Abstract
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.
Highlights
Ghrelin is a peptidergic hormone mainly secreted by the stomach, the effects of which are exerted through the growth hormone secretagogue receptor 1a (GHS-R1a) [1]
Recent evidence has linked hypothalamic mammalian target of rapamycin (mTOR) signaling to modulation of feeding [20,21,22,23,24,25,26,27,28], we aimed to investigate the effect of central ghrelin on this metabolic pathway
Our data showed that ghrelin induced a marked activation of mTOR signaling, as demonstrated by increased protein levels of phosphorylated mTOR at Ser2448, and its downstream targets, namely pS6K1 at Thr389 and pS6 at Ser235/236 (Figures 2A and 2B)
Summary
Ghrelin is a peptidergic hormone mainly secreted by the stomach, the effects of which are exerted through the growth hormone secretagogue receptor 1a (GHS-R1a) [1]. Ghrelin activates hypothalamic Sirtuin (Sirt1)/p53 and AMP-activated protein kinase (AMPK) signaling pathways, leading to inhibition of de novo lipogenesis and increased fatty acid oxidation, which causes changes in mitochondrial respiration and increased production of reactive oxygen species (ROS) [2,4,5,6,7,8,9,10] leading to activation of NPY/AgRP neurons. The molecular mechanisms linking ghrelin with the induction of Agrp and Npy gene expression have been recently identified. It was reported that the hypothalamic homeobox domain transcription factor BSX regulates ghrelin’s stimulatory effect on Agrp and Npy gene expression in rats, an effect that involves an interaction with two other transcription factors: the phosphorylated cAMP responseelement binding protein (pCREB) and forkhead box O1 (FoxO1), respectively [7,13,14]. In spite of this evidence, it is unclear whether selective modulation of hypothalamic lipid metabolism is the unique main effector downstream of AMPK or if alternative pathways might be involved
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