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The aim of this study was to determine whether N-acetylcysteine (NAC), an anti-inflammatory antioxidant, attenuates programmed susceptibility to obesity and insulin resistance in offspring of mothers on a high-fat diet (HFD) during pregnancy. CD1 female mice were acutely fed a standard breeding chow or HFD. NAC was added to the drinking water (1 g\/kg) of the treatment cohorts from embryonic day 0.5 until the end of lactation. NAC treatment normalized HFD-induced maternal weight gain and oxidative stress, improved the maternal lipidome, and prevented maternal leptin resistance. These favorable changes in the in utero environment normalized postnatal growth, decreased white adipose tissue (WAT) and hepatic fat, improved glucose and insulin tolerance and antioxidant capacity, reduced leptin and insulin, and increased adiponectin in HFD offspring. The lifelong metabolic improvements in the offspring were accompanied by reductions in proinflammatory gene expression in liver and WAT and increased thermogenic gene expression in brown adipose tissue. These results, for the first time, provide a mechanistic rationale for how NAC can prevent the onset of metabolic disease in the offspring of mothers who consume a typical Western HFD.<\/jats:p>","DOI":"10.2337\/db19-1129","type":"journal-article","created":{"date-parts":[[2020,5,22]],"date-time":"2020-05-22T19:29:33Z","timestamp":1590175773000},"page":"1650-1661","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":33,"title":["Antioxidant Effects of N-Acetylcysteine Prevent Programmed Metabolic Disease in Mice"],"prefix":"10.2337","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6353-5692","authenticated-orcid":false,"given":"Maureen J.","family":"Charron","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Albert Einstein College of Medicine, New York, NY"},{"name":"Department of Medicine and Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine, New York, 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