Mice with a targeted null mutation of the serotonin 5-HT2C receptor gene exhibit hyperphagia that leads to a late-onset obesity. Here we show that oxygen consumption was decreased in fed and fasted obese mutants. No phenotypic differences were observed in uncoupling protein-1 (UCP-1) mRNA levels in brown adipose tissues and UCP-3 mRNA in skeletal muscle. UCP-2 mRNA levels were significantly increased in white adipose tissue (4-fold) and skeletal muscle (47%) in older obese mutant mice, whereas UCP-2 mRNA in liver are significantly increased in both young lean (54% increase) and older obese (52% increase) mutant mice. In contrast, 5-HT2C receptor mutants displayed age-dependent decreases in beta3-adrenergic receptor (beta3-AR) mRNA levels in white adipose tissue, however, no such changes were observed in brown adipose tissue. These results indicate that a mutation of 5-HT2C receptor gene leads to a secondary decrease in P3-AR gene expression that is related to enhanced adiposity. (C) 2002 Elsevier Science (USA). All rights reserved.