title: Anorexigenic and orexigenic hormone modulation of mammalian target of rapamycin complex 1 activity and the regulation of hypothalamic agouti-related protein mRNA expression.
abstract: Activation 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.
authors.affiliation: Medical Research Institute, Division of Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Watterson
authors.forename: Dawn
authors.initials: D
authors.lastname: Bestow
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gallagher
authors.forename: D Lee
authors.initials: DL
authors.lastname: Hamilton
authors.forename: Fiona B
authors.initials: FB
authors.lastname: Ashford
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Meakin
authors.forename: Michael L J
authors.initials: ML
authors.lastname: Ashford
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D054369:Agouti-Related Protein / Q000096:biosynthesis*; D000818:Animals; D000855:Anorexia / Q000378:metabolism; D001066:Appetite / Q000502:physiology*; D005260:Female; D007031:Hypothalamus / Q000378:metabolism*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D046912:Multiprotein Complexes; D012333:RNA, Messenger; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases