Department of Physiology, Research Center of Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela-Instituto de Investigación Sanitaria (IDIS), Santiago de Compostela, Spain.
PLoS One. 2012;7(10):e46923. doi: 10.1371/journal.pone.0046923. Epub 2012 Oct 9.
Current evidence suggests that ghrelin, a stomach derived peptide, exerts its orexigenic action through specific modulation of Sirtuin1 (SIRT1)/p53 and AMP-activated protein kinase (AMPK) pathways, which ultimately increase the expression of agouti-related protein (AgRP) and neuropeptide Y (NPY) in the arcuate nucleus of the hypothalamus (ARC). However, there is a paucity of data about the possible action of ghrelin on alternative metabolic pathways at this level. Here, we demonstrate that ghrelin elicits a marked upregulation of the hypothalamic mammalian target of rapamycin (mTOR) signaling pathway. Of note, central inhibition of mTOR signaling with rapamycin decreased ghrelin's orexigenic action and normalized the mRNA expression of AgRP and NPY, as well as their key downstream transcription factors, namely cAMP response-element binding protein (pCREB) and forkhead box O1 (FoxO1, total and phosphorylated). Taken together, these data indicate that, in addition to previous reported mechanisms, ghrelin also promotes feeding through modulation of hypothalamic mTOR pathway.
目前的证据表明，胃来源的肽 ghrelin 通过对 Sirtuin1 (SIRT1)/p53 和 AMP 激活蛋白激酶 (AMPK) 途径的特异性调节发挥其食欲刺激作用，最终增加下丘脑弓状核 (ARC) 中 agouti 相关蛋白 (AgRP) 和神经肽 Y (NPY) 的表达。然而，关于 ghrelin 在这一水平上对替代代谢途径的可能作用的数据很少。在这里，我们证明 ghrelin 引起了明显的下丘脑哺乳动物雷帕霉素靶蛋白 (mTOR) 信号通路的上调。值得注意的是，用 rapamycin 抑制中枢 mTOR 信号通路会降低 ghrelin 的食欲刺激作用，并使 AgRP 和 NPY 的 mRNA 表达及其关键下游转录因子，即 cAMP 反应元件结合蛋白 (pCREB) 和叉头框 O1 (FoxO1，总蛋白和磷酸化蛋白) 正常化。总之，这些数据表明，ghrelin 除了以前报道的机制外，还通过调节下丘脑 mTOR 通路促进进食。
