Metformin inhibits adenosine 5'-monophosphate-activated kinase activation and prevents increases in neuropeptide Y expression in cultured hypothalamic neurons

Details

Serval ID
serval:BIB_2249C6A6C51C
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Metformin inhibits adenosine 5'-monophosphate-activated kinase activation and prevents increases in neuropeptide Y expression in cultured hypothalamic neurons
Journal
Endocrinology
Author(s)
Chau-Van  C., Gamba  M., Salvi  R., Gaillard  R. C., Pralong  F. P.
ISSN
0013-7227 (Print)
Publication state
Published
Issued date
02/2007
Volume
148
Number
2
Pages
507-11
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Feb
Abstract
The oral antidiabetic agent metformin acts at least partially via an activation of AMP-activated kinase (AMPK) in liver and muscle cells. It has appeared recently that hypothalamic AMPK is a key regulator of feeding in mammals. Because metformin also exhibits anorectic effects in animal models as well as in humans, we hypothesized that AMPK may be a target of metformin in hypothalamic neurons. In this study, we show that, in primary cultures of rat hypothalamic neurons, low glucose levels stimulate the phosphorylation of AMPK, thus increasing neuropeptide Y (NPY) gene expression. The addition of metformin in low glucose conditions was found to block AMPK phosphorylation. Consistently, the stimulation of NPY observed in low glucose conditions was also inhibited by the drug. Proopiomelanocortin gene expression measured in parallel was inhibited under low glucose conditions, but in contrast to NPY, it was not dependent upon AMPK and not affected by metformin. Taken together, our data demonstrate that metformin can inhibit AMPK activity in hypothalamic neurons, thus modulating the expression of the orexigenic peptide NPY. These results provide, for the first time, a potential mechanism of action for the anorectic effects of metformin, a widely used drug that could represent a valuable adjunct to novel therapies aimed at modulating central feeding pathways.
Keywords
Animals Cells, Cultured Dose-Response Relationship, Drug Enzyme Activation/drug effects Gene Expression/drug effects Glucose/administration & dosage/pharmacology Hypoglycemic Agents/*pharmacology Hypothalamus/cytology/drug effects/*metabolism Metformin/*pharmacology Multienzyme Complexes/*antagonists & inhibitors/metabolism Neurons/drug effects/*metabolism Neuropeptide Y/*antagonists & inhibitors/genetics/metabolism Osmolar Concentration Phosphorylation/drug effects Pro-Opiomelanocortin/antagonists & inhibitors/genetics/metabolism Protein-Serine-Threonine Kinases/*antagonists & inhibitors/metabolism Rats
Pubmed
Web of science
Open Access
Yes
Create date
25/01/2008 16:26
Last modification date
20/08/2019 12:59
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