Selective Liver Estrogen Receptor α Modulation Prevents Steatosis, Diabetes, and Obesity Through the Anorectic Growth Differentiation Factor 15 Hepatokine in Mice

Abstract

Hepatocyte estrogen receptor α (ERα) was recently recognized as a relevant molecular target for nonalcoholic fatty liver disease (NAFLD) prevention. The present study defined to what extent hepatocyte ERα could be involved in preserving metabolic homeostasis in response to a full (17β‐estradiol [E2]) or selective (selective estrogen receptor modulator [SERM]) activation. Ovariectomized mice harboring a hepatocyte‐specific ERα deletion ( LERKO mice) and their wild‐type (WT) littermates were fed a high‐fat diet (HFD) and concomitantly treated with E2, tamoxifen (TAM; the most used SERM), or vehicle. As expected, both E2 and TAM prevented all HFD‐induced metabolic disorders in WT mice, and their protective effects against steatosis were abolished in LERKO mice. However, while E2 still prevented obesity and glucose intolerance in LERKO mice, hepatocyte ERα deletion also abrogated TAM‐mediated control of food intake as well as its beneficial actions on adiposity, insulin sensitivity, and glucose homeostasis, suggesting a whole‐body protective role for liver‐derived circulating factors. Moreover, unlike E2, TAM induced a rise in plasma concentration of the anorectic hepatokine growth differentiation factor 15 (Gdf15) through a transcriptional mechanism dependent on hepatocyte ERα activation. Accordingly, ERα was associated with specific binding sites in the Gdf15 regulatory region in hepatocytes from TAM‐treated mice but not under E2 treatment due to specific epigenetic modifications. Finally, all the protective effects of TAM were abolished in HFD‐fed GDF15‐ knockout mice. Conclusion: We identified the selective modulation of hepatocyte ERα as a pharmacologic strategy to induce sufficient anorectic hepatokine Gdf15 to prevent experimental obesity, type 2 diabetes, and NAFLD.

Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α

“…We found dramatic improvements in phosphorylated AKT (pS473) and FOXO1 (pS256) in male WT mice treated with 17α-E2 ( Figure 5D-E), whereas these benefits were not observed in male ERα KO mice. Our findings are aligned with previous reports demonstrating that hepatic ERα plays a critical role in regulating insulin sensitivity in the liver of male mice [39][40][41]77].…”

“…Furthermore, hepatocyte-specific deletion of ERα was sufficient to abrogate similar estrogen-mediated metabolic benefits [40][41][42]. Given that several reports have linked the administration of 17α-E2 to improvements in metabolic homeostasis, we hypothesized that 17α-E2 signals through ERα to modulate hepatic function and systemic metabolism, thereby potentially contributing to the lifespan-extending effects of 17α-E2.…”

Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α

“…As alluded to previously, evidence in the literature indicates the binding affinity of 17β-E2 for ERs is dramatically greater than 17α-E2, which has been confirmed with competitive binding assays [32][33][34][35]. In males, very few studies have evaluated the role of ERα in metabolism, although a few recent reports have suggested that ERα plays tissue-specific roles, particularly in the liver, by regulating male metabolic homeostasis [38][39][40][41]55]. These studies, coupled with our current findings, led us to speculate that 17α-E2 may be signaling through ERα in the liver to reverse metabolic disease and potentially extend healthspan and/or lifespan in males.…”

“…Other studies have also determined that hepatic steatosis and insulin sensitivity, and therefore the control of gluconeogenesis, are regulated through FOXO1 in an ERα-dependent manner in male mice [39]. Furthermore, liver-specific deletion of ERα was sufficient to abrogate similar estrogen-mediated metabolic benefits [40,41]. Given that several reports have linked the administration of 17α-E2 to improvements in metabolic homeostasis, we hypothesized that 17α-E2 signals through ERα to modulate hepatic function and systemic metabolism, thereby contributing to the lifespan-extending effects of 17α-E2.…”

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

“…The action of the hepatic ERα is particularly relevant when mice are subjected to excess of dietary lipids: with the lack of hepatic ERα, LERKO females result no more protected against the excess of dietary lipids and accumulate lipids in the liver (91), a condition resembling what happens in OVX mice and postmenopausal women (14). However, differently from control OVX females, estrogen treatment fails to prevent lipid deposition in the liver of LERKO females, further stressing the specific relevance of hepatic ERα in the regulation of female hepatic metabolism (287,320).…”