Effects of the melanocortin agonist melanotan II, central pro-opiomelanocortin and interleukin-6 gene therapy on the regulation of body weight and energy homeostasis

Leptin, an adipocyte-derived hormone, reduces food intake and increases energy expenditure via the hypothalamus. Obese animals and humans are associated with elevated serum leptin and leptin resistance. Recent evidence suggests the central melanocortin (MC) system may be located downstream of the hypothalamic leptin signal pathway. We hypothesize direct activation of the central MC system will circumvent leptin resistance and reduce body weight in leptin-resistant animals.; MC3/4-receptor agonist melanotan II (MTII) was infused centrally for six days in chow-fed (CH) and high-fat (HF) diet-induced obese (DIO) Sprague-Dawley rats. MTII reduced body weight and visceral adiposity and suppressed caloric intake in CH and DIO rats. The initial anorexic and thermogenic responses were enhanced in DIO. In both diet groups, MTII reduced serum insulin and cholesterol. HF feeding increased brown adipose tissue (BAT) uncoupling protein 1 (UCP1), which was further elevated by MTII treatment. MTII also appeared to increase fat metabolism in muscle of DIO rats. Hypothalamic MC3/4-receptor expression levels were reduced in DIO.; We employed a recombinant adeno-associated virus encoding pro-opiomelanocortin (rAAV-POMC) to enhance POMC expression in hypothalami of obese Zucker rats with defective leptin receptors. POMC gene therapy resulted in a sustained reduction in food intake, a moderate attenuation of weight gain and a decrease in visceral adiposity. It increased BAT UCP1 and decreased fasting serum leptin, insulin and cholesterol levels.; Interleukin-6 (1L-6) is produced in adipose tissues and shares a similar signaling pathway with leptin. A rAAV expressing murine IL-6 (rAAV-IL-6) was delivered into hypothalami of normal Sprague-Dawley rats. The treatment suppressed weight gain and visceral adiposity and enhanced BAT UCP1 without affecting food intake. Unilateral denervation of BAT abolished weight-reducing effect of rAAV-IL-6 and prevented increases in UCP1 mRNA and protein levels in the denervated BAT pad.; Our studies demonstrate that MTII and POMC gene therapy activate the central MC system, reduce body weight and visceral adiposity, and improve glucose and cholesterol metabolism in leptin-resistant DIO and obese Zucker rats, respectively. Both hypophagia and increased energy expenditure are the likely underlying mechanisms. IL-6 also has a potential role in energy regulation, which involves sympathetic induction of UCP1 in BAT.