{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T12:03:30Z","timestamp":1784289810855,"version":"3.55.0"},"reference-count":26,"publisher":"Institute of Physiology of the Czech Academy of Sciences","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>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)\/I\u03baB kinase \u03b2 (IKK\u03b2) 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\/IKK\u03b2 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\/IKK\u03b2 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\/IKK\u03b2 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\/IKK\u03b2 pathway. Systemic (i.p.) TAK242 showed the least efficacy, particularly on metabolic and endometrial outcomes. Hypothalamic inflammation (TLR4\/IKK\u03b2 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.<\/jats:p>","DOI":"10.33549\/physiolres.935770","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T11:08:54Z","timestamp":1784286534000},"page":"485","source":"Crossref","is-referenced-by-count":0,"title":["Hypothalamic Inflammation as a Critical Link Between Metabolic Dysfunction and Impaired Endometrial Receptivity in Obese Polycystic Ovary Syndrome"],"prefix":"10.33549","author":[{"given":"C","family":"Sun","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Z","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H","family":"Kuang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"19169","published-online":{"date-parts":[[2026,7,7]]},"reference":[{"key":"ref0","doi-asserted-by":"crossref","unstructured":"1.\tSteegers-Theunissen RPM, Wiegel RE, Jansen PW, Laven JSE, Sinclair KD. Polycystic Ovary Syndrome: A Brain Disorder Characterized by Eating Problems Originating during Puberty and Adolescence. Int J Mol Sci 2020;21:8211. https:\/\/doi.org\/10.3390\/ijms21218211","DOI":"10.3390\/ijms21218211"},{"key":"ref1","doi-asserted-by":"crossref","unstructured":"2.\tMirza FG, Tahlak MA, Rjeili RB, Hazari K, Ennab F, Hodgman C, Khamis AH, Atiomo W. Polycystic Ovarian Syndrome (PCOS): Does the Challenge End at Conception? Int J Environ Res Public Health 2022;19:14914. https:\/\/doi.org\/10.3390\/ijerph192214914","DOI":"10.3390\/ijerph192214914"},{"key":"ref2","doi-asserted-by":"crossref","unstructured":"3.\tZhang L, Feng Y, Sun X, Yi S, Xiao X, Ma F. Impact of body mass index on assisted reproductive technology outcomes in patients with polycystic ovary syndrome: a meta-analysis. Reprod Biomed Online 2024;48:103849. https:\/\/doi.org\/10.1016\/j.rbmo.2024.103849","DOI":"10.1016\/j.rbmo.2024.103849"},{"key":"ref3","doi-asserted-by":"crossref","unstructured":"4.\tSumarac-Dumanovic M, Apostolovic M, Janjetovic K, Jeremic D, Popadic D, Ljubic A, et al. Downregulation of autophagy gene expression in endometria from women with polycystic ovary syndrome. Mol Cell Endocrinol 2017;440:116-124. https:\/\/doi.org\/10.1016\/j.mce.2016.11.009","DOI":"10.1016\/j.mce.2016.11.009"},{"key":"ref4","doi-asserted-by":"crossref","unstructured":"5.\tBarlampa D, Bompoula MS, Bargiota A, Kalantaridou S, Mastorakos G, Valsamakis G. Hypothalamic Inflammation as a Potential Pathophysiologic Basis for the Heterogeneity of Clinical, Hormonal, and Metabolic Presentation in PCOS. Nutrients 2021;13:520. https:\/\/doi.org\/10.3390\/nu13020520","DOI":"10.3390\/nu13020520"},{"key":"ref5","doi-asserted-by":"crossref","unstructured":"6.