Ablation of microglial estrogen receptor alpha predisposes male mice to diet-induced obesity.

Estrogen receptor alpha (ERα) signaling has metabolic and anti-inflammatory properties in addition to its impact on reproductive function. Compared to females, male mice generally exhibit greater inflammatory activation of microglia and increased susceptibility to diet-induced obesity (DIO). Given the established metabolic protective effects of estrogen, these observations raise the possibility that sex differences in microglial estrogen signaling contribute to this sexual dimorphism. In this study, we assessed metabolic and CNS histopathological properties in a mouse model with inducible microglia-specific ablation of ERα (MG-ERαKO). Male MG-ERαKO mice developed increased weight gain and insulin resistance relative to controls during high-fat diet (HFD) feeding. Indirect calorimetry and food intake analysis revealed that reduced energy expenditure, coupled with an inadequate compensatory reduction in food intake, was the primary driver of the obese phenotype. In contrast, female MG-ERαKO mice fed HFD developed mild insulin resistance, with no change in body weight gain compared to controls, despite a similar reduction in energy expenditure. Immunohistochemical analyses of the microglial activation marker IBA1 in the mediobasal hypothalamus (MBH) revealed that female MG-ERαKO mice had an increased number of microglia without showing morphological signs of activation. In contrast, MBH microglial number was unchanged in MG-ERαKO male mice, but the cells adopted more activated morphological profiles. Finally, HFD-fed MG-ERαKO male mice had increased POMC neuron-microglia interactions but fewer overall hypothalamic POMC neurons, suggesting microglia may disrupt POMC neuron integrity to promote DIO. Together, these findings indicate that sex-specific actions of estrogen in microglia limit the metabolic complications of HFD feeding.