Blocking AMPK β1 myristoylation enhances AMPK activity and protects mice from high-fat diet-induced obesity and hepatic steatosis.

Autor:	Neopane K; Nestlé Institute of Health Sciences, Nestlé Research, Société des Produits Nestlé S.A., 1015 Lausanne, Switzerland; School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne 1015, Switzerland., Kozlov N; Protein Chemistry and Metabolism, St. Vincent's Institute of Medical Research, Melbourne, VIC 3065, Australia., Negoita F; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen 2200, Denmark., Murray-Segal L; Protein Chemistry and Metabolism, St. Vincent's Institute of Medical Research, Melbourne, VIC 3065, Australia., Brink R; Garvan Institute of Medical Research and St. Vincent's Clinical School, University of New South Wales, Sydney, Darlinghurst, NSW 2010, Australia., Hoque A; Metabolic Signalling, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia., Ovens AJ; Metabolic Signalling, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia., Tjin G; Stem Cell Regulation, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia; Department of Medicine, University of Melbourne, Parkville, VIC 3010, Australia., McAloon LM; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC 3052, Australia., Yu D; Protein Chemistry and Metabolism, St. Vincent's Institute of Medical Research, Melbourne, VIC 3065, Australia., Ling NXY; Metabolic Signalling, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia., Sanders MJ; Nestlé Institute of Health Sciences, Nestlé Research, Société des Produits Nestlé S.A., 1015 Lausanne, Switzerland., Oakhill JS; Metabolic Signalling, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia; Department of Medicine, University of Melbourne, Parkville, VIC 3010, Australia., Scott JW; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC 3052, Australia; The Florey Institute of Neuroscience and Mental Health, Parkville, Melbourne, VIC 3052, Australia., Steinberg GR; Centre for Metabolism, Obesity, and Diabetes Research, Departments of Medicine and Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada., Loh K; Department of Medicine, University of Melbourne, Parkville, VIC 3010, Australia; Diabetes and Metabolic Disease, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia., Kemp BE; Protein Chemistry and Metabolism, St. Vincent's Institute of Medical Research, Melbourne, VIC 3065, Australia; Department of Medicine, University of Melbourne, Parkville, VIC 3010, Australia; Mary McKillop Institute for Health Research, Australian Catholic University, Melbourne 3000, VIC, Australia., Sakamoto K; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen 2200, Denmark. Electronic address: kei.sakamoto@sund.ku.dk., Galic S; Protein Chemistry and Metabolism, St. Vincent's Institute of Medical Research, Melbourne, VIC 3065, Australia; Department of Medicine, University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: sgalic@svi.edu.au.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2022 Dec 20; Vol. 41 (12), pp. 111862.
DOI:	10.1016/j.celrep.2022.111862
Abstrakt:	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. Competing Interests: Declaration of interests K.N. and M.J.S. are employees of Société des Produits Nestlé (Switzerland). G.R.S. has received consulting/speaking fees from Astra Zeneca, Boehringer-Ingelheim, Cambrian BioPharma, EchoR1, Eli-Lilly, Esperion, Fibrocor Therapeutics, Merck, Novo Nordisk, Pfizer, and Poxel Pharmaceuticals; receives research funding from Esperion Therapeutics, Espervita Therapeutics, Nestle, Novo Nordisk, and Poxel Pharmaceuticals; and is co-founder and shareholder of Espervita Therapeutics. (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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