\tValdearcos M, Douglass JD, Robblee MM, Dorfman MD, Stifler DR, Bennett ML, et al. Microglial Inflammatory Signaling Orchestrates the Hypothalamic Immune Response to Dietary Excess and Mediates Obesity Susceptibility. Cell Metab 2017;26:185-197.e3. https:\/\/doi.org\/10.1016\/j.cmet.2017.05.015","DOI":"10.1016\/j.cmet.2017.05.015"},{"key":"ref6","doi-asserted-by":"crossref","unstructured":"7.\tGoodarzi MO, Dumesic DA, Chazenbalk G, Azziz R. Polycystic ovary syndrome: etiology, pathogenesis and diagnosis. Nat Rev Endocrinol 2011;7:219-231. https:\/\/doi.org\/10.1038\/nrendo.2010.217","DOI":"10.1038\/nrendo.2010.217"},{"key":"ref7","doi-asserted-by":"crossref","unstructured":"8.\tBuchanan MM, Hutchinson M, Watkins LR, Yin H. Toll-like receptor 4 in CNS pathologies. J Neurochem 2010;114:13-27. https:\/\/doi.org\/10.1111\/j.1471-4159.2010.06736.x","DOI":"10.1111\/j.1471-4159.2010.06736.x"},{"key":"ref8","doi-asserted-by":"crossref","unstructured":"9.\tYirmiya R, Goshen I. Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun 2011;25:181-213. https:\/\/doi.org\/10.1016\/j.bbi.2010.10.015","DOI":"10.1016\/j.bbi.2010.10.015"},{"key":"ref9","doi-asserted-by":"crossref","unstructured":"10.\tGuven-Maiorov E, Keskin O, Gursoy A, Nussinov R. A Structural View of Negative Regulation of the Toll-like Receptor-Mediated Inflammatory Pathway. Biophys J 2015;109:1214-1226. https:\/\/doi.org\/10.1016\/j.bpj.2015.06.048","DOI":"10.1016\/j.bpj.2015.06.048"},{"key":"ref10","doi-asserted-by":"crossref","unstructured":"11.\tPurkayastha S, Zhang H, Zhang G, Ahmed Z, Wang Y, Cai D. Neural dysregulation of peripheral insulin action and blood pressure by brain endoplasmic reticulum stress. Proc Natl Acad Sci U S A 2011;108:2939-2944. https:\/\/doi.org\/10.1073\/pnas.1006875108","DOI":"10.1073\/pnas.1006875108"},{"key":"ref11","doi-asserted-by":"crossref","unstructured":"12.\tWang L, Song LF, Chen XY, Ma YL, Suo JF, Shi JH, Chen GH. MiR-181b inhibits P38\/JNK signaling pathway to attenuate autophagy and apoptosis in juvenile rats with kainic acid-induced epilepsy via targeting TLR4. CNS Neurosci Ther 2019;25:112-122. https:\/\/doi.org\/10.1111\/cns.12991","DOI":"10.1111\/cns.12991"},{"key":"ref12","doi-asserted-by":"crossref","unstructured":"13.\tYang J, Zhu Y, Duan D, Wang P, Xin Y, Bai L, Liu Y, Xu Y. Enhanced activity of macrophage M1\/M2 phenotypes in periodontitis. Arch Oral Biol 2018;96:234-242. https:\/\/doi.org\/10.1016\/j.archoralbio.2017.03.006","DOI":"10.1016\/j.archoralbio.2017.03.006"},{"key":"ref13","doi-asserted-by":"crossref","unstructured":"14.\tWang QQ, Guo XC, Li L, Gao ZH, Ji M. Treatment with metformin and sorafenib alleviates endometrial hyperplasia in polycystic ovary syndrome by promoting apoptosis via synergically regulating autophagy. J Cell Physiol 2020;235:1339-1348. https:\/\/doi.org\/10.1002\/jcp.29051","DOI":"10.1002\/jcp.29051"},{"key":"ref14","doi-asserted-by":"crossref","unstructured":"15.\tHotamisligil GS. Inflammation and metabolic disorders. Nature 2006;444:860-867. https:\/\/doi.org\/10.1038\/nature05485","DOI":"10.1038\/nature05485"},{"key":"ref15","doi-asserted-by":"crossref","unstructured":"16.