OR01-04 Microglial NF-κB pathway protects reproductive capacity during high-fat diet feeding in female mice.

Abstract Disclosure: I. Velasco: None. V. Baglaev: None. T. Huang: None. T.Z. Jafari: None. S. Schwie: None. J.M. Frey: None. R. Enos: None. M. Tena-Sempere: None. J. Thaler: None. M.D. Dorfman: None. Obesity is linked to reproductive dysfunction. Rodents fed a high-fat diet (HFD) develop hypogonadism and reduced ovulatory capacity via alterations in the KNDy (Kisspeptin, Neurokinin B, Dynorphin) -GnRH neurocircuit in the hypothalamus, which regulates gonadal function through the hypothalamic-pituitary-gonadal (HPG) axis. Microglia, the resident immune cells of the brain, become activated in the hypothalamus during HFD feeding, promoting inflammation and altering neuronal function. Therefore, we hypothesized that microglial inflammation induced by HFD feeding promotes reproductive dysfunction. Female mice with microglia-specific ablation of IKKβ (IKKβ-MGKO), a critical regulator of the proinflammatory NF-κB pathway, were fed a HFD for 15 weeks followed by an assessment of reproductive parameters including estrous cyclicity, ovarian morphology, sex hormone levels, and hypothalamic regulators. Contrary to our hypothesis, IKKβ-MGKO female mice exhibited reduced estrous cyclicity, fewer corpora lutea and lower estradiol levels than WT controls. To determine whether a central defect accounts for this unexpected exacerbation of HFD-induced hypogonadism in IKKβ-MGKO animals, we examined hypothalamic-pituitary regulators of reproductive function (Kisspeptin, Neurokinin B, GnRH, LH). While IKKβ-MGKO mice had fewer preoptic area (POA) GnRH neurons and lower circulating LH levels compared to controls, Neurokinin B expression was increased, suggesting an impairment at the level of the hypothalamus in communication between KNDy and GnRH neurons. Interestingly, colocalization studies using GnRH and Iba1 (microglial marker) immunohistochemistry revealed less cell-cell contact between GnRH neurons and microglia in the POA of IKKβ-MGKO mice compared with controls. These findings suggest that microglial inflammatory responses mediated by NF-κB signaling during HFD feeding play a positive, adaptative role to limit the reduction in ovulatory capacity and HPG axis function due to obesity, possibly by maintaining KNDy-GnRH neuronal communication through microglia-GnRH cell interactions. Presentation: Saturday, July 12, 2025