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Since cysteine can be synthesized from methionine, animal diets are formulated by decreasing methionine and eliminating cysteine. Such diets exert both methionine restriction (MR) and cysteine restriction (CR), that is, sulfur amino acid restriction (SAAR). Contrarily, SAAR diets formulated for human consumption included cysteine, and thus might have exerted only MR. Epidemiological studies positively correlate body adiposity with plasma cysteine but not methionine, suggesting that CR, but not MR, is responsible for the anti\u2010adiposity effects of SAAR. Whether this is true, and, if so, the underlying mechanisms are unknown. Using methionine\u2010 and cysteine\u2010titrated diets, we demonstrate that the anti\u2010adiposity effects of SAAR are due to CR. Data indicate that CR increases serinogenesis (serine biosynthesis from non\u2010glucose substrates) by diverting substrates from glyceroneogenesis, which is essential for fatty acid reesterification and triglyceride synthesis. Molecular data suggest that CR depletes hepatic glutathione and induces Nrf2 and its downstream targets Phgdh (the serine biosynthetic enzyme) and Pepck\u2010M. In mice, the magnitude of SAAR\u2010induced changes in molecular markers depended on dietary fat concentration (60% fat &gt;10% fat), sex (males\u2009&gt;\u2009females), and age\u2010at\u2010onset (young\u2009&gt;\u2009adult). Our findings are translationally relevant as we found negative and positive correlations of plasma serine and cysteine, respectively, with triglycerides and metabolic syndrome criteria in a cross\u2010sectional epidemiological study. Controlled feeding of low\u2010SAA, high\u2010polyunsaturated fatty acid diets increased plasma serine in humans. Serinogenesis might be a target for treating hypertriglyceridemia.<\/jats:p>","DOI":"10.1111\/acel.13739","type":"journal-article","created":{"date-parts":[[2022,11,19]],"date-time":"2022-11-19T23:34:55Z","timestamp":1668900895000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Cysteine restriction\u2010specific effects of sulfur amino acid restriction on lipid metabolism"],"prefix":"10.1111","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5969-3572","authenticated-orcid":false,"given":"Sailendra N.","family":"Nichenametla","sequence":"first","affiliation":[{"name":"Animal Science Laboratory Orentreich Foundation for the Advancement of Science  Cold Spring\u2010on\u2010Hudson New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dwight A. 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