The effects of rexinoids and rosiglitazone on body weight and uncoupling protein isoform expression in the Zucker fa/fa rat

Agonists for the retinoid X receptor (RXR), the rexinoids, and the peroxiso me proliferator-activated receptor gamma (PPAR gamma), the thiazolidinedion es, are effective in the treatment of insulin resistance in rodent models b y enhancing insulin action and improving glycemic control. In the present s tudy, we compared the effects of rexinoids and a thiazolidinedione on body weight and mitochondrial uncoupling protein (UCP) isoform mRNA expression i n the obese Zucker fa/fa rat. Long-term (2 weeks) oral treatment with the r exinoids LG100268 and LG100324 reduced food intake and body weight gain, wh ereas rosiglitazone (BRL49653) tended to increase both food intake and weig ht gain. LG100268 and LG100324 increased brown adipose tissue (BAT) UCP-1 m RNA content by 2.7-fold (P < .002) and 3.1-fold (P < .001), respectively, w hile BRL49653 had no effect on BAT UCP-1 mRNA content. Neither the rexinoid s nor the thiazolidinedione had any effect on the level of mRNA encoding UC P-2 and the recently described PPAR gamma coactivator-l (PGC-1). LG100324 i ncreased UCP-3 mRNA content by 3.6-fold (P < .0005) in muscle and 4.3-fold (P < .0002) in white adipose tissue (WAT). LG100268 increased UCP-3 mRNA co ntent in WAT by 2-fold (P < .005) but was without any effect on muscle UCP- 3. BRL49553 increased UCP-3 mRNA content by 2.1-fold (P < .005) in muscle a nd 2.7-fold (P < .003) in WAT. Thus, the rexinoids, but not the thiazolidin edione, have an antiobesity action by reducing food intake, and the increas e in UCP-1 mRNA content in BAT may reflect a stimulation of BAT UCP-1 activ ity. Copyright (C) 2000 by W.B. Saunders Company.