Central leptin gene therapy fails to overcome leptin resistance associated with diet-induced obesity.
Central leptin gene therapy fails to overcome leptin resistance associated with diet-induced obesity.
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中枢瘦素基因疗法无法克服与饮食引起的肥胖相关的瘦素抵抗。
DOI：
10.1152/ajpregu.00193.2003
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发表时间：
2003
期刊：
影响因子：
--
通讯作者：
Scarpace,PhilipJ
中科院分区：
文献类型：
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作者：
Wilsey,Jared;Zolotukhin,Sergei;Prima,Victor;Scarpace,PhilipJ
本研究的目的是确定是否中枢过表达瘦素可以克服瘦素抵抗所造成的100天的高脂喂养。给三个月大的F344 XBN雄性大鼠喂食对照低脂食物（Chow），其提供15%的脂肪能量，或喂食高脂肪/高蔗糖饮食（HF），其提供59%的脂肪能量。在几周内，HF喂养的动物自发地分成两组动物：HF饮食（DIO）中变得肥胖的动物和HF饮食中没有增加额外体重的动物[饮食抵抗（DR）]。HF喂养100天后，向动物给予含有5.75E10颗粒的编码瘦素的rAAV（rAAV-leptin）或对照病毒（rAAV-con）的单次脑室内注射。Chow动物对rAAV-瘦素反应强烈，包括显著的厌食、体重减轻和脂肪减少。相反，DIO对rAAV-瘦素完全无反应。DR大鼠响应rAAV-瘦素，但在一个更多变的方式比周。与在Chow中观察到的不同，对rAAV-leptin的厌食反应迅速减弱，并且在载体递送后第14天不再显著。DIO和DR动物都被发现具有减少的长型瘦素受体表达和增强的基础P-STAT-3在下丘脑相对于食物。rAAV-瘦素引起的STAT 3磷酸化和阿黑皮素原的表达在下丘脑和解偶联蛋白-1在棕色脂肪组织中的增加，在两个Chow和DR动物，但未能做到这一点在DIO。这表明，中枢过度表达瘦素不是一个可行的策略，以扭转饮食诱导的肥胖。
The objective of this study was to determine if central overexpression of leptin could overcome the leptin resistance caused by 100 days of high-fat feeding. Three-month old-F344XBN male rats were fed either control low fat chow (Chow), which provides 15% of energy as fat, or a high-fat/high-sucrose diet (HF), which provides 59% of energy as fat. Over several weeks, the HF-fed animals spontaneously split into two groups of animals: those that became obese on the HF diet (DIO) and those that did not gain extra weight on the HF diet [diet resistant (DR)]. After 100 days of HF feeding, animals were given a single intracerebroventricular injection containing 5.75E10 particles of rAAV encoding leptin (rAAV-leptin) or control virus (rAAV-con). Chow animals responded robustly to rAAV-leptin, including significant anorexia, weight loss, and lipopenia. In contrast, DIO were completely unresponsive to rAAV-leptin. DR rats responded to rAAV-leptin, but in a more variable fashion than Chow. Unlike what was observed in Chow, the anorectic response to rAAV-leptin rapidly attenuated and was no longer significant byday 14postvector delivery. Both DIO and DR animals were found to have reduced long-form leptin receptor expression and enhanced basal P-STAT-3 in the hypothalamus with respect to Chow. rAAV-leptin caused an increase in STAT3 phosphorylation and proopiomelanocortin expression in the hypothalamus and an increase in uncoupling protein-1 in brown adipose tissue in both Chow and DR animals, but failed to do so in DIO. This suggests that central overexpression of leptin is not a viable strategy to reverse diet-induced obesity.