Estrogen Receptor Beta Activation Coordinates Liver Lipid Remodeling and Metabolic Fluxes, Preventing Lipotoxicity

Nonselective hormone replacement with estradiol is known to improve metabolic homeostasis during menopause. However, this treatment is not recommended for individuals with genetic predisposition to hormone‐responsive cancers. In contrast, selective activation of estrogen receptor beta (ERβ) has shown promising results, promoting antitumor effects and modulating metabolic outcomes, although the mechanisms in which these changes occur remain poorly understood. We investigated the effects of ERβ activation using diarylpropionitrile (DPN), a selective ERβ agonist, in both an in vivo model of postmenopause and an in vitro model of metabolic overload. Female Wistar rats were submitted to ovariectomy (OVX) and later treated with DPN. ERβ agonist treatment recovered fasting glucose and lipid profiles, improved pancreatic islet morphology, and reduced retroperitoneal white adipose tissue. Serum ketone bodies and free fatty acid levels were also recovered to control levels, suggesting modulation in liver lipid oxidation. DPN treatment also promoted substantial lipidome remodeling specifically in OVX animals, generating a lipid‐buffering profile. To isolate the effects mechanistically, hepatocytes were submitted to nutrient overload and treated with DPN. In vitro, DPN also recovered ketone body secretion and promoted an increased dependence on complete fatty acid oxidation, as well as decreased metabolic flexibility, as assessed by modulated extracellular flux analysis. Overall, these findings demonstrate a new role of ERβ in the modulation of hepatic lipid and ketone metabolism, with positive metabolic outcomes in estradiol‐deficient animals.