Grants and Contributions:

Grant or Award spanning more than one fiscal year. (2017-2018 to 2022-2023)

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.