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ABSTRACT: Age-related obesity is associated with impaired hypothalamic pro-opiomelanocortin (Pomc) gene expression. We assessed whether overproduction of POMC in the hypothalamus ameliorates age-related obesity in rats.
Recombinant adeno-associated virus (rAAV) encoding Pomc (rAAV-Pomc) or control vector was delivered bilaterally into the basomedial hypothalamus of aged obese rats with coordinates targeting the arcuate nucleus. Energy balance, glucose metabolism, brown adipose tissue thermogenesis and mRNA levels of hypothalamic neuropeptides and melanocortin receptors were assessed.
Forty-two days after Pomc gene delivery, hypothalamic Pomc expression increased 12-fold while agouti-related protein and neuropeptide Y mRNA levels remained unchanged. Using a punch technique, we detected the highest Pomc RNA level in the arcuate nucleus. Pomc overexpression reduced food consumption from day 10 after vector injection, but this anorexic effect abated by day 30. In contrast, there was a steady decrease in body weight without apparent attenuation. Pomc gene delivery decreased visceral adiposity and induced uncoupling protein 1 in brown adipose tissue in aged rats. Serum NEFA and triglyceride levels were also diminished by rAAV-Pomc treatment. Improved glucose metabolism and insulin sensitivity were observed on day 36 but not day 20 after Pomc gene delivery. The expression of hypothalamic melanocortin 3 and 4 receptor decreased by 17% and 25%, respectively in rAAV-Pomc rats.
This study demonstrates that targeted Pomc gene therapy in the hypothalamus reduces body weight and visceral adiposity, and improves glucose and fat metabolism in aged obese rats. Thus long-term activation of the central melanocortin system may be a viable strategy to combat age-related obesity and diabetes.
Diabetologia 12/2005; 48(11):2376-85. · 6.81 Impact Factor
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ABSTRACT: The effects of the chronic activation of the central melanocortin (MC) system by melanotan II (MTII) were assessed in chow-fed (CH) and high-fat (HF) diet-induced obese (DIO) Sprague-Dawley rats. Six-day central infusion of MTII (1 nmol/day) reduced body weight and visceral adiposity compared with ad libitum-fed control and pair-fed groups and markedly suppressed caloric intake in both CH and DIO rats. The anorexic response to MTII was similar in DIO relative to CH rats. MTII induced a sustained increase in oxygen consumption in DIO but a delayed response in CH rats. In both diet groups, MTII reduced serum insulin and cholesterol levels compared with controls. HF feeding increased brown adipose tissue (BAT) uncoupling protein 1 (UCP1) by over twofold, and UCP1 levels were further elevated in MTII-treated CH and DIO rats. MTII lowered acetyl-CoA carboxylase expression and prevented the reduction in muscle-type carnitine palmitoyltransferase I mRNA by pair-feeding in the muscle of DIO rats. Compared with CH controls, hypothalamic MC3 and MC4 receptor expression levels were reduced in DIO controls. This study has demonstrated that, despite reduced hypothalamic MC3/MC4 receptor expression, anorexic and thermogenic responses to MTII are unabated with an initial augmentation of energy expenditure in DIO versus CH rats. The HF-induced up-regulation of UCP1 in BAT may contribute to the immediate increase in MTII-stimulated thermogenesis in DIO rats. MTII also increased fat catabolism in the muscle of DIO rats and improved glucose and cholesterol metabolism in both groups.
Journal of Endocrinology 08/2004; 182(1):123-32. · 3.55 Impact Factor
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ABSTRACT: Leptin is a peripheral immunoenhancing reagent that directly activates splenic lymphocytes in mice. We found that a 48 h fast in rats resulted in a decrease in serum leptin that was accompanied by a lower delayed-type hypersensitivity (DTH) response. Peripheral leptin replacement completely restored this response in fasted animals. We employed a recombinant adeno-associated virus (rAAV) system to deliver leptin gene directly into rat brain to assess the effect of sustained long-term central expression of leptin on immune responses. The rAAV-leptin rats had elevated central leptin over the 60 day duration of the experiment, whereas body fat and circulating leptin fell to near zero levels. The DTH response was significantly reduced by 10-20% in rats receiving rAAV-leptin compared with the control rats, and the difference was maintained for over 50 h. When the rats undergoing rAAV-leptin gene therapy were given either murine recombinant leptin or PBS s.c., rats receiving leptin had a 17% higher DTH response than rats receiving PBS. The isolated splenocytes from the former group also proliferated 34% more in vitro in response to the mitogen concanavalin A as compared with the latter group. These results suggest that peripheral leptin has a dominant role in maintaining T-cell-mediated immune responses in rats, and central leptin is unable to compensate for the immunosuppression associated with peripheral hypoleptinemia. Furthermore, preservation of normal cell-mediated immune responses does not require fat tissue as along as serum leptin levels are maintained.
Journal of Endocrinology 10/2002; 174(3):455-61. · 3.55 Impact Factor
