Bagnasco Michela, Dube Michael G, Katz Adi, Kalra Pushpa S, Kalra Satya P
Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, Florida 32610-0244, USA.
Obes Res. 2003 Dec;11(12):1463-70. doi: 10.1038/oby.2003.196.
In order to circumvent the multiple peripheral effects of hyperleptinemia and leptin resistance, the efficacy of leptin transgene expression in the hypothalamic paraventricular nucleus (PVN) to reinstate the central energy homeostasis in obesity was examined.
A recombinant adeno-associated viral vector encoding either leptin (rAAV-lep) or green fluorescent protein (rAAV-GFP) was microinjected into the PVN of obesity-prone rats consuming a high-fat diet (HFD).
rAAV-lep, and not rAAV-GFP, microinjection significantly reduced energy intake and enhanced energy expenditure, thereby resulting in normalization of weight and blood levels of leptin, insulin, free fatty acids, and glucose concomitant with enhanced ghrelin secretion during the extended period of observation.
Thus, we show, for the first time, that amelioration of leptin insufficiency with enhanced localized leptin availability in the PVN alone can reverse dietary obesity and the attendant hyperinsulinemia and concurrently block the central stimulatory effects of elevated endogenous ghrelin on food intake and adiposity.
为了规避高瘦素血症和瘦素抵抗的多种外周效应，研究了在下丘脑室旁核（PVN）中进行瘦素转基因表达以恢复肥胖状态下中枢能量稳态的疗效。
将编码瘦素（rAAV-lep）或绿色荧光蛋白（rAAV-GFP）的重组腺相关病毒载体微量注射到食用高脂饮食（HFD）的肥胖易感大鼠的PVN中。
在延长的观察期内，微量注射rAAV-lep而非rAAV-GFP可显著减少能量摄入并增加能量消耗，从而使体重以及瘦素、胰岛素、游离脂肪酸和葡萄糖的血液水平恢复正常，同时伴随胃饥饿素分泌增加。
因此，我们首次表明，仅通过增强PVN中局部瘦素的可用性来改善瘦素不足，就可以逆转饮食性肥胖和随之而来的高胰岛素血症，并同时阻断内源性胃饥饿素升高对食物摄入和肥胖的中枢刺激作用。
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