CDK4 Phosphorylates AMPKα2 to Inhibit Its Activity and Repress Fatty Acid Oxidation

Isabel C Lopez-Mejia; Sylviane Lagarrigue; Albert Giralt; Laia Martinez-Carreres; Nadège Zanou; Pierre-Damien Denechaud; Judit Castillo-Armengol; Carine Chavey; Meritxell Orpinell; Brigitte Delacuisine; Anita Nasrallah; Caterina Collodet; Lianjun Zhang; Benoît Viollet; D Grahame Hardie; Lluis Fajas

doi:10.1016/j.molcel.2017.09.034

CDK4 Phosphorylates AMPKα2 to Inhibit Its Activity and Repress Fatty Acid Oxidation

Mol Cell. 2017 Oct 19;68(2):336-349.e6. doi: 10.1016/j.molcel.2017.09.034.

Authors

Isabel C Lopez-Mejia¹, Sylviane Lagarrigue², Albert Giralt³, Laia Martinez-Carreres³, Nadège Zanou⁴, Pierre-Damien Denechaud¹, Judit Castillo-Armengol³, Carine Chavey⁵, Meritxell Orpinell², Brigitte Delacuisine¹, Anita Nasrallah³, Caterina Collodet⁶, Lianjun Zhang⁷, Benoît Viollet⁸, D Grahame Hardie⁹, Lluis Fajas¹⁰

Affiliations

¹ Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland; Department of Physiology, University of Lausanne, 1005 Lausanne, Switzerland.
² Department of Physiology, University of Lausanne, 1005 Lausanne, Switzerland.
³ Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.
⁴ Department of Physiology, University of Lausanne, 1005 Lausanne, Switzerland; Institute of Sport Sciences, University of Lausanne, 1015 Lausanne, Switzerland.
⁵ IGMM, Université de Montpellier, UMR 5535 CNRS, 34293 Montpellier, France.
⁶ Nestlé Institute of Health Sciences SA, EPFL Innovation Park, 1015 Lausanne, Switzerland; École Polytechnique Fédérale de Lausanne, School of Life Sciences, 1015 Lausanne, Switzerland.
⁷ Ludwig Center for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland.
⁸ Institut Cochin, INSERM U1016, Paris, France; CNRS, UMR 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
⁹ School of Life Sciences, University of Dundee, Dundee, Scotland, UK.
¹⁰ Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland; Department of Physiology, University of Lausanne, 1005 Lausanne, Switzerland. Electronic address: [email protected].

PMID: 29053957
DOI: 10.1016/j.molcel.2017.09.034

Abstract

The roles of CDK4 in the cell cycle have been extensively studied, but less is known about the mechanisms underlying the metabolic regulation by CDK4. Here, we report that CDK4 promotes anaerobic glycolysis and represses fatty acid oxidation in mouse embryonic fibroblasts (MEFs) by targeting the AMP-activated protein kinase (AMPK). We also show that fatty acid oxidation (FAO) is specifically induced by AMPK complexes containing the α2 subunit. Moreover, we report that CDK4 represses FAO through direct phosphorylation and inhibition of AMPKα2. The expression of non-phosphorylatable AMPKα2 mutants, or the use of a CDK4 inhibitor, increased FAO rates in MEFs and myotubes. In addition, Cdk4^-/- mice have increased oxidative metabolism and exercise capacity. Inhibition of CDK4 mimicked these alterations in normal mice, but not when skeletal muscle was AMPK deficient. This novel mechanism explains how CDK4 promotes anabolism by blocking catabolic processes (FAO) that are activated by AMPK.

Keywords: AMPK; CDK4; FAO; metabolism; mitochondria.

MeSH terms

AMP-Activated Protein Kinases / genetics
AMP-Activated Protein Kinases / metabolism*
Animals
Cyclin-Dependent Kinase 4 / genetics
Cyclin-Dependent Kinase 4 / metabolism*
Embryo, Mammalian / metabolism
Fatty Acids / genetics
Fatty Acids / metabolism*
Fibroblasts / metabolism
Mice
Mice, Knockout
Muscle, Skeletal / metabolism*
Mutation
Oxidation-Reduction
Physical Conditioning, Animal*

Substances

Fatty Acids
AMPK alpha2 subunit, mouse
Cdk4 protein, mouse
Cyclin-Dependent Kinase 4
AMP-Activated Protein Kinases

Grants and funding

204766/Z/16/Z/WT_/Wellcome Trust/United Kingdom