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However, the mechanisms involved in the deleterious effects of obesity on cognition remain largely unknown. This study aimed to assess the impact of obesity on the production of sphingolipids (ceramides and sphingomyelins) in the brain and its relationship with the learning deficits displayed by obese individuals. We also sought to determine whether the effects of obesity on brain sphingolipid synthesis could be passed on to the offspring. Learning abilities and brain concentration of sphingolipids in male and female control and obese founder rats (F0) and their offspring (F1) were evaluated, respectively, by the novel object recognition test and by ultra\u2010performance liquid chromatography tandem mass spectrometry. In addition, a global lipidome profiling of the cerebral cortex and hippocampus was performed. Both male and female F0 rats showed impaired learning and increased concentrations of ceramides and sphingomyelins in the hippocampus and frontal cortex compared to their control counterparts. However, the overall lipidome profile of these brain regions did not change with obesity. Remarkably, the alterations in brain sphingolipid synthesis, as well as the cognitive impairment induced by obesity, were also present in adult F1 male rats born to obese mothers or sired by obese fathers and were associated with enhanced expression of mRNAs coding for enzymes involved in the de novo synthesis of ceramides. These results show that the cognitive deficits and impaired sphingolipid metabolism induced by obesity can be transmitted to the offspring through both the maternal and paternal lineages and suggest that an increase in the brain concentration of sphingolipids could play a causal role in the cognitive deficits associated with obesity.<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\/jnc16307-fig-0009-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p>","DOI":"10.1111\/jnc.16307","type":"journal-article","created":{"date-parts":[[2025,1,20]],"date-time":"2025-01-20T13:52:11Z","timestamp":1737381131000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Diet\u2010Induced Obesity in the Rat Impairs Sphingolipid Metabolism in the Brain and This Metabolic Dysfunction Is Transmitted to the Offspring via Both the Maternal and the Paternal Lineage"],"prefix":"10.1111","volume":"169","author":[{"given":"Juan Antonio Garc\u00eda","family":"Santill\u00e1n","sequence":"first","affiliation":[{"name":"Nantes Universit\u00e9, INRAE, UMR 1280, Physiologie des Adaptations Nutritionnelles  Nantes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla Elena","family":"Mezo\u2010Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Nantes Universit\u00e9, INRAE, UMR 1280, Physiologie des Adaptations Nutritionnelles  Nantes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathilde","family":"Gourdel","sequence":"additional","affiliation":[{"name":"CRNH\u2010O Mass Spectrometry Core Facility  Nantes France"},{"name":"Nantes Universit\u00e9, CNRS, INSERM, L'institut du Thorax  Nantes France"},{"name":"Nantes Universit\u00e9, CHU Nantes, Inserm, CNRS, SFR Sant\u00e9, Inserm UMS 016, CNRS UMS 3556  Nantes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mika\u00ebl","family":"Croyal","sequence":"additional","affiliation":[{"name":"CRNH\u2010O Mass Spectrometry Core Facility  Nantes France"},{"name":"Nantes Universit\u00e9, CNRS, INSERM, L'institut du Thorax  Nantes France"},{"name":"Nantes Universit\u00e9, CHU Nantes, Inserm, CNRS, SFR Sant\u00e9, Inserm UMS 016, CNRS UMS 3556  Nantes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6604-4386","authenticated-orcid":false,"given":"Francisco","family":"Bola\u00f1os\u2010Jim\u00e9nez","sequence":"additional","affiliation":[{"name":"Nantes Universit\u00e9, INRAE, UMR 1280, Physiologie des Adaptations Nutritionnelles  Nantes France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,1,20]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2019.08.010"},{"key":"e_1_2_10_3_1","first-page":"25","article-title":"Ceramide Content Is Increased in Skeletal Muscle From Obese Insulin\u2010Resistant Humans","volume":"53","author":"Adams J. 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