PKA-RIIB Deficiency Induces Brown Fatlike Adipocytes in Inguinal WAT and Promotes Energy Expenditure in Male FVB/NJ Mice.

Obesity has become the most common metabolic disorder worldwide. Promoting brown adipose tissue (BAT) and beige adipose tissue formation, and therefore, a functional increase in energy expenditure, may counteract obesity. Mice lacking type IIß regulatory subunit of adenosine 3',5' cyclic monophosphate (cAMP)-dependent protein kinase A (PKA-RIIB) display reduced adiposity and resistance to diet-induced obesity. PKA-RIIB, encoded by the Prkar2b gene, is most abundant in BAT and white adipose tissue (WAT) and in the brain. In this study, we show that mice lacking PKA-RIIB have increased energy expenditure, limited weight gain, and improved glucose metabolism. PKA-RIIB deficiency induces brownlike adipocyte in inguinal WAT (iWAT). PKA-RIIB deficiency also increases the expression of uncoupling protein 1 and other thermogenic genes in iWAT and primary preadipocytes from iWAT through a mechanism involving increased PKA activity, which is represented by increased phosphorylation of PKA substrate, cAMP response element binding protein, and P38 mitogen-activated protein kinase. Our study provides evidence for the role of PKA-RIIB deficiency in regulating thermogenesis in WAT, which may potentially have therapeutic implications for the treatment of obesity and related metabolic disorders.

Hematopoietic neoplasms in Prkar2a-deficient mice.

BACKGROUND: Protein kinase A (PKA) is a holoenzyme that consists of a dimer of regulatory subunits and two inactive catalytic subunits that bind to the regulatory subunit dimer. Four regulatory subunits (RIα, RIß, RIIα, RIIß) and four catalytic subunits (Cα, Cß, Cγ, Prkx) have been described in the human and mouse genomes. Previous studies showed that complete inactivation of the Prkar1a subunit (coding for RIα) in the germline leads to embryonic lethality, while Prkar1a-deficient mice are viable and develop schwannomas, thyroid, and bone neoplasms, and rarely lymphomas and sarcomas. Mice with inactivation of the Prkar2a and Prkar2b genes (coding for RIIα and RIIß, respectively) are also viable but have not been studied for their susceptibility to any tumors. METHODS: Cohorts of Prkar1a (+/-) , Prkar2a (+/-) , Prkar2a (-/-) , Prkar2b (+/-) and wild type (WT) mice have been observed between 5 and 25 months of age for the development of hematologic malignancies. Tissues were studied by immunohistochemistry; tumor-specific markers were also used as indicated. Cell sorting and protein studies were also performed. RESULTS: Both Prkar2a (-/-) and Prkar2a (+/-) mice frequently developed hematopoietic neoplasms dominated by histiocytic sarcomas (HS) with rare diffuse large B cell lymphomas (DLBCL). Southern blot analysis confirmed that the tumors diagnosed histologically as DLBCL were clonal B cell neoplasms. Mice with other genotypes did not develop a significant number of similar neoplasms. CONCLUSIONS: Prkar2a deficiency predisposes to hematopoietic malignancies in vivo. RIIα's likely association with HS and DLBCL was hitherto unrecognized and may lead to better understanding of these rare neoplasms.

Protein kinase A is a target for aging and the aging heart.

PKA is an important mediator of signal transduction downstream of G-protein-coupled receptors and plays a key role in the regulation of metabolism and triglyceride storage. It is a ubiquitous cellular kinase that phosphorylates serine and threonine residues in response to cAMP. PKA consists of two regulatory subunits, RI and RII, that are activated by cAMP to release two catalytic subunits, Calpha and Cbeta. We have shown that C57/BL6J male mice lacking the regulatory RIIbeta subunit have extended lifespan and are resistant to age-related conditions including cardiac decline. In addition to being protected from diet-induced pathologies, PKA Cbeta null mutant mice are protected from age-related problems such as weight gain and enlarged livers, as well as cardiac dysfunction and hypertrophy. Several possible mechanisms for the age sparing effects of PKA inhibition are discussed including A kinase anchoring protein signaling, alterations in the beta-adrenergic pathway, and activation of AMPK. Since PKA is a major metabolic regulator of gene signaling, the human gene homologs are potential pharmacological targets for age-related conditions including heart disease associated with declining cardiac performance.