\tAndre C, Guzman-Quevedo O, Rey C, Remus-Borel J, Clark S, Castellanos-Jankiewicz A, et al. Inhibiting Microglia Expansion Prevents Diet-Induced Hypothalamic and Peripheral Inflammation. Diabetes 2017;66:908-919. https:\/\/doi.org\/10.2337\/db16-0586","DOI":"10.2337\/db16-0586"},{"key":"ref16","doi-asserted-by":"crossref","unstructured":"17.\tThaler JP, Yi CX, Schur EA, Guyenet SJ, Hwang BH, Dietrich MO, et al. Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest 2012;122:153-162. https:\/\/doi.org\/10.1172\/JCI59660","DOI":"10.1172\/JCI59660"},{"key":"ref17","doi-asserted-by":"crossref","unstructured":"18.\tAl-Qassab H, Smith MA, Irvine EE, Guillermet-Guibert J, Claret M, Choudhury AI, et al. Dominant role of the p110beta isoform of PI3K over p110alpha in energy homeostasis regulation by POMC and AgRP neurons. Cell Metab 2009;10:343-354. https:\/\/doi.org\/10.1016\/j.cmet.2009.09.008","DOI":"10.1016\/j.cmet.2009.09.008"},{"key":"ref18","doi-asserted-by":"crossref","unstructured":"19.\tTakeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell 2010;140:805-820. https:\/\/doi.org\/10.1016\/j.cell.2010.01.022","DOI":"10.1016\/j.cell.2010.01.022"},{"key":"ref19","doi-asserted-by":"crossref","unstructured":"20.\tMilanski M, Degasperi G, Coope A, Morari J, Denis R, Cintra DE, et al. Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: implications for the pathogenesis of obesity. J Neurosci 2009;29:359-370. https:\/\/doi.org\/10.1523\/JNEUROSCI.2760-08.2009","DOI":"10.1523\/JNEUROSCI.2760-08.2009"},{"key":"ref20","doi-asserted-by":"crossref","unstructured":"21.\tLancaster GI, Langley KG, Berglund NA, Kammoun HL, Reibe S, Estevez E, et al. Evidence that TLR4 Is Not a Receptor for Saturated Fatty Acids but Mediates Lipid-Induced Inflammation by Reprogramming Macrophage Metabolism. Cell Metab 2018;27:1096-1110.e5. https:\/\/doi.org\/10.1016\/j.cmet.2018.03.014","DOI":"10.1016\/j.cmet.2018.03.014"},{"key":"ref21","doi-asserted-by":"crossref","unstructured":"22.\tWu W, Wang S, Liu Q, Shan T, Wang Y. Metformin Protects against LPS-Induced Intestinal Barrier Dysfunction by Activating AMPK Pathway. Mol Pharm 2018;15:3272-3284. https:\/\/doi.org\/10.1021\/acs.molpharmaceut.8b00332","DOI":"10.1021\/acs.molpharmaceut.8b00332"},{"key":"ref22","doi-asserted-by":"crossref","unstructured":"23.\tNavarro VM. Metabolic regulation of kisspeptin - the link between energy balance and reproduction. Nat Rev Endocrinol 2020;16:407-420. https:\/\/doi.org\/10.1038\/s41574-020-0363-7","DOI":"10.1038\/s41574-020-0363-7"},{"key":"ref23","doi-asserted-by":"crossref","unstructured":"24.\tSchneider A, Saccon TD, Garcia DN, Zanini BM, Isola JVV, Hense JD, et al. The Interconnections Between Somatic and Ovarian Aging in Murine Models. J Gerontol A Biol Sci Med Sci 2021;76:1579-1586. https:\/\/doi.org\/10.1093\/gerona\/glaa258","DOI":"10.1093\/gerona\/glaa258"},{"key":"ref24","doi-asserted-by":"crossref","unstructured":"25.\tValsamakis G, Lois K, Kumar S, Mastorakos G. Metabolic and other effects of pioglitazone as an add-on therapy to metformin in the treatment of polycystic ovary syndrome (PCOS). Hormones (Athens) 2013;12:363-378. https:\/\/doi.org\/10.1007\/BF03401302","DOI":"10.1007\/BF03401302"},{"key":"ref25","doi-asserted-by":"crossref","unstructured":"26.\tSergi D, Williams LM. Potential relationship between dietary long-chain saturated fatty acids and hypothalamic dysfunction in obesity. 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