Estrogen receptor-α signaling maintains immunometabolic function in males and is obligatory for exercise-induced amelioration of nonalcoholic fatty liver

Abstract

The role of estrogen receptor-α (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 with females is related to reduced ERα expression. ERα protein expression in metabolically active tissues was lower in males than in females, and this lower expression was associated with worse glucose tolerance. Second, we determined whether ERα is required for optimal immunometabolic function in male mice consuming a 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. Last, 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 wk 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 in 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.

The role of estrogens in the adipose tissue milieu

“…126 This was true in both mice and pigs, suggesting that this sex difference is consistent across species. Indeed, we recently showed that male white adipose tissue expresses significantly lower levels of ERα protein than age-matched females in both the visceral and subcutaneous depots.…”

“…Indeed, we recently showed that male white adipose tissue expresses significantly lower levels of ERα protein than age-matched females in both the visceral and subcutaneous depots. 126 This was true in both mice and pigs, suggesting that this sex difference is consistent across species. Moreover, that sex difference also existed across other tissues, such as skeletal muscle and liver, in which females consistently had greater ERα expression.…”

Age, Sex, and Depot‐Specific Differences in Adipose‐Tissue Estrogen Receptors in Individuals with Obesity

“…OBESITY BIOLOGY AND INTEGRATED PHYSIOLOGY resistance, and inflammation, suggesting that ERα signaling positively influences insulin sensitivity and cardiometabolic health (9)(10)(11). The role of ERβ on AT and systemic metabolism is less clear, but research suggests antilipogenic and/or antiobesity effects (12).…”

Non-alcoholic Fatty Liver Disease as a Canonical Example of Metabolic Inflammatory-Based Liver Disease Showing a Sex-Specific Prevalence: Relevance of Estrogen Signaling

“…Recent studies suggest that hepatic ERα is required for the estrogen-mediated programming of the hepatic metabolism of males, contributing to hepatic sexual dimorphism ( 152 ) and accounting for the sex-specific metabolic response to diets enriched in lipids ( 91 ). In the liver of males, ERα is required also for optimal immune-metabolic function, as its lack causes increased expression of several inflammatory genes ( 327 ).…”