title: Intracerebroventricular administration of metformin inhibits ghrelin-induced Hypothalamic AMP-kinase signalling and food intake.
abstract: OBJECTIVE
  The antihyperglycaemic drug metformin reduces food consumption through mechanisms that are not fully elucidated. The present study investigated the effects of intracerebroventricular administration of metformin on food intake and hypothalamic appetite-regulating signalling pathways induced by the orexigenic peptide ghrelin.
  
  
  METHODS
  Rats were injected intracerebroventricularly with ghrelin (5 µg), metformin (50, 100 or 200 µg), 5-amino-imidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR, 25 µg) and L-leucine (1 µg) in different combinations. Food intake was monitored during the next 4 h. Hypothalamic activation of AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC), regulatory-associated protein of mTOR (Raptor), mammalian target of rapamycin (mTOR) and p70 S6 kinase 1 (S6K) after 1 h of treatment was analysed by immunoblotting.
  
  
  RESULTS
  Metformin suppressed the increase in food consumption induced by intracerebroventricular ghrelin in a dose-dependent manner. Ghrelin increased phosphorylation of hypothalamic AMPK and its targets ACC and Raptor, which was associated with the reduced phosphorylation of mTOR. The mTOR substrate, S6K, was activated by intracerebroventricular ghrelin despite the inhibition of mTOR. Metformin treatment blocked ghrelin-induced activation of hypothalamic AMPK/ACC/Raptor and restored mTOR activity without affecting S6K phosphorylation. Metformin also reduced food consumption induced by the AMPK activator AICAR while the ghrelin-triggered food intake was inhibited by the mTOR activator L-leucine.
  
  
  CONCLUSIONS
  Metformin could reduce food intake by preventing ghrelin-induced AMPK signalling and mTOR inhibition in the hypotalamus.
authors.affiliation: Institute of Medical Physiology, University of Belgrade, Belgrade, Serbia.
authors.forename: Darko
authors.initials: D
authors.lastname: Stevanovic
authors.forename: Kristina
authors.initials: K
authors.lastname: Janjetovic
authors.forename: Maja
authors.initials: M
authors.lastname: Misirkic
authors.forename: Ljubica
authors.initials: L
authors.lastname: Vucicevic
authors.forename: Mirjana
authors.initials: M
authors.lastname: Sumarac-Dumanovic
authors.forename: Dragan
authors.initials: D
authors.lastname: Micic
authors.forename: Vesna
authors.initials: V
authors.lastname: Starcevic
authors.forename: Vladimir
authors.initials: V
authors.lastname: Trajkovic
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000263:Adenylate Kinase / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D004435:Eating / Q000187:drug effects*; D054439:Ghrelin / Q000633:toxicity; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012265:Ribonucleotides / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D054439:Ghrelin; D007004:Hypoglycemic Agents; D012265:Ribonucleotides; C032566:imidazole-4-carboxamide; D000620:Aminoimidazole Carboxamide; D008687:Metformin; D000263:Adenylate Kinase; D000103:Acetyl-CoA Carboxylase; C031143:AICA ribonucleotide