Central leptin gene therapy blocks high-fat diet-induced weight gain, hyperleptinemia, and hyperinsulinemia - Increase in serum ghrelin levels
Central leptin gene therapy blocks high-fat diet-induced weight gain, hyperleptinemia, and hyperinsulinemia - Increase in serum ghrelin levels
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DOI：
10.2337/diabetes.51.6.1729
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发表时间：
2002-06-01
期刊：
影响因子：
7.7
通讯作者：
Kalra, SP
中科院分区：
文献类型：
--
作者：
Dube, MG;Beretta, E;Kalra, SP
将编码大鼠瘦素(rAAV-lep)或绿色荧光蛋白(rAAV-GFP，对照)的重组腺相关病毒(RAAV)注入高脂饮食(HFD；45kcal%)大鼠的脑室。每周监测卡路里消耗和体重，直到9周时处死大鼠。未处理的对照组大鼠食用常规大鼠饮食(RCD；11kcal%)，平行监测。与服用RCD的大鼠相比，rAAV-GFP+HFD对照组大鼠的体重增加速度更快，尽管消耗的卡路里相同。9周时，HFD对照组大鼠血清瘦素、游离脂肪酸、甘油三酯和胰岛素水平升高。相反，rAAV-LEP治疗减少了摄入，并阻止了HFD诱导的体重、肥胖症和代谢变量的增加。RAAV-LEP+HFD大鼠血糖略有下降，但在正常范围内，血清Ghrelin水平显著升高。服用HFD的大鼠棕色脂肪组织(BAT)中解偶联蛋白-1(UCP1)的mRNA水平降低，这是一种通过非颤抖产热来消耗能量的指标。经rAAV-LEP处理后，BAT UCP1基因的表达显著增加，表明生热能量消耗增加。这些发现表明，中枢瘦素基因疗法通过减少能量摄入和增加热能消耗，有效地预防了服用HFD的大鼠的体重增加、肥胖增加和高胰岛素血症。
Recombinant adeno-associated virus (rAAV), encoding either rat leptin (rAAV-lep) or green fluorescent protein (rAAV-GFP, control), was injected intracerebroventricularly in rats consuming a high-fat diet (HFD; 45 kcal%). Caloric consumption and body weight were monitored weekly until the rats were killed at 9 weeks. Untreated control rats consuming regular rat diet (RCD; 11 kcal%) were monitored in parallel. Body weight gain was accelerated in rAAV-GFP + HFD control rats relative to those consuming RCD, despite equivalent kcal consumption. At 9 weeks, serum leptin, free fatty acids, triglycerides, and insulin were elevated in HFD control rats. In contrast, rAAV-lep treatment reduced intake and blocked the HFD-induced increase in weight, adiposity, and metabolic variables. Blood glucose was slightly reduced but within the normal range, and serum ghrelin levels were significantly elevated in rAAV-lep + HFD rats. Uncoupling protein-1 (UCP1) mRNA in brown adipose tissue (BAT), an index of energy expenditure through nonshivering thermogenesis, was decreased in rats consuming HFD. Treatment with rAAV-lep significantly augmented BAT UCP1 mRNA expression, indicating increased thermogenic energy expenditure. These findings demonstrate that central leptin gene therapy efficiently prevents weight gain, increased adiposity, and hyperinsulinemia in rats consuming an HFD by decreasing energy intake and increasing thermogenic energy expenditure.