Effects of Exercise on Adipose Tissue Remodeling

Abstract

An excessive amount of fat in abdominal subcutaneous adipose tissue (aSAT) is a hallmark of obesity that often exhibits low capillary density, fibrotic extracellular matrix, immune cell infiltration, and dysregulated metabolic function. These abnormalities in aSAT are linked to excessive release of fat into the bloodstream, which can cause insulin resistance and systemic inflammation. Therefore, strategies to remodel aSAT structure and metabolic function for healthful fat storage hold high clinical interest. Regular exercise is recommended to treat obesity-induced health complications but the direct effects of exercise on aSAT are poorly understood. The aim of this dissertation were to assess the direct effects of exercise on aSAT morphology and factors regulating aSAT morphology, metabolic function, and inflammation. In Project 1, a total of 45 healthy adults who exercise regularly performed a single session of either low- (LOW), moderate- (MOD), or high- (HIGH) intensity exercise (n=15 in each group). aSAT samples were collected before and 1.5 hours after exercise. Transcriptomic analysis revealed a robust upregulation in the global “inflammatory response” pathway in all groups (adjusted p<1e-07), yet HIGH induced more extensive inflammatory responses than both LOW and MOD. Conversely, ribosomal and oxidative phosphorylation pathways were upregulated after MOD and LOW, but not HIGH. Of the few overlapping differentially expressed genes, we found the most robust changes in some core clock genes (adjusted p<0.0001). Findings from Project 1 suggest changes in the inflammatory, circadian clock, ribosomal, and oxidative phosphorylation gene sets shortly after acute exercise may be important contributors to exercise-induced aSAT adaptations. In Project 2, aSAT samples were collected from 36 adults with obesity before and after 12 weeks of moderate-intensity continuous training (MICT; 70%HRmax, 45 min; n=17) or high-intensity interval training (HIIT; 90%HRmax, 10×1min; n=19), maintaining their body weight throughout. MICT and HIIT induced similar modifications in aSAT structure (reduced adipocyte size, increased Col5a3, increased capillary density, all P≤0.05) and altered protein abundance of factors that regulate structural remodeling (reduced MMP9; increased ANGPTL2; both P≤0.02), lipid and oxidative metabolism (increased HSL, CD36, and COX4; P<0.03), and key proteins involved in the MAPK pathway when measured the day after the last exercise session. These findings from Project 2 indicate that exercise training may induce some early structural and metabolic adaptations in aSAT even without weight loss. In Project 3, aSAT was collected from 16 adults with overweight/obesity who exercise regularly for at least 2 years (EX) and 16 well-matched sedentary/non-exercisers (SED) who were tightly pair-matched for adiposity. Compared with SED, aSAT collected from EX had greater capillary density and a lower abundance of Col6a and macrophages (P<0.05). Global proteomics analysis revealed ribosomal, mitochondrial, and lipogenic proteins were upregulated, whereas complement and proteasomal proteins were downregulated in EX vs. SED (FDR<0.1). Phosphoproteomics indicated a greater abundance of phosphoproteins involved in protein translation, lipogenesis, and direct regulation of transcripts in EX vs. SED (P<0.01). Findings from Project 3 suggest that regular exercise in adults with overweight/obesity favorably remodels the aSAT structure and proteomic profile in ways that may lead to improved lipid storage capacity, which can contribute to preserved cardiometabolic health. Overall, the projects in this dissertation demonstrate regular exercise may induce robust structural and functional adaptations in aSAT that may contribute to improved/sustained cardiometabolic health. My dissertation projects also shed light on potential molecular mechanisms that may mediate the exercise effects on aSAT.