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 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.
Djouder
Nabil
N
Institute of Cell Biology, ETH Zurich, Zurich, Switzerland.
Tuerk
Roland D
RD
Suter
Marianne
M
Salvioni
Paolo
P
Thali
Ramon F
RF
Scholz
Roland
R
Vaahtomeri
Kari
K
Auchli
Yolanda
Y
Rechsteiner
Helene
H
Brunisholz
René A
RA
Viollet
Benoit
B
Mäkelä
Tomi P
TP
Wallimann
Theo
T
Neumann
Dietbert
D
Krek
Wilhelm
W
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
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