1541-P: The Role of Microglia Estrogen Receptor Alpha Signaling in Obesity Pathogenesis

The sex steroid estrogen reduces susceptibility to obesity and its metabolic complications by suppressing food intake, enhancing energy expenditure, improving insulin sensitivity, and reducing immune cell activation. However, the mechanisms involved remain incompletely understood. In rodents, high-fat diet (HFD) feeding is associated with increased inflammatory activation of microglia (brain myeloid cells) in the mediobasal hypothalamus (MBH), which promotes diet-induced obesity (DIO). Importantly, surgical or chemical castration exacerbates HFD-induced microglial activation, an effect reversed by estrogen replacement therapy. Therefore, we hypothesize that estrogen reduces DIO susceptibility through a cell-autonomous anti-inflammatory action on microglia via the nuclear receptor estrogen receptor alpha (ERα). To test this hypothesis, we generated a mouse model with microglia-specific deletion of ERα (MG-ERαKO). We found that MG-ERαKO male mice exposed to HFD for 15 weeks have increased weight gain and fat mass relative to control mice, attributable to a significant reduction in energy expenditure. In contrast, HFD feeding of MG-ERαKO female mice did not elicit a body weight difference with controls. Nevertheless, a small but significant reduction in insulin sensitivity was observed in both sexes of MG-ERαKO mice. Immunohistochemical analyses of MBH brain sections from MG-ERαKO mice demonstrated higher immunoreactivity for the microglial marker IBA1 along with an increase in microglial number and cell size, all indicators of a more activated cellular profile. These findings strongly support a sex-specific action of estrogen to limit the metabolic complications of HFD feeding through microglial ERα signaling.