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A Small Molecule, UAB126, Reverses Diet-Induced Obesity and Its Associated Metabolic Disorders

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posted on 08.07.2020 by Ada Admin, Guang Ren, Teayoun Kim, Hae-Suk Kim, Martin E. Young, Donald D. Muccio, Venkatram R. Atigadda, Samuel I. Blum, Hubert M. Tse, Kirk M. Habegger, Sushant Bhatnagar, Tatjana Coric, Mary-Ann Bjornsti, Anath Shalev, Stuart J. Frank, Jeong-a Kim
Targeting rexinoid X receptor (RXR) has been proposed as one of the therapeutic strategies to treat individuals with metabolic syndrome, because RXR heterodimerizes with multiple nuclear receptors that regulate genes involved in metabolism. 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. Herein, 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-seq analysis revealed that UAB126 regulates the expression of genes in the liver that are modulated by several nuclear receptors, including peroxisome proliferator-activated receptor (PPAR) alpha and/or liver X receptor (LXR) in conjunction with retinoid X receptor (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 present study reveals that UAB126 offers as an attractive therapy to treat individuals with obesity and its co-morbidities.

Funding

This study was supported by the UAB Diabetes Research Center sponsored pilot and feasibility program supported by National Institutes of Health (P30DK079626), UAB Center for Clinical and Translational Science pilot and feasibility program by National Institutes of Health (UL1TR003096), and UAB Comprehensive Diabetes Center and National Heart Lung and Blood Institute (R01 HL128695 to JK) National Institute of Aging (R03 AG058078 to JK), National Institute of Diabetes and Digestive and Kidney NIH-NIDDK (R01 DK112934 to KMH, R00 DK95975 and 1R01DK120684 to SB, and DK099550 to HMT), and National Institute of General Medical Sciences (T32 GM109780 to SIB).

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