Female adipose tissue has improved adaptability and metabolic health compared to males in aged obesity

Abstract

Aging, like obesity, is associated with metabolic and inflammatory alterations within adipose tissue in older individuals. Younger females are protected from adipose inflammation, but older post-menopausal females exhibit exaggerated visceral adiposity correlated with increased disease risk. Obesity accelerates the onset and progression of age-associated diseases, but it is unclear if aging and obesity drive adipose tissue dysfunction in a sexually dimorphic fashion. We investigated adipose tissue metabolism and inflammation in a diet-induced obesity model in young and old mice. We identified age related sex differences in adipose tissue macrophages (ATMs), fibrosis and lipid metabolism in male and female visceral fat depot (GWAT). Although aging normalized body weights between the sexes, females remained protected from proinflammatory ATMs and stimulated lipolysis failed to adversely affect the inflammatory state even with obesity. Older obese males had augmented CD11c + ATMs and higher insulin levels, while females showed increased visceral adiposity and exaggerated Pparγ, and Pgc1α expression. Obesity in aging demonstrated similar expression of GWAT p53, p16, p21, Timp1 and Tgfβ1 in both sexes. Our studies suggest that even with aging, female GWAT shows an attenuated inflammatory response compared to males due to an efficient oxidative metabolism combined with an active tissue remodeling state.

Aging Leukocytes and the Inflammatory Microenvironment of the Adipose Tissue

“…Transcriptomics reveal a spectrum of macrophage phenotypes present in the young and old male visceral AT, with IL-4-responsive macrophages predominant in the young and high-density lipoprotein-responsive macrophages in the old tissue (16). Overall, this research points toward a decrease in macrophages of the M2 phenotype and an increase in the inflammatory phenotype that occurs in both sexes, although to a lesser extent in female mice (8,16).…”

“…The production of sex hormones declines with advancing age and is associated with a greater risk for obesity and type 2 diabetes in females (5). Although aged female mice show increased AT mass and impaired glucose uptake when placed on a high-fat diet, the visceral AT maintains its lipolysisinduced metabolic flexibility and still shows an attenuated inflammatory response compared with aged male mice (8). Some recent research focuses on sex-specific differences in aged AT immune cells (highlighted in specific sections of this Perspective).…”

“…M2 macrophages are predominant in the young, lean environment and can be further divided into the subsets M2a, M2b, and M2c, which are polarized by IL-4/IL-13 (M2a), immune complexes (M2b), and IL-10 or glucocorticoids (M2c), respectively (30). Aged AT macrophages are of the proinflammatory phenotype, but reports differ on whether they express CD11c and other common markers to differentiate between the subsets (8,16,17). Transcriptomics reveal a spectrum of macrophage phenotypes present in the young and old male visceral AT, with IL-4-responsive macrophages predominant in the young and high-density lipoprotein-responsive macrophages in the old tissue (16).…”

Regulation of p27 and Cdk2 Expression in Different Adipose Tissue Depots in Aging and Obesity

“…However, a significant increase of both was observed in the gWAT of aged mice, suggesting a depot-specific role/regulation of these cell cycle regulators during the aging process. The expression of p21 was found to be increased in the gWAT of old female mice [ 49 ] and to be involved on later stages of differentiation and on adipocyte hypertrophy [ 50 ].…”

“…It has been shown that male and female mice have different susceptibility to develop obesity [ 83 ]. Furthermore, a recent study has shown differences in adipose tissue adaptability and metabolic health between aged obese female and male mice [ 49 ]. It was also reported that long term HFD-fed female mice presented larger gWAT and scWAT depots compared to male mice [ 84 ], which could be influenced by the function of the cell cycle regulators [ 51 ].…”