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

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posted on 10.02.2021, 01:18 by Pasquale Nigro, Roeland J. W. Middelbeek, Christiano R. R. Alves, Susana Rovira–Llopis, Krithika Ramachandran, Leslie A. Rowland, Andreas B. Møller, Hirokazu Takahashi, Ana B. Alves-Wagner, Maria Vamvini, Nathan S. Makarewicz, Brent G. Albertson, Michael F. Hirshman, Laurie J. Goodyear
Recent studies demonstrate that adaptations to white adipose tissue are important components of the beneficial effects of exercise training on metabolic health. Exercise training favorably alters the phenotype of subcutaneous inguinal white adipose tissue (iWAT) in male mice including decreasing fat mass, improving mitochondrial function, inducing beiging and stimulating the secretion of adipokines. Here, we find that despite performing more voluntary wheel running compared to 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 co-activators are 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.

Funding

This work was supported by NIH grant R01DK099511 and R01DK101043 (to L.J.G.), K23DK114550 (to R.J.W.M), 5T32DK00726042 and 1F32DK12643201 (to M.V.), ADA 1-17-PMF-009 (to A.B.A.W.)and the Joslin Diabetes Center DRC (P30 DK36836).

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