Pro-opiomelanocortin (
POMC) neurons are identified in two brain sites, the arcuate nucleus of the hypothalamus and nucleus of the solitary tract (NTS) in brainstem. Earlier pharmacological and
POMC gene transfer studies demonstrate that
melanocortin activation in either site alone improves
insulin sensitivity and reduces
obesity. The present study, for the first time, investigated the long-term efficacy of
POMC gene transfer concurrently into both sites in the regulation of energy metabolism in aged F344xBN rats bearing adult-onset
obesity. Pair feeding was included to reveal food-independent
POMC impact on energy expenditure. We introduced adeno-associated virus encoding either
POMC or green fluorescence
protein to the two brain areas in 22-month-old rats, then recorded food intake and
body weight, assessed oxygen consumption, serum
leptin,
insulin and
glucose, tested voluntary wheel running, analysed
POMC expression, and examined fat metabolism in brown and white adipose tissues.
POMC mRNA was significantly increased in both the hypothalamus and NTS region at termination. Relative to pair feeding,
POMC caused sustained
weight reduction and additional fat loss, lowered fasting
insulin and
glucose, and augmented white fat
hormone-sensitive lipase activity and brown fat
uncoupling protein 1 level. By wheel running assessment, the
POMC animals ran twice the distance as the Control or pair-fed rats. Thus, the dual-site
POMC treatment ameliorated adult-onset
obesity effectively, involving a moderate hypophagia lasting ∼60 days, enhanced lipolysis and thermogenesis, and increased physical activity in the form of voluntary wheel running. The latter finding provides a clue for countering age-related decline in physical activity.