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Here, we find that adipose expression of the small neutral amino acid transporter SLC7A10, also known as alanine-serine-cysteine transporter-1 (ASC-1), shows strong inverse correlates with visceral adiposity, insulin resistance, and adipocyte hypertrophy across multiple cohorts. Concordantly, loss of Slc7a10 function in zebrafish in vivo accelerates diet-induced body weight gain and adipocyte enlargement. Mechanistically, SLC7A10 inhibition in human and murine adipocytes decreases adipocyte serine uptake and total glutathione levels and promotes reactive oxygen species (ROS) generation. Conversely, SLC7A10 overexpression decreases ROS generation and increases mitochondrial respiratory capacity. RNA sequencing revealed consistent changes in gene expression between human adipocytes and zebrafish visceral adipose tissue following loss of SLC7A10, e.g., upregulation of SCD (lipid storage) and downregulation of CPT1A (lipid oxidation). Interestingly, ROS scavenger reduced lipid accumulation and attenuated the lipid-storing effect of SLC7A10 inhibition. These data uncover adipocyte SLC7A10 as a novel important regulator of adipocyte resilience to nutrient and oxidative stress, in part by enhancing glutathione levels and mitochondrial respiration, conducive to decreased ROS generation, lipid accumulation, adipocyte hypertrophy, insulin resistance, and type 2 diabetes.<\/jats:p>","DOI":"10.2337\/db20-0096","type":"journal-article","created":{"date-parts":[[2021,1,6]],"date-time":"2021-01-06T17:29:22Z","timestamp":1609954162000},"page":"680-695","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":31,"title":["Role of the Neutral Amino Acid Transporter SLC7A10 in Adipocyte Lipid Storage, Obesity, and Insulin Resistance"],"prefix":"10.2337","volume":"70","author":[{"given":"Regine \u00c5.","family":"Jersin","sequence":"first","affiliation":[{"name":"1Mohn Nutrition Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway"},{"name":"2Hormone 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Hospital, Bergen, Norway"},{"name":"5Center of Health Research, F\u00f8rde Hospital Trust, F\u00f8rde, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans J\u00f8rgen","family":"Nielsen","sequence":"additional","affiliation":[{"name":"6Department of Surgery, Voss Hospital, Bergen Health Trust, Voss, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e5vard Luong","family":"Thorsen","sequence":"additional","affiliation":[{"name":"7Department of Surgery, Haugesund Hospital, Haugesund, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f8rn Gunnar","family":"Nedreb\u00f8","sequence":"additional","affiliation":[{"name":"1Mohn Nutrition Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway"},{"name":"8Department of Medicine, Haugesund Hospital, Haugesund, 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Jebsen Center for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen, Norway"},{"name":"11Dr. E. Martens Research Group for Biological Psychiatry, Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Bl\u00fcher","sequence":"additional","affiliation":[{"name":"12Clinic for Endocrinology and Nephrology, Medical Research Center, Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0208-2065","authenticated-orcid":false,"given":"Peter","family":"Jacobson","sequence":"additional","affiliation":[{"name":"13Institute of Medicine, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Per-Arne","family":"Svensson","sequence":"additional","affiliation":[{"name":"13Institute of Medicine, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, 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