Blocking AMPK β1 myristoylation enhances AMPK activity and protects mice from high-fat diet-induced obesity and hepatic steatosis
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Dokumenter
- Fulltext
Forlagets udgivne version, 5,22 MB, PDF-dokument
AMP-activated protein kinase (AMPK) is a master regulator of cellular energy homeostasis and a therapeutic target for metabolic diseases. Co/post-translational N-myristoylation of glycine-2 (Gly2) of the AMPK β subunit has been suggested to regulate the distribution of the kinase between the cytosol and membranes through a “myristoyl switch” mechanism. However, the relevance of AMPK myristoylation for metabolic signaling in cells and in vivo is unclear. Here, we generated knockin mice with a Gly2-to-alanine point mutation of AMPKβ1 (β1-G2A). We demonstrate that non-myristoylated AMPKβ1 has reduced stability but is associated with increased kinase activity and phosphorylation of the Thr172 activation site in the AMPK α subunit. Using proximity ligation assays, we show that loss of β1 myristoylation impedes colocalization of the phosphatase PPM1A/B with AMPK in cells. Mice carrying the β1-G2A mutation have improved metabolic health with reduced adiposity, hepatic lipid accumulation, and insulin resistance under conditions of high-fat diet-induced obesity.
Originalsprog | Engelsk |
---|---|
Artikelnummer | 111862 |
Tidsskrift | Cell Reports |
Vol/bind | 41 |
Udgave nummer | 12 |
Antal sider | 26 |
ISSN | 2211-1247 |
DOI | |
Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
This work was supported by grants from the Australian Research Council ( DP170101196 ), the National Health and Medical Research Council of Australia ( 1085460 to B.E.K., S.G., and G.R.S.; 1145836 to S.G., K.L., G.R.S., and B.E.K.; and 1145265 to J.S.O. and B.E.K.) and supported in part by the Victorian Government Operational Infrastructure Support Scheme. G.R.S. is supported by a Tier 1 Canada Research Chair and a J. Bruce Duncan Endowed Chair in Metabolic Diseases. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent research center based at the University of Copenhagen , Denmark, and partially funded by an unconditional donation from the Novo Nordisk Foundation ( NNF18CC0034900 ). We acknowledge the Core Facility for Integrated Microscopy, Faculty of Health and Medical Sciences, University of Copenhagen.
Publisher Copyright:
© 2022 The Author(s)
Antal downloads er baseret på statistik fra Google Scholar og www.ku.dk
ID: 331255154