PKA phosphorylates and inactivates AMPKalpha to promote efficient lipolysis

The mobilization of metabolic energy from adipocytes depends on a tightly regulated balance between hydrolysis and resynthesis of triacylglycerides (TAGs). Hydrolysis is stimulated by beta-adrenergic signalling to PKA that mediates phosphorylation of lipolytic enzymes, including hormone-sensitive li...

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Bibliographic Details
Published in:The EMBO journal 2010-01, Vol.29 (2), p.469-481
Main Authors: Djouder, Nabil, Tuerk, Roland D, Suter, Marianne, Salvioni, Paolo, Thali, Ramon F, Scholz, Roland, Vaahtomeri, Kari, Auchli, Yolanda, Rechsteiner, Helene, Brunisholz, René A, Viollet, Benoit, Mäkelä, Tomi P, Wallimann, Theo, Neumann, Dietbert, Krek, Wilhelm
Format: Article
Language:English
Subjects:
Adipocytes - enzymology
Adrenergic beta-Agonists - pharmacology
AMP-Activated Protein Kinases - genetics
AMP-Activated Protein Kinases - metabolism
Animals
Cells, Cultured
Cyclic AMP-Dependent Protein Kinases - metabolism
Fatty Acids - metabolism
Glycerol - metabolism
Isoproterenol - pharmacology
Lipolysis
Mice
Phosphorylation
Point Mutation
Protein Subunits - genetics
Protein Subunits - metabolism
Protein-Serine-Threonine Kinases - metabolism
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Summary:The mobilization of metabolic energy from adipocytes depends on a tightly regulated balance between hydrolysis and resynthesis of triacylglycerides (TAGs). Hydrolysis is stimulated by beta-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 AMPKalpha1 at Ser-173 to impede threonine (Thr-172) phosphorylation and thus activation of AMPKalpha1 by LKB1 in response to lipolytic signals. Activation of AMPKalpha1 by LKB1 is also blocked by PKA-mediated phosphorylation of AMPKalpha1 in vitro. Functional analysis of an AMPKalpha1 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.
ISSN:1460-2075
DOI:10.1038/emboj.2009.339