Central overexpression of leptin antagonist reduces wheel running and underscores importance of endogenous leptin receptor activity in energy homeostasis
Central overexpression of leptin antagonist reduces wheel running and underscores importance of endogenous leptin receptor activity in energy homeostasis
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DOI：
10.1152/ajpregu.90449.2008
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发表时间：
2009-11-01
影响因子：
2.8
通讯作者：
Scarpace, Philip J.
中科院分区：
文献类型：
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作者：
Matheny, Michael;Zhang, Yi;Scarpace, Philip J.
Matheny M，Zhang Y，Shapiro A，Tumer N，Scarpace PJ.中枢过表达瘦素拮抗剂减少车轮运行，并强调内源性瘦素受体活性在能量稳态中的重要性。Am J Physiol Regul Integr Comp Physiol 297：R1254-R1261，2009。首次发表于2009年9月2日; doi：10.1152/ajpregu.90449.2008。我们使用重组腺相关病毒（rAAV）介导的基因传递过表达大鼠瘦素产生的蛋白质，作为一个中性瘦素受体拮抗剂的突变体。在F344 X Brown Norway（BN）大鼠中测定了这种过度表达对体重稳态和体力活动的长期影响（通过自愿轮跑（WR）进行评估）。通过检查下丘脑中的mRNA水平证实了瘦素拮抗剂过表达。在192天的实验中，在食物和高脂肪喂养期间，拮抗剂组的摄食量和体重增加均加剧。在第二个实验中，使用较低剂量的拮抗剂载体，其导致食物消耗没有变化，但体重仍然增加。拮抗剂过表达的程度足以部分阻断由于急性次最大剂量瘦素给药引起的信号转导和转录激活因子3（STAT 3）磷酸化。在食物和高脂肪喂养期间，大鼠自由接近转轮4天。在两种拮抗剂剂量下以及在食物和高脂肪喂养期间，WR在拮抗剂过表达的情况下显著降低。相反，当瘦素在下丘脑过度表达时，WR活性增加了两倍以上。在死亡时，拮抗剂组的肥胖和血清瘦素水平更高。这些数据表明，次最大中枢瘦素受体阻断促进肥胖和减少WR活动。这些发现强调了不受限制的瘦素受体活性在长期能量稳态中的关键作用，并表明即使是瘦素受体功能的轻微破坏也会促进肥胖。
Matheny M, Zhang Y, Shapiro A, Tumer N, Scarpace PJ. Central overexpression of leptin antagonist reduces wheel running and underscores importance of endogenous leptin receptor activity in energy homeostasis. Am J Physiol Regul Integr Comp Physiol 297: R1254-R1261, 2009. First published September 2, 2009; doi: 10.1152/ajpregu.90449.2008.-We used recombinant adeno-associated virus (rAAV)-mediated gene delivery to overexpress a mutant of rat leptin yielding a protein that acts as a neutral leptin receptor antagonist. The long-term consequences of this overexpression on body weight homeostasis and physical activity, as assessed by voluntary wheel running (WR), were determined in F344 X Brown Norway (BN) rats. Leptin antagonist overexpression was confirmed by examination of mRNA levels in the hypothalamus. Food consumption and body weight gain were exacerbated in the antagonist group during both chow and high-fat feeding periods over the 192-day experiment. In a second experiment, a lower dose of antagonist vector was used that resulted in no change in food consumption but still increased body weight. The degree of antagonist overexpression was sufficient to partially block signal transducer and activator of transcription 3 (STAT3) phosphorylation due to administration of an acute submaximal dose of leptin. Rats were provided free access to running wheels for 4 days during both the chow and high-fat feeding periods. With both antagonist doses and during both chow and high-fat feeding, WR was substantially less with antagonist overexpression. In contrast, when leptin was overexpressed in the hypothalamus, WR activity was increased by greater than twofold. At death, adiposity and serum leptin levels were greater in the antagonist group. These data indicate that submaximal central leptin receptor blockade promotes obesity and diminishes WR activity. These findings underscore the critical role of unrestrained leptin receptor activity in long-term energy homeostasis and suggest that even minor disruption of leptin receptor function can promote obesity.