Exercise Training Promotes Sex-Specific Adaptations in Mouse Inguinal White Adipose Tissue

Abstract

Recent studies demonstrate that adaptations to white adipose tissue (WAT) are important components of the beneficial effects of exercise training on metabolic health. Exercise training favorably alters the phenotype of subcutaneous inguinal WAT (iWAT) in male mice, including decreasing fat mass, improving mitochondrial function, inducing beiging, and stimulating the secretion of adipokines. In this study, we find that despite performing more voluntary wheel running compared with males, these adaptations do not occur in the iWAT of female mice. Consistent with sex-specific adaptations, we report that mRNA expression of androgen receptor coactivators is upregulated in iWAT from trained male mice and that testosterone treatment of primary adipocytes derived from the iWAT of male, but not female mice, phenocopies exercise-induced metabolic adaptations. Sex specificity also occurs in the secretome profile, as we identify cysteine-rich secretory protein 1 (Crisp1) as a novel adipokine that is only secreted from male iWAT in response to exercise. Crisp1 expression is upregulated by testosterone and functions to increase glucose and fatty acid uptake. Our finding that adaptations to iWAT with exercise training are dramatically greater in male mice has potential clinical implications for understanding the different metabolic response to exercise training in males and females and demonstrates the importance of investigating both sexes in studies of adipose tissue biology.

The confounding effects of sub-thermoneutral housing temperatures on aerobic exercise-induced adaptations in mouse subcutaneous white adipose tissue

“…Aerobic exercise training can induce favourable adaptations in iWAT [31,33,35,36,45,46], and these adaptations mediate improvements in whole-body glucose homeostasis following aerobic exercise training [35,47,48]. However, this notion is inconsistent with accumulating evidence from our group [11,36] and others [42] demonstrating that iWAT has a negligible role, if any, on whole-body metabolism.…”

“…We failed to observe an aerobic exercise training-induced increase in serum TGFβ2 concentrations in mice housed at thermoneutrality [11] and, interestingly, moderate-intensity aerobic exercise training in human participants also failed to increase serum concentrations of TGFβ2 [47], supporting our argument that sub-thermoneutral housing confounds the adaptive response to aerobic exercise training in rodent WAT. Similarly, the same group recently identified Crisp1 as a novel androgen-mediated sex-specific aerobic exercise-inducible adipokine that regulates browning and glucose metabolism in differentiated white adipocytes and 3T3-L1 adipocytes, respectively [48]. Again, this work was conducted at sub-thermoneutral temperatures and needs to be validated at thermoneutrality to establish its translational relevance.…”

“…Moreover, these adaptations in the lipectomized group were not explained by compensatory alterations in other tissues, effectively highlighting that aerobic exercise-induced adaptations in iWAT are dispensable for the whole-body metabolic benefits of aerobic exercise [36]. Despite this fact, recent work from Goodyear's group [47,48] perpetuates the idea that iWAT mediates the beneficial metabolic effects of aerobic exercise via the secretion of adipokines such as transforming growth factor-β2 (i.e. TGFβ2) and cysteine-rich secretory protein 1 (i.e.…”

“…Despite this fact, recent work from Goodyear's group [47,48] perpetuates the idea that iWAT mediates the beneficial metabolic effects of aerobic exercise via the secretion of adipokines such as transforming growth factor-β2 (i.e. TGF β 2) and cysteine-rich secretory protein 1 (i.e.…”

Distinct Effects of High-Fat and High-Phosphate Diet on Glucose Metabolism and the Response to Voluntary Exercise in Male Mice

“…Chronic exercise results in systemic adaptations including improved glucose tolerance and increased energy expenditure, as well as tissue-specific adaptations to skeletal muscle, heart, and adipose tissue, among others [ 16 , 17 , 18 ]. Exercise induces a wide variety of adaptations to WAT; it increases glucose metabolism and lipolysis, decreases adipocyte size, and increases its endocrine activity [ 18 , 19 , 20 , 21 , 22 , 23 ]. Exercise prevents many of the detrimental adaptations induced by HFD in WAT [ 5 , 7 , 24 , 25 , 26 , 27 , 28 , 29 ].…”