Hypothalamic mTOR signaling mediates the orexigenic action of ghrelin.
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.
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.
Luís
L
Martins
Diana
D
Fernández-Mallo
Marta G
MG
Novelle
María J
MJ
Vázquez
Manuel
M
Tena-Sempere
Rubén
R
Nogueiras
Miguel
M
López
Carlos
C
Diéguez
D054369:Agouti-Related Protein / Q000378:metabolism; D000818:Animals; D019167:Appetite Stimulants / Q000008:administration & dosage / Q000494:pharmacology*; D001111:Arcuate Nucleus of Hypothalamus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D004435:Eating / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology; D054439:Ghrelin / Q000008:administration & dosage / Q000494:pharmacology*; D007031:Hypothalamus / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D008297:Male; D009478:Neuropeptide Y / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism
D054369:Agouti-Related Protein; D019167:Appetite Stimulants; D054439:Ghrelin; D009478:Neuropeptide Y; D014157:Transcription Factors; D058570:TOR Serine-Threonine Kinases