provided by applicant): Chronic exercise training, consisting of repeated bouts of exercise over a sustained period, has undisputed effects to improve whole-body glucose homeostasis and insulin sensitivity, adaptations critical for people with diabetes. While these beneficial adaptations to training are well described, the underlying cellular and molecular mechanisms are not fully understood. Although the effects of exercise training have largely been investigated in the context of adaptations to skeletal muscle, there has been little investigation into the role that other tissues may play in mediating the effects of exercise training on glucose homeostasis. Preliminary data generated for this application show that transplantation of subcutaneous white adipose tissue from exercise trained mice into sedentary recipients dramatically improves glucose tolerance, well above what occurs in adipose tissue transplanted from untrained animals. This effect is short-lived, present at 9 days post- transplantation and gone by 4 weeks. In addition, the increase in glucose tolerance is associated with an increase in skeletal muscle glucose uptake. Based on these findings, this project is designed to test the novel hypothesis that that exercise training causes adaptations to subcutaneous adipose tissue that result in secretion of adipokines that in turn function in a paracrine or endocrine manner to improve whole body and skeletal muscle glucose homeostasis. There are two specific aims: 1) To determine if subcutaneous adipose tissue from exercise trained mice has paracrine or endocrine effects to increase whole body metabolic homeostasis, increase skeletal muscle glucose uptake, and increase insulin signaling; and 2) To identify adipokines from subcutaneous adipose tissue of exercise trained mice that function to improve whole body and skeletal muscle glucose metabolism. This project should identify novel adipocyte-derived factors that function to mediate the beneficial effects of exercise training on whole body and skeletal muscle glucose homeostasis. These studies have the potential to significantly impact the treatment of obesity and type 2 diabetes. PUBLIC HEALTH RELEVANCE: Diabetes is a major public health problem and exercise has an undisputed role in the treatment and prevention of this disease. The goal of this research proposal is to discover how exercise training causes fundamental changes to adipose tissue that signal the body to improve glucose uptake in skeletal muscle and overall glucose homeostasis. This will lead to a better understanding of the beneficial effects of exercise in diabetes and could help to identify novel therapies for diabetes.