Mutation of the RII beta subunit of protein kinase A differentially affects lipolysis but not gene induction in white adipose tissue

Targeted disruption of the RII beta subunit of protein kinase A (PKA) produ ces lean mice that resist diet-induced obesity. In this report we examine t he effects of the RII beta knockout on white adipose tissue physiology, Los s of RII beta is compensated by an increase in the RI alpha isoform, genera ting an isoform switch from a type II to a type I PKA, Type I holoenzyme bi nds cAMP more avidly and is more easily activated than the type II enzyme. These alterations are associated with increases in both basal kinase activi ty and the basal rate of lipolysis, possibly contributing to the lean pheno type, However, the ability of both beta(3)-selective and nonspecific beta-a drenergic 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-s ensitive lipase genes. In contrast, beta-adrenergic stimulated gene transcr iption remains intact, and the expression of key genes involved in lipid me tabolism is normal under both fasted and fed conditions. We suggest that th e R subunit isoform switch disrupts the subcellular localization of PHA tha t is required for efficient transduction of signals that modulate lipolysis but not for those that mediate gene expression.