title: Ghrelin and cannabinoids require the ghrelin receptor to affect cellular energy metabolism.
abstract: BACKGROUND
  Ghrelin is a potent orexigenic brain-gut peptide with lipogenic and diabetogenic effects, possibly mediated by growth hormone secretagogue receptor (GHS-R1a). Cannabinoids also have orexigenic and lipogenic effects. AMPK is a regulator of energy homeostasis and we have previously shown that ghrelin and cannabinoids stimulate hypothalamic AMPK activity while inhibiting it in the liver and adipose tissue, suggesting that AMPK mediates both the central appetite-inducing and peripheral effects of ghrelin and cannabinoids.
  
  
  OBJECTIVE
  Using GHS-R KO mice, we investigated whether the known ghrelin receptor GHS-R1a is required for the tissue-specific effects of ghrelin on AMPK activity, and if an intact ghrelin signalling pathway is necessary for the effects of cannabinoids on AMPK activity.
  
  
  METHODS
  Wild-type and GHS-R KO mice were treated intraperitoneally with ghrelin 500 ng/g bodyweight or CB1 agonist HU210 20 ng/g and hypothalamic, hepatic and adipose AMPK activity was studied using a functional kinase assay.
  
  
  RESULTS
  Ghrelin and HU210 significantly stimulated hypothalamic AMPK activity in wild-type animals (mean±SEM, 122.5±5.2% and 128±11.6% of control, p<0.05) and inhibited it in liver (55.1±4.8% and 62.2±14.5%, p<0.01) and visceral fat (mesenteric fat (MF): 54.6±16% and 52.0±9.3%, p<0.05; epididymal fat (EF): 47.9±12.1% and 45.6±1.7%, p<0.05). The effects of ghrelin, and interestingly also HU210, on hypothalamic, visceral fat and liver AMPK activity were abolished in the GHS-R KO mice (hypothalamus: 107.9±7.7% and 87.4±13.3%, liver: 100.5±11.6% and 116.7±5.4%, MF: 132.1±29.9% and 107.1±32.7%, EF: 89.8±7.3% and 91.7±18.3%, p>0.05).
  
  
  CONCLUSIONS
  Ghrelin requires GHS-R1a for its effect on hypothalamic, liver and adipose tissue AMPK activity. An intact ghrelin signalling pathway is necessary for the effects of cannabinoids on AMPK activity.
authors.affiliation: Centre for Endocrinology, William Harvey Research Institute, Barts and the London, London EC1M 6BQ, UK.
authors.forename: Chung Thong
authors.initials: CT
authors.lastname: Lim
authors.forename: Blerina
authors.initials: B
authors.lastname: Kola
authors.forename: Daniel
authors.initials: D
authors.lastname: Feltrin
authors.forename: Diego
authors.initials: D
authors.lastname: Perez-Tilve
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Tschöp
authors.forename: Ashley B
authors.initials: AB
authors.lastname: Grossman
authors.forename: Márta
authors.initials: M
authors.lastname: Korbonits
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000494:pharmacology; D002149:Energy Intake; D004734:Energy Metabolism; D015870:Gene Expression; D054439:Ghrelin / Q000494:pharmacology / Q000502:physiology*; D007031:Hypothalamus / Q000187:drug effects / Q000201:enzymology; D050152:Intra-Abdominal Fat / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism; D054440:Receptors, Ghrelin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D050151:Subcutaneous Fat / Q000187:drug effects / Q000201:enzymology
chemical_list: D063386:Cannabinoid Receptor Agonists; D054439:Ghrelin; D043884:Receptor, Cannabinoid, CB1; D054440:Receptors, Ghrelin; D013759:Dronabinol; D000263:Adenylate Kinase; C062018:HU 211