Mechanisms of exercise effects in obese humans: sex-specific regulation of novel adipose tissue function

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Project Summary/Abstract Obesity is a major health crisis and there is a great need to develop new treatments for this disease. Regular physical activity is crucial for the prevention and treatment of obesity and type 2 diabetes, but the mechanisms that underlie these effects are not well understood. While exercise training has been extensively studied for its effect on improving glucose homeostasis and skeletal muscle metabolism, the effects of exercise training on adipose tissue function are only poorly understood. This is especially the case for obese men and women. Recently, we have provided evidence using rodent models that exercise training can cause adaptations to adipose tissue that mediate some of the beneficial effects on exercise on glucose homeostasis. Some of these benefits may be mediated by novel adipose-derived factors called adipokines. Another putative mediator of the effects of exercise on adipose tissue metabolism may be the induction of beiging. Beige adipocytes have increased fuel oxidation and thermogenesis, making beiging a potential therapy for obesity. Our research, along with others, has clearly shown that exercise training causes scWAT beiging in male rodents, but our more recent data show that obesity may negate exercise-induced beiging. In addition, we find that exercise training only increases beiging in male, but not female mice. There have only been limited, or no studies of beiging and novel exercise-induced adipokines in humans. Thus, the research focus of this career development award is to determine whether exercise training regulates novel adipokine physiology, circulating factors, and beiging in obese women and men. The Specific Aims are: 1) To elucidate the effects of obesity on exercise training- induced regulation of scWAT beiging in human subjects, and to determine if training-induced adaptations to scWAT are sex-specific; 2) To determine the underlying mechanisms of sex-specific regulation of exercise training-induced adaptations to scWAT; and 3) To characterize and discover novel exercise-regulated adipokines, and to identify circulating factors as biomarkers of exercise-induced metabolic changes in lean and obese men and women. The Principal Investigator on this Career Development Award has a strong background in exercise physiology and human translational research, but will benefit from additional career development to transform into a successful, independent investigator. The mentoring committee consists of a strong multi-disciplinary team of nationally recognized leaders in exercise physiology, adipose tissue biology and physician-scientists with expertise in human translational physiology. The proposed career development plan outlines detailed coursework and utilizes the stimulating, resource-rich environments available through the Joslin Diabetes Center and Harvard University to ensure a successful transition toward independence. By conducting these studies, working closely with the mentoring committee, and completing the educational objectives, the Principal Investigator will acquire the expertise to embark upon a career as an independent translational investigator elucidating the mechanisms underlying the benefits of exercise on health.