Genetically lean mice result from targeted disruption of the RII beta subunit of protein kinase A.
Cyclic AMP is an important second messenger in the coordinated regulation of cellular metabolism. Its effects are mediated by cAMP-dependent protein kinase (PKA), which is assembled from two regulatory (R) and two catalytic (C) subunits. In mice there are four R genes (encoding RI alpha, RI beta, RII alpha, and RII beta) and two C gene (encoding C alpha and C beta), expressed in tissue-specific patterns. The RII beta isoform is abundant in brown and white adipose tissue and brain, with limited expression elsewhere. To elucidate its functions, we generated RII beta knockout mice. Here we report that mutants appear healthy but have markedly diminished white adipose tissue despite normal food intake. They are protected against developing diet-induced obesity and fatty livers. Mutant brown adipose tissue exhibits a compensatory increase in RI alpha, which almost entirely replaces lost RII beta, generating an isoform switch. The holoenzyme from mutant adipose tissue binds cAMP more avidly and is more easily activated than wild-type enzyme. This causes induction of uncoupling protein and elevations of metabolic rate and body temperature, contributing to the lean phenotype. Our results demonstrate a role for the RII beta holoenzyme in regulating energy balance and adiposity.
Cummings
D E
DE
Department of Pharmacology, University of Washington School of Medicine, Seattle, 98195-7750, USA.
Brandon
E P
EP
Planas
J V
JV
Motamed
K
K
Idzerda
R L
RL
McKnight
G S
GS
D000273:Adipose Tissue / Q000201:enzymology; D002001:Adipose Tissue, Brown / Q000201:enzymology; D000818:Animals; D001835:Body Weight / Q000502:physiology; D002352:Carrier Proteins; D000242:Cyclic AMP / Q000378:metabolism; D054757:Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit; D017868:Cyclic AMP-Dependent Protein Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D004041:Dietary Fats / Q000494:pharmacology; D004435:Eating; D004734:Energy Metabolism; D005260:Female; D007473:Ion Channels; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D020738:Leptin; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D013851:Thinness / Q000201:enzymology* / Q000235:genetics; D014280:Triglycerides / Q000378:metabolism; D000071256:Uncoupling Protein 1
D002352:Carrier Proteins; D054757:Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit; D004041:Dietary Fats; D007473:Ion Channels; D007527:Isoenzymes; D020738:Leptin; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C517838:Prkar2b protein, mouse; D011506:Proteins; D014280:Triglycerides; D000071256:Uncoupling Protein 1; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases