AbstractObjectivesHypothalamic dysfunction leads to glucose metabolic imbalance; however, the mechanisms still need clarification. Our current study was to explore the role of hypothalamicHnscrin glucose metabolism.Materials and MethodsUsingHnscrknockout or htNSC‐specificHnscroverexpression mice, we evaluated the effects ofHnscron 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.ResultsHnscrexpression decreased in the hypothalamus after high‐fat diet feed.Hnscr‐null mice displayed aggravated systematic insulin resistance, while mice with htNSC‐specificHnscroverexpression had the opposite phenotype. Notably,Hnscr‐null mice had increased NF‐κB signal in htNSCs, along with enhanced inflammation and damaged insulin signal in neurons located in arcuate nucleus of hypothalamus. The secretions, including sEVs, ofHnscr‐deficient htNSCs mediated the detrimental effects on the CNS cell line. Locally implantation withHnscr‐depleted htNSCs disrupted glucose homeostasis.ConclusionsThis study demonstrated that decreased Hnscr in htNSCs led to systematic glucose imbalance through activating NF‐κB signal and dampening insulin signal in hypothalamic neurons.