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Although the underlying mechanism(s) remain unclear, evidence suggests a role for altered DNA methylation. We utilized a murine model of diet\u2010induced obesity to investigate the impact of maternal obesity on the offspring brain transcriptome and DNA methylation. C57Bl\/6 dams were fed high\u2010fat high\u2010sugar (HFD,\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20097) or control (CON,\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20097) diets. Maternal obesity\/hyperglycemia associated with offspring growth restriction, with brain\u2010sparing specifically in females. Postnatal hypoglycemia was seen in HFD males, but not females. The 3\u2032 RNA\u2010sequencing revealed perturbations in metabolic and cell differentiation pathways in neonatal male and female offspring frontal cortex and cerebellum. Compared with controls, HFD males, but not females, had lower cortical and cerebellar DNMT gene and protein expression, and reduced cerebellar TET enzyme mRNA. Whilst female offspring had lower cerebellar 5\u2010methylcytosine (5mC) and 5\u2010hydroxymethylcytosine (5hmC) than males, there were no effects of HFD on 5mC\/5hmC in cortex or cerebellum in either sex. Our data suggest that maternal obesity has sex\u2010specific effects on fetal neurodevelopment, including enzymes involved in DNA methylation\/demethylation. These mechanisms may play a role in the increased risk of neurodevelopmental disorders following obese\/diabetic pregnancies, including increased male susceptibility to these disorders.\n                  <\/jats:p>","DOI":"10.1111\/jne.70046","type":"journal-article","created":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T18:58:53Z","timestamp":1747335533000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Maternal high fat and high sugar diet impacts on key\n                    <scp>DNA<\/scp>\n                    methylation enzymes in offspring brain in a sex\u2010specific manner"],"prefix":"10.1111","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3995-0655","authenticated-orcid":false,"given":"Kahyee","family":"Hor","sequence":"first","affiliation":[{"name":"Centre for Reproductive Health, Institute for Regeneration and Repair University of Edinburgh  Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Dearden","sequence":"additional","affiliation":[{"name":"University of Cambridge Metabolic Research Laboratories Institute of Metabolic Science, Addenbrooke's Hospital  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Herzstein","sequence":"additional","affiliation":[{"name":"Centre for Reproductive Health, Institute for Regeneration and Repair University of Edinburgh  Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Ozanne","sequence":"additional","affiliation":[{"name":"University of Cambridge Metabolic Research Laboratories Institute of Metabolic Science, Addenbrooke's Hospital  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giles","family":"Hardingham","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute University of Edinburgh, Edinburgh Medical School  Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda J.","family":"Drake","sequence":"additional","affiliation":[{"name":"Centre for Reproductive Health, Institute for Regeneration and Repair University of Edinburgh  Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,5,15]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/ijo.2008.102"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(11)60814\u20103"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(14)60460\u20108"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471\u20100528.2005.00685.x"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.15585\/mmwr.mm665152a3"},{"key":"e_1_2_9_7_1","unstructured":"Euro\u2010Peristat Project.European Perinatal Health Report. 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