PMID- 22343549
OWN - NLM
STAT- MEDLINE
DCOM- 20121221
LR  - 20131121
IS  - 1423-0194 (Electronic)
IS  - 0028-3835 (Linking)
VI  - 96
IP  - 1
DP  - 2012
TI  - Intracerebroventricular administration of metformin inhibits ghrelin-induced 
      Hypothalamic AMP-kinase signalling and food intake.
PG  - 24-31
LID - 10.1159/000333963 [doi]
AB  - BACKGROUND/AIMS: 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 microg), metformin (50, 100 or 200 microg), 
      5-amino-imidazole-4-carboxamide 1-beta-D-ribofuranoside (AICAR, 25 microg) and L-leucine 
      (1 microg) 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. CONCLUSION: Metformin could reduce food intake by preventing 
      ghrelin-induced AMPK signalling and mTOR inhibition in the hypotalamus.
CI  - Copyright (c) 2012 S. Karger AG, Basel.
FAU - Stevanovic, Darko
AU  - Stevanovic D
AD  - Institute of Medical Physiology, University of Belgrade, Belgrade, Serbia.
FAU - Janjetovic, Kristina
AU  - Janjetovic K
FAU - Misirkic, Maja
AU  - Misirkic M
FAU - Vucicevic, Ljubica
AU  - Vucicevic L
FAU - Sumarac-Dumanovic, Mirjana
AU  - Sumarac-Dumanovic M
FAU - Micic, Dragan
AU  - Micic D
FAU - Starcevic, Vesna
AU  - Starcevic V
FAU - Trajkovic, Vladimir
AU  - Trajkovic V
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120214
PL  - Switzerland
TA  - Neuroendocrinology
JT  - Neuroendocrinology
JID - 0035665
RN  - 0 (Ghrelin)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Ribonucleotides)
RN  - 26832-08-6 (imidazole-4-carboxamide)
RN  - 360-97-4 (Aminoimidazole Carboxamide)
RN  - 9100L32L2N (Metformin)
RN  - EC 2.7.4.3 (Adenylate Kinase)
RN  - EC 6.4.1.2 (Acetyl-CoA Carboxylase)
RN  - F0X88YW0YK (AICA ribonucleotide)
SB  - IM
MH  - Acetyl-CoA Carboxylase/metabolism
MH  - Adenylate Kinase/metabolism
MH  - Aminoimidazole Carboxamide/analogs & derivatives/metabolism
MH  - Animals
MH  - Eating/*drug effects
MH  - Ghrelin/toxicity
MH  - Hypoglycemic Agents/*pharmacology
MH  - Hypothalamus/*drug effects/metabolism
MH  - Male
MH  - Metformin/*pharmacology
MH  - Rats
MH  - Rats, Wistar
MH  - Ribonucleotides/metabolism
MH  - Signal Transduction/*drug effects
EDAT- 2012/02/22 06:00
MHDA- 2012/12/22 06:00
CRDT- 2012/02/21 06:00
PHST- 2011/04/19 00:00 [received]
PHST- 2011/09/26 00:00 [accepted]
PHST- 2012/02/21 06:00 [entrez]
PHST- 2012/02/22 06:00 [pubmed]
PHST- 2012/12/22 06:00 [medline]
AID - 000333963 [pii]
AID - 10.1159/000333963 [doi]
PST - ppublish
SO  - Neuroendocrinology. 2012;96(1):24-31. doi: 10.1159/000333963. Epub 2012 Feb 14.