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Anorexigenic and orexigenic hormone modulation of mammalian target of rapamycin complex 1 activity and the regulation of hypothalamic agouti-related protein mRNA expression
journal contribution
posted on 2013-02-01, 00:00 authored by Kenneth R Watterson, Dawn Bestow, Jennifer Gallagher, Lee HamiltonLee Hamilton, Fiona B Ashford, Paul J Meakin, Michael L J AshfordActivation of mammalian target of rapamycin 1 (mTORC1) by nutrients, insulin and leptin leads to appetite suppression (anorexia). Contrastingly, increased AMP-activated protein kinase (AMPK) activity by ghrelin promotes appetite (orexia). However, the interplay between these mechanisms remains poorly defined. The relationship between the anorexigenic hormones, insulin and leptin, and the orexigenic hormone, ghrelin, on mTORC1 signalling was examined using S6 kinase phosphorylation as a marker for changes in mTORC1 activity in mouse hypothalamic GT1-7 cells. Additionally, the contribution of AMPK and mTORC1 signalling in relation to insulin-, leptin- and ghrelin-driven alterations to mouse hypothalamic agouti-related protein (AgRP) mRNA levels was examined. Insulin and leptin increase mTORC1 activity in a phosphoinositide-3-kinase (PI3K)- and protein kinase B (PKB)-dependent manner, compared to vehicle controls, whereas increasing AMPK activity inhibits mTORC1 activity and blocks the actions of the anorexigenic hormones. Ghrelin mediates an AMPK-dependent decrease in mTORC1 activity and increases hypothalamic AgRP mRNA levels, the latter effect being prevented by insulin in an mTORC1-dependent manner. In conclusion, mTORC1 acts as an integration node in hypothalamic neurons for hormone-derived PI3K and AMPK signalling and mediates at least part of the assimilated output of anorexigenic and orexigenic hormone actions in the hypothalamus.
History
Journal
NeurosignalsVolume
21Issue
1-2Pagination
28 - 41Publisher
KargerLocation
Basel, SwitzerlandPublisher DOI
Link to full text
eISSN
1424-8638Language
engPublication classification
C1 Refereed article in a scholarly journalCopyright notice
2012, S. Karger AG, BaselUsage metrics
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No categories selectedKeywords
Agouti-Related ProteinAnimalsAnorexiaAppetiteHypothalamusMechanistic Target of Rapamycin Complex 1Mice, Inbred C57BLMultiprotein ComplexesRNA, MessengerTOR Serine-Threonine KinasesGhrelinLeptinInsulinAgRPAMP-activated protein kinaseScience & TechnologyLife Sciences & BiomedicineBiochemistry & Molecular BiologyBiophysicsCell BiologyNeurosciencesNeurosciences & NeurologyARCUATE NUCLEUSNEUROPEPTIDE-YKINASEENERGYMTORNEURONSAMPK
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