Project Summary
Excess adiposity – obesity – causes insulin resistance (IR) in white adipose tissue (WAT) and other tissues. The
role of poor WAT quality in IR, however, is less clear. Low adipocyte triglyceride (TG) turnover, high formation
rates of new adipocytes, high senescent cell burden, tissue and cellular inflammation and high circulating free
fatty acids (FFAs) all characterize poor WAT quality. Exercise enhances whole-body IR and decreases fasting
FFAs, independent of reductions in fat mass, thus highlighting the significance of exercise effects on WAT quality.
Evidence of the direct impact of exercise – independent of weight loss – on IR within WAT is limited and
inconclusive. The underlying mechanisms that drive exercise-induced changes in WAT biology, such as new
adipocyte formation and TG turnover rates, cell composition, senescence, and inflammation, are poorly
understood in humans. Ours will be the first study to comprehensively assess the direct effects of exercise on
WAT-specific IR and WAT quality in vivo and ex vivo in humans. We have conducted groundbreaking studies of
in vivo formation of new adipocytes and adipocyte TG turnover rates using a metabolic labeling protocol that
incorporates deuterium (2H), administered as 2H2O, into the DNA and triglycerides of adipose cells. We now have
compelling published and preliminary evidence that exercise reduces in vivo formation of new adipocytes in both
mice and humans, suggesting an important exercise-induced mechanism of WAT remodeling. We reason that
increased adipocyte TG turnover rates improve adipocyte-specific and overall WAT quality and thus abrogate
the need for increased formation of new adipocytes. Using our established method, we will employ innovative
single nuclei transcriptomics (snRNAseq) to discover the effects of exercise on senescence and inflammation
within adipocytes and non-adipocytes of WAT to further understand how exercise impacts WAT quality and WAT-
specific IR via in vivo microdialysis during insulin suppression. In this study, we will perform a randomized,
controlled clinical trial to evaluate the impact of 12 weeks of endurance exercise on abdominal subcutaneous
WAT adipocyte formation and TG turnover in vivo, cell composition and WAT-specific lipolytic rates under
physiological insulin suppression in men and pre-menopausal women with obesity. We hypothesize that
endurance exercise will increase adipocyte TG turnover rates thereby decreasing formation of new adipocytes,
the size of existing adipocytes and reducing inflammation and senescent cell burden in adipocytes and non-
adipocytes within WAT. These cell-specific changes will play a key role in exercise-induced improvements in
WAT-specific insulin-suppressed lipolytic rates in vivo and reduced fasting FFA levels. By performing
comprehensive metabolic and molecular phenotyping of WAT in humans in response to exercise, these pivotal
studies will expand our understanding of WAT remodeling and how changes in the cellular composition impact
the overall metabolic health of the adipose tissue in the context of obesity and help identify viable targets for
interventions to improve metabolic health.
