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

Abstract

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(<i>Crisp1</i>) as a novel adipokine that is only secreted from male iWAT in response to exercise. <i>Crisp1</i> 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.

Single-cell dissection of obesity-exercise axis in adipose-muscle tissues

“…Regular exercise is known to improve metabolic function in numerous tissues, and to delay, prevent, or alleviate the effects of T2D, obesity, and cardiovascular disease 5 . Recent studies show that exercise-induced adaptations to WAT and skeletal muscle contribute to the benefits of exercise on health, with subcutaneous and visceral adipose depots exhibiting distinct adaptations to exercise training [6][7][8][9][10] .…”

Sex-specific effects of voluntary wheel running on behavior and the gut microbiota-immune-brain axis in mice

“…Despite the total amounts of exercise being comparable among sexes, voluntary access to running wheels limited weight gains in males but not in females, suggesting that the metabolic response to exercise may have occurred differently in each sex. In line with this possibility, decreases in fat mass, improvements in mitochondrial function, and increases in adipokine secretion in white adipose tissue apparent in male mice with voluntary access to running wheels were absent in females (Nigro et al, 2021). We did not assess physiological metabolic parameters directly, but predictive microbiota functional outputs inferred from the PICRUSt2 analysis indicate that two pathways related to carbohydrate metabolism, the fructose and mannose metabolism and the amino sugar and nucleotide sugar metabolism, were enriched in males but not in females.…”

Exercise Training Remodels Inguinal White Adipose Tissue Through Adaptations in Innervation, Vascularization and the Extracellular Matrix

“…Exercise training can reverse many of the detrimental effects of obesity on metabolic health, and adaptations to WAT have been proposed to play a major role in these beneficial effects of exercise. While exercise training has been shown to alter processes such as adipocyte beiging and secretion of metabolically active adipokines (Nigro et al, 2021; Takahashi et al, 2019; Stanford et al, 2015), to our knowledge there had been no investigation of WAT ECM remodeling in response to exercise. This is an important question because recent data suggest the essential role of ECM remodeling in WAT homeostasis.…”

“…Pathological expansion of the extracellular matrix (ECM), excessive tissue fibrosis, inflammation and dysregulated lipid accumulation have been established as important factors in this dysregulation of WAT (Ruiz-Ojeda et al, 2019). In contrast to obesity, exercise training can improve systemic metabolic homeostasis, and recent data suggest that some of these beneficial effects of exercise are mediated through adaptations to the subcutaneous inguinal WAT (iWAT) (Yang et al, 2022; Nigro et al, 2021; Takahashi et al, 2019; Stanford et al, 2015; Trevellin et al, 2014; Lira et al, 2014; Gollisch et al, 2009;). The underlying molecular and cellular mechanisms mediating the effects of exercise training on iWAT are still poorly understood.…”