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Submitted on July 21, 2003
Accepted on October 28, 2003
1 Departments of Pharmacology and Retinoid Research, Ligand Pharmaceuticals, Inc. 10275 Science Center Drive, San Diego, CA 92121; Department of Nutrition Sciences, University of Alabama, 439 Webb Building, 1675 University Boulevard, Birmingham, AL 35294
* To whom correspondence should be addressed. E-mail: kogilvie{at}pfizer.com.
The retinoid X receptor (RXR), a ubiquitously expressed intracellular receptor, regulates pathways controlling glucose, triglycerides, cholesterol and bile acid metabolism. In addition to its role in those metabolic pathways, we have reported that RXR activation with a pan agonist [e.g. LG100268 (LG268)] decreases both body weight gain (BWG) and food consumption (FC) in obese, insulin resistant rodents. In parallel with those changes in energy balance, we show here that activation of RXR pathways results in adipose tissue remodeling, particularly within subcutaneous fat, where the rate of apoptosis is increased 5 fold. This change may underlie the selective decrease in fat mass observed in Zucker fatty rats treated with LG268 for 6 weeks. Since FC is strongly correlated with BWG in treated animals, we hypothesized that regulation of FC might be the primary mechanism underlying reduced BWG during RXR agonist administration. Importantly, decreased FC is due to decreased meal size, suggestive of induced satiety rather than malaise and/or aversion to food. Furthermore, administration of LG268 directly into the brain via intracerebroventricular injection also reduces FC, BWG and insulin, whereas the elevation in triglycerides observed after oral administration is absent. The latter observation suggests that RXR actions on energy balance and lipid homeostasis are separable. Therefore, ligand-mediated activation of either an RXR homodimer or an unidentified heterodimeric complex regulates pathways controlling energy balance at least in part via a CNS-mediated mechanism.
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