Troglitazone treatment of aging Brown Norway rats improves food intake and weight gain after fasting without increasing hypothalamic NPY gene expression

Compared to younger animals, aged male Brown Norway (BN) rats demonstrate increased body fat and serum insulin, and lower prepro-neuropeptide Y (ppNPY) mRNA content in the arcuate nucleus (ARC), and blunted food intake (FI) and body weight (BW) gain in response to a 72 h fast. Since centrally administered insulin decreases FI and weight of young rats and inhibits fasting-induced increases of NPY gene expression, we hypothesized that hyperinsulinemia in old rats contributes to an age-related central dysregulation of energy balance. Young, middle-aged and old BN rats were fed chow with troglitazone (Trog; 200 mg/kg BW/d) or without drug for 75 d (Experiment 1) or 66 d (Experiment 2). Rats were then fasted for 72 h, refed for 2 weeks and sacrificed after an overnight fast (Experiment 1) or fasted for 72 h and sacrificed (Experiment 2). Serum insulin and leptin were measured from trunk blood and brains were analyzed for ppNPY mRNA by in situ hybridization. In Experiment 1, troglitazone treatment resulted in increased post-fast weight gain, rate of gain and FI in old rats. Troglitazone decreased serum insulin by 50% in old rats, while leptin levels decreased 20-30% in all age groups in Experiment 1. No differences in serum insulin or leptin were detectable with troglitazone treatment in Experiment 2, due to the extreme suppression caused by the 72 h fast. Troglitazone treatment did not increase ARC NPY gene expression either after a 72 h fast and re-feeding for 2 weeks (Experiment 1) or immediately after a 72 h fast (Experiment 2). These findings suggest that increased insulin levels may contribute to age-related impairments of FI and BW regulation. However, improvements in these defects in energy regulation induced by troglitazone do not appear to result from changes in NPY gene expression, and may be due to alterations in other hypothalamic neuropeptides that regulate energy balance.