PKA phosphorylates and inactivates AMPKα to promote efficient lipolysis |
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Authors: | Marianne Suter Paolo Salvioni Ramon F Thali Roland Scholz Kari Vaahtomeri Yolanda Auchli Helene Rechsteiner René A Brunisholz Benoit Viollet Tomi P Mäkelä Theo Wallimann Dietbert Neumann Wilhelm Krek |
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Affiliation: | 1. Institute of Cell Biology, ETH Zurich, Zurich, Switzerland;2. Institute of Biotechnology and Genome‐Scale Biology Program, University of Helsinki, Helsinki, Finland;3. Functional Genomics Center Zurich (FGCZ), University of Zurich, Zurich, Switzerland;4. Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France;5. INSERM, U567, Paris, France;6. Competence Center for Systems Physiology and Metabolic Diseases, ETH Zurich, Zurich, Switzerland |
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Abstract: | The mobilization of metabolic energy from adipocytes depends on a tightly regulated balance between hydrolysis and resynthesis of triacylglycerides (TAGs). Hydrolysis is stimulated by β‐adrenergic signalling to PKA that mediates phosphorylation of lipolytic enzymes, including hormone‐sensitive lipase (HSL). TAG resynthesis is associated with high‐energy consumption, which when inordinate, leads to increased AMPK activity that acts to restrain hydrolysis of TAGs by inhibiting PKA‐mediated activation of HSL. Here, we report that in primary mouse adipocytes, PKA associates with and phosphorylates AMPKα1 at Ser‐173 to impede threonine (Thr‐172) phosphorylation and thus activation of AMPKα1 by LKB1 in response to lipolytic signals. Activation of AMPKα1 by LKB1 is also blocked by PKA‐mediated phosphorylation of AMPKα1 in vitro. Functional analysis of an AMPKα1 species carrying a non‐phosphorylatable mutation at Ser‐173 revealed a critical function of this phosphorylation for efficient release of free fatty acids and glycerol in response to PKA‐activating signals. These results suggest a new mechanism of negative regulation of AMPK activity by PKA that is important for converting a lipolytic signal into an effective lipolytic response. |
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Keywords: | adipocytes AMPK β ‐adrenergic lipolysis PKA |
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