Lean rats with hypothalamic pro-opiomelanocortin overexpression exhibit greater diet-induced obesity and impaired central melanocortin responsiveness

Recombinant adeno-associated virus encoding Pomc (rAAV-Pomc) was delivered bilaterally into the basomedial hypothalamus of lean rats for 42 days. Food intake, body weight, serum hormones, brown adipose tissue (BAT) uncoupling protein 1 (UCP1) and mRNA levels of hypothalamic neuropeptides and melanocortin receptors were assessed. Beginning on day 43, half of the rats remained on chow while the others received a high-fat diet for 89 days. We examined energy balance and responsiveness to the melanocortin agonist melanotan II (MTII) or the antagonist SHU9119.

Pomc gene delivery produced elevated hypothalamic Pomc mRNA (fourfold) and α-melanocyte-stimulating hormone levels in the arcuate nucleus (twofold). Food intake and body weight were not altered by rAAV-Pomc in rats fed standard-chow. In rAAV-Pomc rats at day 42, perirenal fat and serum leptin decreased but overall visceral adiposity did not; expression of the hypothalamic agouti-related protein (Agrp) mRNA was elevated, whereas expression of melanocortin 3 and 4 receptor mRNA was reduced; BAT UCP1 protein increased nearly fourfold. The rAAV-Pomc rats fed the high-fat diet consumed more energy and gained more body weight compared with chow- or high-fat-fed controls that did not receive Pomc gene delivery. The anorexic response to MTII was impaired, whereas the orexigenic effect of SHU9119 was enhanced by rAAV-Pomc pretreatment.

Delivery of the Pomc gene alters energy homeostasis in lean rats, predisposing them to diet-induced obesity. Diminished hypothalamic melanocortin receptors, increased Agrp expression, and potential rewiring of brain circuits may underlie the exacerbated obesity.