title: Role of the AMP-activated protein kinase (AMPK) signaling pathway in the orexigenic effects of endogenous ghrelin.
abstract: Ghrelin, released from the stomach, stimulates food intake through activation of the ghrelin receptor (GHS-R) located on neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons in the hypothalamus. A role for the energy sensor AMP-activated protein kinase (AMPK) and its downstream effector uncoupling protein 2 (UCP2) in the stimulatory effect of exogenous ghrelin on NPY/AgRP expression and food intake has been suggested. This study aimed to investigate whether a rise in endogenous ghrelin levels is able to influence hypothalamic AMPK activity, pACC, UCP2 and NPY/AgRP expression through activation of GHS-R. An increase in endogenous ghrelin levels was established by fasting (24h) or by induction of streptozotocin(STZ)-diabetes (15 days) in GHS-R(+/+) and GHS-R(-/-) mice. GHS-R(+/+) mice showed a significant increase in AgRP and NPY mRNA expression after fasting, which was not observed in GHS-R(-/-) mice. Fasting did not affect AMPK activity nor ACC phosphorylation in both genotypes and increased UCP2 mRNA expression. The hyperghrelinemia associated with STZ-induced diabetes was accompanied by an increased NPY and AgRP expression in GHS-R(+/+) but not in GHS-R(-/-) mice. AMPK activity and UCP2 expression in GHS-R(+/+) mice after induction of diabetes were decreased to a similar extent in both genotypes. Exogenous ghrelin administration tended to decrease hypothalamic AMPK activity. In conclusion, an increase in endogenous ghrelin levels triggered by fasting or STZ-induced diabetes stimulates the expression of AgRP and NPY via interaction with the GHS-R. The changes in AMPK activity, pACC and UCP2 occur independently from GHS-R suggesting that they do not play a major role in the orexigenic effect of endogenous ghrelin.
authors.affiliation: Translational Research Center for Gastrointestinal Disorders, Catholic University of Leuven, Belgium.
authors.forename: P J
authors.initials: PJ
authors.lastname: Verhulst
authors.forename: S
authors.initials: S
authors.lastname: Janssen
authors.forename: J
authors.initials: J
authors.lastname: Tack
authors.forename: I
authors.initials: I
authors.lastname: Depoortere
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism; D000263:Adenylate Kinase / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D001066:Appetite; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000378:metabolism; D004435:Eating; D005215:Fasting; D055786:Gene Knockout Techniques; D054439:Ghrelin / Q000097:blood / Q000494:pharmacology / Q000502:physiology*; D007031:Hypothalamus / Q000201:enzymology / Q000378:metabolism; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D054440:Receptors, Ghrelin / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D000071246:Uncoupling Protein 2
chemical_list: D054439:Ghrelin; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009478:Neuropeptide Y; D054440:Receptors, Ghrelin; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D000217:Acyltransferases; C526983:Mboat4 protein, mouse; D000263:Adenylate Kinase; D000103:Acetyl-CoA Carboxylase