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Here, we integrated single-nucleus RNA sequencing (snRNA-seq) with bulk ATAC-seq to characterize hypothalamic remodeling in an HFD\/STZ-induced T2D mouse model. High-resolution snRNA-seq revealed pronounced cell type-specific alterations involving several neuronal subpopulations, including Gal.Nts.Npy, Nxph4.Adcyap1, and Lmx1a.Gpr149.Tcf4 neurons, together with substantial changes in oligodendrocyte-lineage cells. Increased Npy expression was accompanied by greater tissue-level chromatin accessibility at the Npy locus, providing convergent evidence for activation of the hypothalamic Npy regulatory axis. Pseudotime analysis further showed increased representation of a transcriptionally distinct Cntnap2-positive oligodendrocyte-lineage state, together with reduced representation of canonical myelination-associated states. Ligand\u2013receptor analysis predicted reduced signaling across selected neuron\u2013oligodendrocyte interactions and altered communication among glial populations. Collectively, these findings reveal coordinated neuronal, oligodendrocyte-lineage, intercellular signaling, and chromatin-accessibility alterations in the diabetic hypothalamus, and identify the Npy regulatory axis and Cntnap2-positive oligodendrocyte-lineage state as candidate features for further mechanistic investigation.<\/jats:p>","DOI":"10.3390\/cells15181672","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T07:58:59Z","timestamp":1789545539000},"page":"1672","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated Single-Nucleus and Epigenomic Profiling Reveals Coordinated Neuro-Glial and Chromatin Remodeling in the Type 2 Diabetic Hypothalamus"],"prefix":"10.3390","volume":"15","author":[{"given":"Shuoyang","family":"Zhao","sequence":"first","affiliation":[{"name":"Institute of Reproduction and Development, Shanghai Key Laboratory of Reproduction and Development, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3903-0519","authenticated-orcid":false,"given":"Shengwei","family":"Sui","sequence":"additional","affiliation":[{"name":"Institute of Reproduction and Development, Shanghai Key Laboratory of Reproduction and Development, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinghui","family":"Guo","sequence":"additional","affiliation":[{"name":"School of Public Health, State Key Laboratory of Digital Medical Engineering, Advanced Institute for Life and Health, Southeast University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofeng","family":"Ji","sequence":"additional","affiliation":[{"name":"School of Public Health, State Key Laboratory of Digital Medical Engineering, Advanced Institute for Life and Health, Southeast University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Public Health, State Key Laboratory of Digital Medical Engineering, Advanced Institute for Life and Health, Southeast University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongbo","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute of Reproduction and Development, Shanghai Key Laboratory of Reproduction and Development, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200030, China"},{"name":"Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200090, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/S0896-6273(00)81084-3","article-title":"From lesions to leptin: Hypothalamic control of food intake and body weight","volume":"22","author":"Elmquist","year":"1999","journal-title":"Neuron"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1038\/35007534","article-title":"Central nervous system control of food intake","volume":"404","author":"Schwartz","year":"2000","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1038\/nature03439","article-title":"Hypothalamic K(ATP) channels control hepatic glucose production","volume":"434","author":"Pocai","year":"2005","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/nrn2647","article-title":"Neural regulation of endocrine and autonomic stress responses","volume":"10","author":"Herman","year":"2009","journal-title":"Nat. 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