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J Biol Chem, Vol. 274, Issue 51, 36281-36287, December 17, 1999
From the Department of Pharmacology, University of Washington
School of Medicine, Seattle, Washington 98195-7750
Targeted disruption of the RII
Mutation of the RII
Subunit of Protein Kinase A Differentially
Affects Lipolysis but Not Gene Induction in White Adipose Tissue*
§,
subunit of
protein kinase A (PKA) produces lean mice that resist diet-induced
obesity. In this report we examine the effects of the RII knockout
on white adipose tissue physiology. Loss of RII is compensated by an
increase in the RI
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 3-selective and
nonspecific -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 -adrenergic receptor or hormone-sensitive
lipase genes. In contrast, -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.
*
This work was supported in part by National Institutes of
Health Grant GM82375 (to G. S. M.) and by a grant from Pfizer Inc.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Current address: Departament de Fisiologia, Facultat de Biologia,
Universitat de Barcelona, Avenue Diagonal 645, 08028 Barcelona, Spain.
§
Both authors contributed equally to this work.
¶
Supported by National Institutes of Health Grant DK01964.
To whom correspondence should be addressed: Dept. of
Pharmacology, University of Washington, Box 357750, Seattle, WA
98195-7750. Tel.: 206-616-4237; Fax: 206-616-4230; E-mail:
mcknight@u.washington.edu.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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