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Estrogen receptor alpha signaling maintains immunometabolic function in males and is obligatory for exercise-induced amelioration of nonalcoholic fatty liver.
American Journal of Physiology. Endocrinology and Metabolism 2018 December 5
The role of estrogen receptor alpha (ERα) signaling in immunometabolic function is established in females. However, its necessity in males, while appreciated, requires further study. Accordingly, we first determined whether lower metabolic function in male mice compared to females is related to reduced ERα expression. ERα protein expression in metabolically active tissues was lower in males than females and this lower expression was associated with worse glucose tolerance. Second, we determined if ERα is required for optimal immunometabolic function in male mice consuming chow diet. Despite lower expression of ERα in males, its genetic ablation (KO) caused an insulin resistant phenotype characterized by enhanced adiposity, glucose intolerance, hepatic steatosis, and metaflammation in adipose tissue and liver. Lastly, we determined whether ERα is essential for exercise-induced metabolic adaptations. Twelve-week-old wild type (WT) and ERα KO mice either remained sedentary (SED) or were given access to running wheels (WR) for 10 weeks, while fed an obesogenic diet. Body weight and fat mass were lower in WR mice regardless of genotype. Daily exercise obliterated immune cell infiltration and inflammatory gene transcripts in adipose tissue in both genotypes. In the liver, however, wheel running suppressed hepatic steatosis and inflammatory gene transcripts in WT but not KO mice. In conclusion, the present findings indicate that ERα is required for optimal immunometabolic function in male mice despite their reduced ERα protein expression in metabolically active tissues. Furthermore, for the first time we show that ERα signaling appears to be obligatory for exercise-induced prevention of hepatic steatosis.
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