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Our current study was to explore the role of hypothalamic<jats:italic>Hnscr<\/jats:italic>in glucose metabolism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and Methods<\/jats:title><jats:p>Using<jats:italic>Hnscr<\/jats:italic>knockout or htNSC\u2010specific<jats:italic>Hnscr<\/jats:italic>overexpression mice, we evaluated the effects of<jats:italic>Hnscr<\/jats:italic>on glucose metabolism through GTTs, ITTs, serum indicator measurements, etc. Immunofluorescence staining and Western blotting were performed to test inflammation levels and insulin signalling in hypothalamus. Conditioned medium intervene were used to investigate the effects of htNSCs on neuronal cell line. We also detected the glucose metabolism of mice with htNSCs implantation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>Hnscr<\/jats:italic>expression decreased in the hypothalamus after high\u2010fat diet feed.<jats:italic>Hnscr<\/jats:italic>\u2010null mice displayed aggravated systematic insulin resistance, while mice with htNSC\u2010specific<jats:italic>Hnscr<\/jats:italic>overexpression had the opposite phenotype. Notably,<jats:italic>Hnscr<\/jats:italic>\u2010null mice had increased NF\u2010\u03baB signal in htNSCs, along with enhanced inflammation and damaged insulin signal in neurons located in arcuate nucleus of hypothalamus. The secretions, including sEVs, of<jats:italic>Hnscr<\/jats:italic>\u2010deficient htNSCs mediated the detrimental effects on the CNS cell line. Locally implantation with<jats:italic>Hnscr<\/jats:italic>\u2010depleted htNSCs disrupted glucose homeostasis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study demonstrated that decreased Hnscr in htNSCs led to systematic glucose imbalance through activating NF\u2010\u03baB signal and dampening insulin signal in hypothalamic neurons.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cpr.13332","type":"journal-article","created":{"date-parts":[[2022,8,31]],"date-time":"2022-08-31T04:30:10Z","timestamp":1661920210000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Hypothalamic<i>Hnscr<\/i>regulates glucose balance by mediating central inflammation and insulin signal"],"prefix":"10.1111","volume":"56","author":[{"given":"Ya","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Endocrinology, Endocrinology Research Center Xiangya Hospital of Central South University 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