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This review examines current evidence on how maternal nutrition, particularly overnutrition and its complications, such as gestational diabetes mellitus (GDM) and obesity, affects offspring health. It also explores the biochemical and epigenetic mechanisms underlying aberrant fetal programming induced by an unfavorable intrauterine environment. Excess nutrient exposure in utero alters fetal metabolic pathways by modifying the expression of key metabolic genes and nutrient sensors, increasing susceptibility to metabolic syndrome later in life. Maternal obesity has additionally been linked to cognitive dysfunction, immune alterations, and elevated cancer-related mortality in the offspring. GDM exposure disrupts fetal hypothalamic development, impairing appetite regulation. Emerging evidence suggests that epigenetic changes induced by maternal overnutrition may be transmitted across generations and that paternal obesity may also contribute to fetal metabolic programming. Although lifestyle interventions during pregnancy have been tested, they show limited long-term benefits, whereas pre-pregnancy BMI remains the strongest predictor of offspring obesity, emphasizing the critical role of preconception care and the prevention of overweight in women of reproductive age.<\/jats:p>","DOI":"10.3390\/cells15040366","type":"journal-article","created":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T15:28:18Z","timestamp":1771428498000},"page":"366","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Maternal Overnutrition and Fetal Programming: Long-Term Metabolic, Cognitive, and Epigenetic Consequences"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8638-6455","authenticated-orcid":false,"given":"Gabriella","family":"Schiera","sequence":"first","affiliation":[{"name":"Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale Delle Scienze Building 16, 90128 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Macajone","sequence":"additional","affiliation":[{"name":"Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale Delle Scienze Building 16, 90128 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9288-9859","authenticated-orcid":false,"given":"Sara","family":"Volpes","sequence":"additional","affiliation":[{"name":"Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale Delle Scienze Building 16, 90128 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5949-784X","authenticated-orcid":false,"given":"Laura","family":"Greco","sequence":"additional","affiliation":[{"name":"Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale Delle Scienze Building 16, 90128 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo Maria","family":"Di Liegro","sequence":"additional","affiliation":[{"name":"Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale Delle Scienze Building 16, 90128 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5479-6145","authenticated-orcid":false,"given":"Graziella","family":"Serio","sequence":"additional","affiliation":[{"name":"Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale Delle Scienze Building 16, 90128 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7659-7312","authenticated-orcid":false,"given":"Fabio","family":"Caradonna","sequence":"additional","affiliation":[{"name":"Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale Delle Scienze Building 16, 90128 Palermo, Italy"},{"name":"NBFC, National Biodiversity Future Center, 90133 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8075-0642","authenticated-orcid":false,"given":"Flores","family":"Naselli","sequence":"additional","affiliation":[{"name":"Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale Delle Scienze Building 16, 90128 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Barker, D. 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