title: PKA phosphorylates and inactivates AMPKalpha to promote efficient lipolysis.
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 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.
authors: Institute of Cell Biology, ETH Zurich, Zurich, Switzerland.
authors: Nabil
authors: N
authors: Djouder
authors: Roland D
authors: RD
authors: Tuerk
authors: Marianne
authors: M
authors: Suter
authors: Paolo
authors: P
authors: Salvioni
authors: Ramon F
authors: RF
authors: Thali
authors: Roland
authors: R
authors: Scholz
authors: Kari
authors: K
authors: Vaahtomeri
authors: Yolanda
authors: Y
authors: Auchli
authors: Helene
authors: H
authors: Rechsteiner
authors: René A
authors: RA
authors: Brunisholz
authors: Benoit
authors: B
authors: Viollet
authors: Tomi P
authors: TP
authors: Mäkelä
authors: Theo
authors: T
authors: Wallimann
authors: Dietbert
authors: D
authors: Neumann
authors: Wilhelm
authors: W
authors: Krek
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017667:Adipocytes / Q000201:enzymology*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D005990:Glycerol / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008066:Lipolysis; D051379:Mice; D010766:Phosphorylation; D017354:Point Mutation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism
chemical_list: D000318:Adrenergic beta-Agonists; D005227:Fatty Acids; D021122:Protein Subunits; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D017868:Cyclic AMP-Dependent Protein Kinases; D055372:AMP-Activated Protein Kinases; D007545:Isoproterenol; D005990:Glycerol