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Accumulating evidence demonstrates that obesity is a risk factor for CNS neuroinflammation and cognitive impairment. However, the extent to which CNS disruption influences peripheral metabolism remains to be elucidated. We previously reported that myelin-enriched sulfatide loss leads to CNS neuroinflammation and cognitive decline. In this study, we further investigated the impact of CNS sulfatide deficiency on peripheral metabolism while considering sex- and age-specific effects. We found that female sulfatide-deficient mice gained significantly more body weight, exhibited higher basal glucose levels, and were glucose-intolerant during glucose-tolerance test (GTT) compared to age-matched controls under a normal diet, whereas male sulfatide-deficient mice only displayed glucose intolerance at a much older age compared to female sulfatide-deficient mice. Mechanistically, we found that increased body weight was associated with increased food intake and elevated neuroinflammation, especially in the hypothalamus, in a sex-specific manner. Our results suggest that CNS sulfatide deficiency leads to sex-specific alterations in energy homeostasis via dysregulated hypothalamic control of food intake.<\/jats:p>","DOI":"10.3390\/ijms241310483","type":"journal-article","created":{"date-parts":[[2023,6,23]],"date-time":"2023-06-23T01:54:56Z","timestamp":1687485296000},"page":"10483","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Adult-Onset CNS Sulfatide Deficiency Causes Sex-Dependent Metabolic Disruption in Aging"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8784-7436","authenticated-orcid":false,"given":"Shulan","family":"Qiu","sequence":"first","affiliation":[{"name":"Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA"},{"name":"Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3786-8770","authenticated-orcid":false,"given":"Sijia","family":"He","sequence":"additional","affiliation":[{"name":"Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianing","family":"Wang","sequence":"additional","affiliation":[{"name":"Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hu","family":"Wang","sequence":"additional","affiliation":[{"name":"Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anindita","family":"Bhattacharjee","sequence":"additional","affiliation":[{"name":"Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Li","sequence":"additional","affiliation":[{"name":"Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moawiz","family":"Saeed","sequence":"additional","affiliation":[{"name":"Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey L.","family":"Dupree","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, VA 23284, USA"},{"name":"McGuire Veterans Affairs Medical Center, Research Division, Richmond, VA 23249, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8615-2413","authenticated-orcid":false,"given":"Xianlin","family":"Han","sequence":"additional","affiliation":[{"name":"Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA"},{"name":"Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e12941","DOI":"10.1111\/jne.12941","article-title":"Central regulation of glucose metabolism in an insulin-dependent and -independent manner","volume":"33","author":"Fujikawa","year":"2021","journal-title":"J. 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