Journal article
Blocking AMPK β1 myristoylation enhances AMPK activity and protects mice from high-fat diet-induced obesity and hepatic steatosis
K Neopane, N Kozlov, F Negoita, L Murray-Segal, R Brink, A Hoque, AJ Ovens, G Tjin, LM McAloon, D Yu, NXY Ling, MJ Sanders, JS Oakhill, JW Scott, GR Steinberg, K Loh, BE Kemp, K Sakamoto, S Galic
Cell Reports | CELL PRESS | Published : 2022
Open access
Abstract
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 ac..
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Awarded by State Government of Victoria
Funding Acknowledgements
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 uncondi-tional donation from the Novo Nordisk Foundation (NNF18CC0034900) . We acknowledge the Core Facility for Integrated Microscopy, Faculty of Health and Medical Sciences, University of Copenhagen.