Hypothalamic κ-opioid receptor modulates the orexigenic effect of ghrelin.
The opioid system is well recognized as an important regulator of appetite and energy balance. We now hypothesized that the hypothalamic opioid system might modulate the orexigenic effect of ghrelin. Using pharmacological and gene silencing approaches, we demonstrate that ghrelin utilizes a hypothalamic κ-opioid receptor (KOR) pathway to increase food intake in rats. Pharmacological blockade of KOR decreases the acute orexigenic effect of ghrelin. Inhibition of KOR expression in the hypothalamic arcuate nucleus is sufficient to blunt ghrelin-induced food intake. By contrast, the specific inhibition of KOR expression in the ventral tegmental area does not affect central ghrelin-induced feeding. This new pathway is independent of ghrelin-induced AMP-activated protein kinase activation, but modulates the levels of the transcription factors and orexigenic neuropeptides triggered by ghrelin to finally stimulate feeding. Our novel data implicate hypothalamic KOR signaling in the orexigenic action of ghrelin.
Department of Physiology, School of Medicine-CIMUS-Instituto de Investigaciones Sanitarias (IDIS), CIBER Fisiopatologia de la Obesidad y Nutricion (CIBERobn), San Francisco s/n, Santiago de Compostela (A Coruña), University of Santiago de Compostela, Santiago de Compostela, Spain.
Amparo
A
Romero-Picó
Maria J
MJ
Vázquez
David
D
González-Touceda
Cintia
C
Folgueira
Karolina P
KP
Skibicka
Mayte
M
Alvarez-Crespo
Margriet A
MA
Van Gestel
Douglas A
DA
Velásquez
Christoph
C
Schwarzer
Herbert
H
Herzog
Miguel
M
López
Roger A
RA
Adan
Suzanne L
SL
Dickson
Carlos
C
Diéguez
Rubén
R
Nogueiras
D054369:Agouti-Related Protein / Q000378:metabolism; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology*; D004347:Drug Interactions; D004435:Eating / Q000187:drug effects / Q000502:physiology*; D004745:Enkephalins / Q000378:metabolism; D020868:Gene Silencing; D054439:Ghrelin / Q000037:antagonists & inhibitors / Q000502:physiology*; D057967:Infusions, Intraventricular; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008845:Microinjections; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D009478:Neuropeptide Y / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D000068797:Orexins; D011498:Protein Precursors / Q000378:metabolism; D051381:Rats; D054440:Receptors, Ghrelin / Q000378:metabolism / Q000502:physiology; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012055:Reinforcement Schedule; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism / Q000502:physiology
D054369:Agouti-Related Protein; D004745:Enkephalins; D054439:Ghrelin; D047908:Intracellular Signaling Peptides and Proteins; D009292:Narcotic Antagonists; D009478:Neuropeptide Y; D009479:Neuropeptides; D000068797:Orexins; D011498:Protein Precursors; D054440:Receptors, Ghrelin; D017473:Receptors, Opioid, kappa; C033660:preproenkephalin