G Li1, Y Zhang, K Y Cheng, P J Scarpace. 1. Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Box 100267, Gainesville, FL 32610, USA.
Abstract
AIMS/HYPOTHESIS: Central pro-opiomelanocortin (Pomc) gene therapy ameliorates genetic- or age-related obesity. We hypothesised that this treatment would delay or prevent dietary obesity in young, lean rats. MATERIALS AND METHODS: 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. RESULTS: Pomc gene delivery produced elevated hypothalamic Pomc mRNA (fourfold) and alpha-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. CONCLUSIONS/ INTERPRETATION: 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.
AIMS/HYPOTHESIS: Central pro-opiomelanocortin (Pomc) gene therapy ameliorates genetic- or age-related obesity. We hypothesised that this treatment would delay or prevent dietary obesity in young, lean rats. MATERIALS AND METHODS: 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. RESULTS:Pomc gene delivery produced elevated hypothalamic Pomc mRNA (fourfold) and alpha-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-Pomcrats 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-Pomcrats 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. CONCLUSIONS/ INTERPRETATION: 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.
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