The action of leptin in the ventral tegmental area to decrease food intake is dependent on Jak-2 signaling
The action of leptin in the ventral tegmental area to decrease food intake is dependent on Jak-2 signaling
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DOI：
10.1152/ajpendo.90865.2008
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发表时间：
2009-07-01
影响因子：
5.1
通讯作者：
Figlewicz, Dianne P.
中科院分区：
文献类型：
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作者：
Morton, Gregory J.;Blevins, James E.;Figlewicz, Dianne P.
Morton GJ，Blevins JE，Kim F，Matsen M，Figlewicz DP.腹侧被盖区瘦素减少食物摄入的作用依赖于Jak-2信号传导。Am J Physiol Endocrinol Metab 297：E202-E210，2009.首次发表于2009年5月12日; doi：10.1152/ajpendo.90865.2008。最近的证据表明，瘦素通过食物奖励的大脑回路中的作用减少食物摄入，例如腹侧被盖区（VTA），因为瘦素受体存在于VTA中，并且VTA中的瘦素注射减少食物摄入。在下丘脑中，瘦素诱导的厌食症需要通过Janus激酶-信号转导子和转录激活子（Jak-STAT）、胰岛素受体底物（IRS）-磷脂酰肌醇3-激酶（PI 3-激酶）和哺乳动物雷帕霉素靶蛋白（mTOR）进行信号传导。在这项研究中，我们确定瘦素是否激活腹侧被盖区的这些信号转导通路，以及这些信号转导通路是否是腹侧被盖区瘦素诱导的厌食症所必需的。在这里，我们表明，pSTAT 3-Tyr（705），瘦素激活的标志物，诱导中脑区域包含腹侧被盖区和黑质后，无论是脑室内瘦素或直接管理瘦素的腹侧被盖区，但这些干预措施未能增加无论是pAKT-Ser（473）或磷酸-p70 S6 K-Thr（389），IRS-PI 3-激酶和mTOR信号的标志物，分别水平。此外，VTA内瘦素给药减少4小时和20小时食物摄入量和20小时体重的作用被Jak-2抑制剂阻断，其剂量本身对食物摄入量或体重没有影响，但在此时间范围内不能通过PI 3-激酶（LY-294002）或mTOR（雷帕霉素）的局部抑制来阻断。总之，这些数据支持腹侧被盖区中的瘦素信号传导参与能量平衡调节的假设，但是，与下丘脑中的瘦素信号传导相反，这些作用主要通过Jak-2信号传导而不是通过IRS-PI 3-激酶或mTOR信号传导途径介导。
Morton GJ, Blevins JE, Kim F, Matsen M, Figlewicz DP. The action of leptin in the ventral tegmental area to decrease food intake is dependent on Jak-2 signaling. Am J Physiol Endocrinol Metab 297: E202-E210, 2009. First published May 12, 2009; doi: 10.1152/ajpendo.90865.2008.-Recent evidence suggests that leptin reduces food intake via actions in the brain circuitry of food reward, such as the ventral tegmental area (VTA), as leptin receptors are present in the VTA, and leptin injection in the VTA reduces food intake. In the hypothalamus, leptin-induced anorexia requires signaling via Janus kinase-signal transducer and activator of transcription (Jak-STAT), insulin receptor substrate (IRS)-phosphatidylinositol 3-kinase (PI 3-kinase), and mammalian target of rapamycin ( mTOR). In this study, we determined whether leptin activates each of these signal transduction pathways in the VTA and whether these signaling pathways are required for VTA-leptin induced anorexia. Here, we show that pSTAT3-Tyr(705), a marker of leptin activation, was induced in a midbrain region containing the VTA and substantia nigra following either intracerebroventricular leptin or direct administration of leptin to the VTA, but these interventions failed to increase levels of either pAKT-Ser(473) or phospho-p70S6K-Thr(389), markers of IRS-PI 3-kinase and mTOR signaling, respectively. Moreover, the effect of intra-VTA leptin administration to reduce 4- and 20-h food intake and 20-h body weight was blocked by an inhibitor of Jak-2, at a dose that had no effect on food intake or body weight by itself, but not by local inhibition of either PI 3-kinase (LY-294002) or mTOR (rapamycin) in this timeframe. Taken together, these data support the hypothesis that leptin signaling in the VTA is involved in the regulation of energy balance, but, in contrast to the leptin signaling in the hypothalamus, these effects are mediated predominantly via Jak-2 signaling rather than via the IRS-PI 3-kinase or mTOR signaling pathway.