Mutation of the RIIbeta subunit of protein kinase A differentially affects lipolysis but not gene induction in white adipose tissue.
Targeted disruption of the RIIbeta subunit of protein kinase A (PKA) produces lean mice that resist diet-induced obesity. In this report we examine the effects of the RIIbeta knockout on white adipose tissue physiology. Loss of RIIbeta is compensated by an increase in the RIalpha isoform, generating an isoform switch from a type II to a type I PKA. Type I holoenzyme binds cAMP more avidly and is more easily activated than the type II enzyme. These alterations are associated with increases in both basal kinase activity and the basal rate of lipolysis, possibly contributing to the lean phenotype. However, the ability of both beta(3)-selective and nonspecific beta-adrenergic agonists to stimulate lipolysis is markedly compromised in mutant white adipose tissue. This defect was found in vitro and in vivo and does not result from reduced expression of beta-adrenergic receptor or hormone-sensitive lipase genes. In contrast, beta-adrenergic stimulated gene transcription remains intact, and the expression of key genes involved in lipid metabolism is normal under both fasted and fed conditions. We suggest that the R subunit isoform switch disrupts the subcellular localization of PKA that is required for efficient transduction of signals that modulate lipolysis but not for those that mediate gene expression.
Planas
J V
JV
Department of Pharmacology, University of Washington School of Medicine, Seattle, Washington 98195-7750, USA.
Cummings
D E
DE
Idzerda
R L
RL
McKnight
G S
GS
D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D054757:Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics* / Q000378:metabolism*; D008066:Lipolysis / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009765:Obesity / Q000235:genetics* / Q000378:metabolism*
D054757:Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit; C517838:Prkar2b protein, mouse; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases