Scarpace P J, Matheny M, Tümer N, Cheng K Y, Zhang Y
Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville, FL, USA.
Diabetologia. 2005 Jun;48(6):1075-83. doi: 10.1007/s00125-005-1763-x. Epub 2005 Apr 30.
AIMS/HYPOTHESIS: Leptin resistance is generally considered a consequence of obesity. We postulated that leptin resistance is associated with diminished hypothalamic leptin signalling capacity and that leptin resistance is causal to obesity. We assessed maximal leptin-mediated binding of the transcription factor signal transducer and activator of transcription 3 (STAT3), and the response to high-fat feeding in lean leptin-resistant rats.
Recombinant adeno-associated virus encoding rat leptin cDNA (rAAV-leptin) or control vector were administered by intracerebroventricular injection to lean F344 x BN rats for up to 150 days, and food consumption, body weight, serum leptin and glucose tolerance were measured. Leptin-mediated hypothalamic transcription factor binding was assessed at day 150 following an intracerebroventricular injection of 2 mug leptin. Rats pretreated with either control or rAAV-leptin vector for 94 days were given a high-fat diet, and energy intake, body weight gain and adiposity were examined.
The rAAV-leptin-treated rats initially responded to leptin gene delivery then became leptin-resistant. They displayed persistent submaximal hypothalamic leptin signalling and enhanced insulin sensitivity, yet maximal hypothalamic signalling capacity was decreased by more than 50%. On a high-fat diet, the leptin-resistant rats consumed more energy, gained more weight and accumulated greater visceral fat mass than controls.
CONCLUSIONS/INTERPRETATION: The maximal hypothalamic leptin signalling capacity was diminished in leptin-resistant rats receiving central rAAV-leptin gene therapy. Moreover, this leptin-invoked leptin resistance perturbs the regulation of energy homeostasis in response to high fat exposure, producing augmented energy consumption. This, coupled with potential hypersensitivity to insulin, creates a milieu favouring fat deposition. Our data suggest that leptin resistance is both a consequence and cause of obesity.
目的/假设：瘦素抵抗通常被认为是肥胖的结果。我们推测瘦素抵抗与下丘脑瘦素信号传导能力减弱有关，且瘦素抵抗是肥胖的病因。我们评估了转录因子信号转导子和转录激活子3（STAT3）的最大瘦素介导结合，以及瘦素抵抗的瘦大鼠对高脂喂养的反应。
通过脑室内注射将编码大鼠瘦素cDNA的重组腺相关病毒（rAAV-瘦素）或对照载体给予瘦的F344×BN大鼠，持续150天，测量食物摄入量、体重、血清瘦素和葡萄糖耐量。在脑室内注射2μg瘦素后第150天评估瘦素介导的下丘脑转录因子结合。用对照或rAAV-瘦素载体预处理94天的大鼠给予高脂饮食，检查能量摄入、体重增加和肥胖情况。
rAAV-瘦素处理的大鼠最初对瘦素基因传递有反应，然后变得瘦素抵抗。它们表现出持续的下丘脑瘦素信号亚最大反应和增强的胰岛素敏感性，但下丘脑最大信号传导能力下降超过50%。在高脂饮食中，瘦素抵抗的大鼠比对照消耗更多能量、体重增加更多且内脏脂肪量积累更多。
结论/解读：接受中枢rAAV-瘦素基因治疗的瘦素抵抗大鼠下丘脑最大瘦素信号传导能力减弱。此外，这种瘦素引发的瘦素抵抗扰乱了对高脂暴露的能量稳态调节,导致能量消耗增加。这与对胰岛素的潜在超敏反应相结合，营造了有利于脂肪沉积的环境。我们的数据表明瘦素抵抗既是肥胖的结果也是肥胖的原因。
