Effects of Exercise on Factors Regulating Adipose Tissue Expandability

Abstract

Obesity is tightly linked with the development of insulin resistance and associated metabolic diseases, including type 2 diabetes. Many of the health complications in obesity can be attributed to abnormalities associated with the excessive storage of fat within subcutaneous adipose tissue (SAT), such as hypertrophic adipocytes, tissue hypoxia, fibrosis, and inflammation. Therefore, given the continued alarming increase in the prevalence of obesity, identifying strategies to modify SAT structure and metabolic function in ways to more “healthfully” store body fat has very high clinical impact. Exercise is a powerful tool to reduce cardio-metabolic disease risk, but the effects of exercise on SAT are poorly understood. The overall purpose of this dissertation was to assess the effects of exercise on factors regulating SAT structural remodeling, metabolic function, and inflammation. In Project 1, RNA sequencing was performed on abdominal SAT samples collected from obese adults before and 1 hour after a session of exercise at either high-intensity (10x1min ~90% HRpeak; n=14) or moderate-intensity (45min ~70% HRpeak; n=15). Interestingly, gene set responses were not different between the high- and moderate-intensity exercise protocols, and gene sets involved in inflammation were up-regulated after exercise (IL6-JAK-STAT3 signaling, allograft rejection, TNFA signaling via NFKB, and inflammatory response; FDR q-value < 0.25), while gene sets related to adipogenesis and oxidative metabolism were down-regulated. These findings from Project 1 indicate that rapid responses to acute exercise at both moderate- and high-intensity feature coordinated changes in inflammatory signaling genes. In Project 2, we collected abdominal SAT from a separate cohort of obese adults (BMI 33±3kg/m2, body fat 41±7%) the morning after a 1-hour session of moderate/vigorous intensity endurance-type exercise (80±3% HRpeak) versus sedentary control to establish whether these signals alter stromal vascular cell (SVC) proportions 12 hours after exercise. Exercise decreased preadipocyte number (38±7% vs. 30±13% SVC; P=0.04), which was driven exclusively by a reduction in CD34hi preadipocytes (18±5% vs. 13±6% SVC; P=0.002), a subset of preadipocytes that yield highly lipolytic fat cells. There was no change in the proportion of immune cells in SAT. Not only do these findings demonstrate exercise can rapidly remodel the adipocyte progenitor pool, but these changes may also contribute to an important health benefit by modifying SAT metabolism. Finally, Project 3 was designed to examine the effects overeating on factors regulating adipose tissue remodeling in regular endurance exercisers (EX, n=11) compared with a cohort of non-exercisers (nonEX, n=11) who were matched for BMI (25±3kg/m2). After 1 week of a standardized overeating protocol (30% energy surplus/day) all subjects gained ~1 kg (P< 0.01), and insulin sensitivity (Matsuda ISI) declined by ~15% in both groups (P=0.04). Gene expression of factors involved in lipid metabolism (HSL, ATGL, DGAT, PPARγ) and angiogenesis (HIF1A, KDR) were increased (P< 0.05). Interestingly, there was no difference in SAT responses between EX and nonEX. Findings from Project 3 indicate that overeating can rapidly impair insulin sensitivity, and modify gene expression for factors regulating angiogenesis and metabolism in SAT, but regular endurance-type exercise does not appear to alter these early adaptive responses to overeating. Overall, the projects in this dissertation demonstrate exercise can rapidly trigger signals involved in SAT remodeling, metabolic function, and inflammatory signaling. These outcomes have important health implications by revealing new metabolic pathways that could impact SAT structure and function and help reduce obesity-related insulin resistance, and/or other obesity-related health complications.