GDF15 activates AMPK and inhibits gluconeogenesis and fibrosis in the liver by attenuating the TGF-β1/SMAD3 pathway.
Details
Serval ID
serval:BIB_5FAD6B60FEA6
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
GDF15 activates AMPK and inhibits gluconeogenesis and fibrosis in the liver by attenuating the TGF-β1/SMAD3 pathway.
Journal
Metabolism
ISSN
1532-8600 (Electronic)
ISSN-L
0026-0495
Publication state
Published
Issued date
03/2024
Peer-reviewed
Oui
Volume
152
Pages
155772
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Publication Status: ppublish
Abstract
The levels of the cellular energy sensor AMP-activated protein kinase (AMPK) have been reported to be decreased via unknown mechanisms in the liver of mice deficient in growth differentiation factor 15 (GDF15). This stress response cytokine regulates energy metabolism mainly by reducing food intake through its hindbrain receptor GFRAL.
To examine how GDF15 regulates AMPK.
Wild-type and Gdf15 <sup>-/-</sup> mice, mouse primary hepatocytes and the human hepatic cell line Huh-7 were used.
Gdf15 <sup>-/-</sup> mice showed glucose intolerance, reduced hepatic phosphorylated AMPK levels, increased levels of phosphorylated mothers against decapentaplegic homolog 3 (SMAD3; a mediator of the fibrotic response), elevated serum levels of transforming growth factor (TGF)-β1, as well as upregulated gluconeogenesis and fibrosis. In line with these observations, recombinant (r)GDF15 promoted AMPK activation and reduced the levels of phosphorylated SMAD3 and the markers of gluconeogenesis and fibrosis in the liver of mice and in mouse primary hepatocytes, suggesting that these effects may be independent of GFRAL. Pharmacological inhibition of SMAD3 phosphorylation in Gdf15 <sup>-/-</sup> mice prevented glucose intolerance, the deactivation of AMPK and the increase in the levels of proteins involved in gluconeogenesis and fibrosis, suggesting that overactivation of the TGF-β1/SMAD3 pathway is responsible for the metabolic alterations in Gdf15 <sup>-/-</sup> mice.
Overall, these findings indicate that GDF15 activates AMPK and inhibits gluconeogenesis and fibrosis by lowering the activity of the TGF-β1/SMAD3 pathway.
To examine how GDF15 regulates AMPK.
Wild-type and Gdf15 <sup>-/-</sup> mice, mouse primary hepatocytes and the human hepatic cell line Huh-7 were used.
Gdf15 <sup>-/-</sup> mice showed glucose intolerance, reduced hepatic phosphorylated AMPK levels, increased levels of phosphorylated mothers against decapentaplegic homolog 3 (SMAD3; a mediator of the fibrotic response), elevated serum levels of transforming growth factor (TGF)-β1, as well as upregulated gluconeogenesis and fibrosis. In line with these observations, recombinant (r)GDF15 promoted AMPK activation and reduced the levels of phosphorylated SMAD3 and the markers of gluconeogenesis and fibrosis in the liver of mice and in mouse primary hepatocytes, suggesting that these effects may be independent of GFRAL. Pharmacological inhibition of SMAD3 phosphorylation in Gdf15 <sup>-/-</sup> mice prevented glucose intolerance, the deactivation of AMPK and the increase in the levels of proteins involved in gluconeogenesis and fibrosis, suggesting that overactivation of the TGF-β1/SMAD3 pathway is responsible for the metabolic alterations in Gdf15 <sup>-/-</sup> mice.
Overall, these findings indicate that GDF15 activates AMPK and inhibits gluconeogenesis and fibrosis by lowering the activity of the TGF-β1/SMAD3 pathway.
Keywords
Humans, AMP-Activated Protein Kinases/metabolism, Fibrosis, Gluconeogenesis, Glucose Intolerance/metabolism, Growth Differentiation Factor 15/genetics, Liver/metabolism, Signal Transduction, Smad3 Protein, Transforming Growth Factor beta1/metabolism, AMPK, GDF15, SMAD3, TGF-β
Pubmed
Web of science
Open Access
Yes
Create date
10/01/2024 13:43
Last modification date
02/03/2024 7:10