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Sex differences in adipose tissue distribution determine susceptibility to neuroinflammation in mice with dietary obesity

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posted on 2022-11-11, 18:17 authored by Alexis M. Stranahan, De-Huang Guo, Masaki Yamamoto, Caterina M. Hernandez, Hesam Khodadadi, Babak Baban, Wenbo Zhi, Yun Lei, Xinyun Lu, Kehong Ding, Carlos M. Isales

Preferential energy storage in subcutaneous adipose tissue (SAT) confers protection against obesity-induced pathophysiology in females. Females also exhibit distinct immunological responses, relative to males. These differences are often attributed to sex hormones, but reciprocal interactions between metabolism, immunity, and gonadal steroids remain poorly understood. Here, we systematically characterized adipose tissue hypertrophy, sex steroids, and inflammation in male and female mice after increasing durations of high-fat diet (HFD)-induced obesity. After observing that sex differences in adipose tissue distribution before HFD were correlated with lasting protection against inflammation in females, we hypothesized that a priori differences in the ratio of subcutaneous to visceral fat might mediate this relationship. To test this, male and female mice received SAT lipectomy (LPX) or sham surgery before HFD challenge, followed by analysis of glial reactivity, adipose tissue inflammation, and reproductive steroids. Because LPX eliminated female resistance to the pro-inflammatory effects of HFD without changing circulating sex hormones, we conclude that sexually dimorphic organization of subcutaneous and visceral fat determines susceptibility to inflammation in obesity. 

Funding

This research was supported by grants R01DK110586 and R01DK110586S1 to A.M.S., and by P01AG036675 to C.M.I. Circulating lipid assays were performed by the University of Cincinnati Medical Center Mouse Metabolic Phenotyping Core with support from U2CDK059630.

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