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Its activity in the brain was proposed to regulate bioactive lipid availability, namely eicosanoids that are inflammatory mediators and regulate cerebral blood flow (CBF). We aimed at testing whether HSL deletion increases susceptibility to neuroinflammation and impaired brain perfusion upon diet\u2010induced obesity. HSL\u2212\/\u2212, HSL+\/\u2212, and HSL+\/+ mice of either sex were fed high\u2010fat diet (HFD) or control diet for 8\u2009weeks, and then assessed in behavior tests (object recognition, open field, and elevated plus maze), metabolic tests (insulin and glucose tolerance tests and indirect calorimetry in metabolic cages), and CBF determination by arterial spin labeling (ASL) magnetic resonance imaging (MRI). Immunofluorescence microscopy was used to determine coverage of blood vessels, and morphology of astrocytes and microglia in brain slices. HSL deletion reduced CBF, most prominently in cortex and hippocampus, while HFD feeding only lowered CBF in the hippocampus of wild\u2010type mice. CBF was positively correlated with lectin\u2010stained vessel density. HSL deletion did not exacerbate HFD\u2010induced microgliosis in the hippocampus and hypothalamus. HSL\u2212\/\u2212 mice showed preserved memory performance when compared to wild\u2010type mice, and HSL deletion did not significantly aggravate HFD\u2010induced memory impairment in object recognition tests. In contrast, HSL deletion conferred protection against HFD\u2010induced obesity, glucose intolerance, and insulin resistance. Altogether, this study points to distinct roles of HSL in periphery and brain during diet\u2010induced obesity. While HSL\u2212\/\u2212 mice were protected against metabolic syndrome development, HSL deletion reduced brain perfusion without leading to aggravated HFD\u2010induced neuroinflammation and memory dysfunction.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc16064-fig-0009-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p>","DOI":"10.1111\/jnc.16064","type":"journal-article","created":{"date-parts":[[2024,2,7]],"date-time":"2024-02-07T07:12:12Z","timestamp":1707289932000},"page":"781-800","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Genetic deletion of hormone\u2010sensitive lipase in mice reduces cerebral blood flow but does not aggravate the impact of diet\u2010induced obesity on memory"],"prefix":"10.1111","volume":"168","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4999-1939","authenticated-orcid":false,"given":"Cecilia","family":"Skoug","sequence":"first","affiliation":[{"name":"Department of Experimental Medical Science, Faculty of Medicine Lund University  Lund Sweden"},{"name":"Wallenberg Centre for Molecular Medicine, Faculty of Medicine Lund University  Lund Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5104-2943","authenticated-orcid":false,"given":"Oksana","family":"Rogova","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Centre for Analysis and Synthesis Lund University  Lund Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6092-2387","authenticated-orcid":false,"given":"Peter","family":"Sp\u00e9gel","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Centre for Analysis and Synthesis Lund University  Lund Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7496-8167","authenticated-orcid":false,"given":"Cecilia","family":"Holm","sequence":"additional","affiliation":[{"name":"Department of Experimental Medical Science, Faculty of Medicine Lund University  Lund Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5984-1574","authenticated-orcid":false,"given":"Jo\u00e3o M. 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