GENETICALLY LEAN MICE RESULT FROM TARGETED DISRUPTION OF THE RII-BETASUBUNIT OF PROTEIN-KINASE-A

CYCLIC AMP is an important second messenger in the coordinated regulat ion 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 R I alpha, RI beta, RII alpha, and RII beta) and two C genes (encoding C alpha and C beta), expressed in tissue specific patterns(1). The RII beta isoform is abundant in brown and white adipose tissue and brain, with limited expression elsewhere. To elucidate its functions, we gene rated RII beta knockout mice, Here we report that mutants appear healt hy but have markedly diminished white adipose tissue despite normal fo od 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, ge nerating an isoform switch, The holoenzyme from mutant adipose tissue binds cAMP more avidly and is more easily activated than wild-type enz yme, This causes induction of uncoupling protein and elevations of met abolic rate and body temperature, contributing to the lean phenotype. Our results demonstrate a role for the RII beta holoenzyme in regulati ng energy balance and adiposity.