The Role of Adipose Tissue and IL-6 in Liver Metabolism Following Exercise

越来越多的人认识到，定期进行锻炼可以调节体内许多不同组织的功能，包括脂肪组织和肝脏。我的研究计划的一个主要长期目标是了解这是如何发生的。循环白细胞介素6（IL-6）水平在运动过程中增加，这种细胞因子被认为是运动全身效应的重要介质。虽然骨骼肌传统上被认为是运动诱导的IL-6增加的主要来源，但最近的研究结果对这一假设提出了挑战，表明肌外组织的参与。包括我们自己在内的几个实验室的工作提供了证据，表明皮下脂肪组织可能是运动诱导的IL-6升高的来源。虽然运动诱导的循环IL-6增加已被很好地记录，但其所起的具体作用尚未明确定义。在我们小组的初步工作中，我们已经表明，IL-6信号传导的标志物在高脂肪饮食小鼠的肝脏运动后显着增加，这与肝脏胰岛素信号传导的恢复有关。这些发现强调了运动在挽救肝脏胰岛素作用方面的强大作用，并指出IL-6可能参与介导这种作用。在喂食高脂肪饮食的小鼠中，运动后肝脏IL-6信号传导的急剧增加是非常有趣的，因为肝脏IL-6抗性在慢性营养过剩的条件下发展。总之，这些发现表明，运动诱导因子增加了肝脏对IL-6作用的敏感性。一个潜在的候选者可能是胰高血糖素。这种激素在运动过程中向肝脏发出信号，并激活降低一种称为SHP 2的蛋白质的含量和活性的途径，SHP 2是一种与肝脏IL-6抗性的发展有关的磷酸酶。考虑到这些发现，拟议的研究计划的短期目标是检查皮下脂肪组织-IL-6-肝脏代谢回路在调节肝脏胰岛素作用中的参与。使用免疫中和、组织特异性敲除和脂肪切除术（脂肪组织去除），将测试以下假设：1）IL-6介导运动对改善肝脏胰岛素作用的影响，2）胰高血糖素增强肝脏IL-6响应性，和3）皮下脂肪组织是运动诱导的循环IL-6增加的来源。拟议的研究计划将为HQP提供多方面和独特的培训经验，并接触到广泛的实验技术。从拟议的工作中产生的数据将增加我们对脂肪组织和肝脏生物学以及这些组织之间发生的通信的基本理解。

There is a growing appreciation that regularly performed exercise modulates the functioning of many different tissues in the body including adipose tissue and liver. A primary long-term goal of my research program is to understand how this occurs. Circulating Interleukin 6 (IL-6) levels increase during exercise and this cytokine has been implicated as an important mediator of the systemic effects of exercise. While skeletal muscle has traditionally been viewed as the primary source of exercise-induced increases in IL-6, recent findings have challenged this assumption suggesting the involvement of extra-muscular tissues. Work from several laboratories, including our own, have provided evidence that subcutaneous adipose tissue could be a source of the exercise-induced rise in IL-6. Although exercise-induced increases in circulating IL-6 have been well documented the specific role that this plays has not been clearly defined. In preliminary work from our group we have shown that markers of IL-6 signaling are dramatically increased following exercise in livers from mice that had been fed a high fat diet and this was associated with a restoration of liver insulin signaling. These findings highlight a powerful role of exercise in rescuing liver insulin action and point towards a potential involvement of IL-6 in mediating this effect. The dramatic increase in liver IL-6 signaling following exercise in mice fed a high fat diet is very interesting as liver IL-6 resistance develops in conditions of chronic nutrient excess. Together these findings suggest that an exercise-inducible factor increases the sensitivity of liver to the actions of IL-6. One potential candidate could be glucagon. This hormone signals to the liver during exercise and activates pathways that reduce the content and activity of a protein called SHP2, a phosphatase that has been linked to the development of liver IL-6 resistance. With these findings in mind the short-term goal of the proposed research program is to examine the involvement of a subcutaneous adipose tissue-IL-6-liver metabolic circuit in regulating hepatic insulin action. Using immunological neutralization, tissue specific knockouts and lipectomy surgeries (adipose tissue removal) the following hypotheses will be tested: 1) IL-6 mediates the effects of exercise on improving liver insulin action, 2) glucagon enhances liver IL-6 responsiveness and 3) subcutaneous adipose tissue is a source of exercise-induced increases in circulating IL-6. The proposed research program will provide HQP with a multifaceted and unique training experience with exposure to a wide range of experimental techniques. The data generated from the proposed work will increase our basic, fundamental understanding of adipose tissue and liver biology and the communication that occurs between these tissues.