To examine the role of the brainstem melanocortin system in long-term energy regulation, we assessed the effects of overproduction of pro-opiomelanocortin (POMC) in the caudal brainstem on F344xBN rats with adult-onset obesity. Recombinant adeno-associated viral vector (rAAV) encoding POMC gene was delivered to the nucleus of solitary tract (NTS) in the hindbrain, and food intake, body weight, glucose and fat metabolism, brown adipose tissue (BAT) thermogenesis, and mRNA levels of neuropeptides and melanocortin receptors assessed. POMC delivery resulted in sustained reduction in food intake and body weight over 42 days and improved insulin sensitivity. At sacrifice, in rAAV-POMC-treated compared with control rats: -melanocyte-stimulating hormone in NTS increased nearly 21-fold while its level in the hypothalamus - MSH remained unchanged; visceral adiposity decreased by 37%; tissue triglyeride content diminished by 26% and 47% in liver and muscle, respectively; serum triglyeride and NEFA were reduced by 35% and 34%, respectively; phosphorylation of acetyl-CoA carboxylase was elevated by 63% in soleus muscle; BAT uncoupling protein 1 increased by 30%; and MC3 receptor expression declined by 60% while neuropeptide Y, agouti-related protein (AgRP) and MC4 receptor mRNA levels were unchanged in the NTS. In conclusion, POMC overexpression in the NTS produces a characteristic unabated hypophagia that is uniquely different than the anorexic tachyphylaxis following POMC overexpression in the hypothalamus. The sustained anorectic response may result from absence of compensatory elements in the NTS, such as increased AgRP expression, suggesting melanocortin activation of the brainstem may be a viable strategy to alleviate obesity.