Hypothalamic Inflammation as a Critical Link Between Metabolic Dysfunction and Impaired Endometrial Receptivity in...

Obese polycystic ovary syndrome (PCOS) involves insulin resistance (IR) and impaired endometrial receptivity, potentially driven by hypothalamic inflammation. We investigated if inhibiting the hypothalamic Toll-like receptor 4 (TLR4)/IkappaB kinase beta (IKKbeta) pathway could ameliorate IR and improve endometrial receptivity in an obese PCOS rat model. An obese PCOS rat model was established using letrozole and high-fat diet. Rats were divided into control, PCOS, and three intervention groups: PCOS + intracerebroventricular (i.c.v.) TAK242 (central TLR4 inhibitor), PCOS + intraperitoneal (i.p.) TAK242 (systemic inhibitor), and PCOS + Metformin. We assessed hypothalamic inflammation (TLR4/IKKbeta pathway), metabolic parameters (body weight, OGTT, ITT, HOMA-IR), systemic inflammation, and reproductive phenotypes. Endometrial receptivity was evaluated at pregnancy day 6 by uterine morphology, histology, pinopode development (SEM), and receptivity markers (BMP2, VEGF, IGFBP-1). The obese PCOS model successfully induced hypothalamic inflammation (activated TLR4/IKKbeta pathway), systemic inflammation, profound IR, and impaired endometrial receptivity (poor decidualization, sparse pinopodes, suppressed receptivity markers). Central (i.c.v.) TAK242 administration was most effective, significantly suppressing the hypothalamic TLR4/IKKbeta pathway, attenuating weight gain, normalizing insulin sensitivity, and, critically, restoring endometrial receptivity. Metformin also improved IR and receptivity, but was less potent at inhibiting the hypothalamic TLR4/IKKbeta pathway. Systemic (i.p.) TAK242 showed the least efficacy, particularly on metabolic and endometrial outcomes. Hypothalamic inflammation (TLR4/IKKbeta pathway) appears to be a critical mechanism linking IR and impaired endometrial receptivity in obese PCOS. Targeted central inhibition was more effective than systemic inhibition, suggesting this pathway is a novel therapeutic target. Key words Polycystic ovary syndrome (PCOS) " Hypothalamic inflammation " Insulin resistance " Endometrial receptivity " TLR4/IKKbeta pathway.