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.
The Small Molecule Nobiletin Targets the Molecular Oscillator to Enhance Circadian Rhythms and Protect against Metabolic Syndrome
