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Despite numerous efforts, RXR ligands (rexinoids) have not been approved for clinical trials to treat metabolic syndrome due to the serious side effects such as hypertriglyceridemia and altered thyroid hormone axis. In this study, we demonstrate a novel rexinoid-like small molecule, UAB126, which has positive effects on metabolic syndrome without the known side effects of potent rexinoids. Oral administration of UAB126 ameliorated obesity, insulin resistance, hepatic steatosis, and hyperlipidemia without changes in food intake, physical activity, and thyroid hormone levels. RNA-sequencing analysis revealed that UAB126 regulates the expression of genes in the liver that are modulated by several nuclear receptors, including peroxisome proliferator\u2013activated receptor \u03b1 and\/or liver X receptor in conjunction with RXR. Furthermore, UAB126 not only prevented but also reversed obesity-associated metabolic disorders. The results suggest that optimized modulation of RXR may be a promising strategy to treat metabolic disorders without side effects. Thus, the current study reveals that UAB126 could be an attractive therapy to treat individuals with obesity and its comorbidities.<\/jats:p>","DOI":"10.2337\/db19-1001","type":"journal-article","created":{"date-parts":[[2020,7,1]],"date-time":"2020-07-01T15:35:11Z","timestamp":1593617711000},"page":"2003-2016","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":11,"title":["A Small Molecule, UAB126, Reverses Diet-Induced Obesity and its Associated Metabolic Disorders"],"prefix":"10.2337","volume":"69","author":[{"given":"Guang","family":"Ren","sequence":"first","affiliation":[{"name":"Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL"},{"name":"UAB Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, 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