β3-Adrenergic regulation of leptin, food intake, and adiposity is impaired with age

With age, there are increases in adiposity, leptin mRNA in white adipose tissue (WAT), and serum leptin levels in rats. beta(3)-Adrenergic agonists are anti-obesity agents in rodents, and activation of beta(3)-adrenergic receptors (beta(3)AR) mediates an acute decrease in food consumption, increased thermogenesis in brown adipose tissue (BAT), increased lipolysis in WAT, and suppression of leptin gene expression and serum leptin levels. Because beta(3)AR signal transduction is impaired with age in BAT and WAT, beta(3)AR-mediated regulation of leptin, feeding behavior, and adiposity may also be impaired with age. To test this hypothesis, we infused young (6 month) and old (24 month) F344 x BN rats with the beta(3)AR agonist CL316,243 (1 mg kg(-1) day(-1)) using osmotic minipumps for 7 days. Food intake, body mass, adiposity, and serum leptin, as well as leptin, uncoupling protein 1 (UCP1), and lipoprotein lipase (LPL) mRNA in BAT or WAT were determined. In young rats, CL316,243 infusion reduced body mass and adiposity, suppressed serum leptin and leptin mRNA levels in WAT, induced UCP1 in WAT, and increased UCP1 and LPL mRNA levels in BAT. Moreover, treatment with CL316,243 was associated with a marked but transient suppression of food intake. Most of the responses elicited in the old rats with CL316,243 treatment were qualitatively similar to those in the young rats, but blunted in magnitude. beta(3)AR activation of adenylyl cyclase was also reduced in the aged rats. These data suggest that, although CL316,243 is an effective agent in aged rats, the maximum responses are reduced, suggesting that the impaired beta(3)AR signal transduction with age is a major determining factor in the reduced effectiveness of CL316,243 in older rats.