| First Author | Zheng R | Year | 2013 |
| Journal | Proc Natl Acad Sci U S A | Volume | 110 |
| Issue | 17 | Pages | E1631-40 |
| PubMed ID | 23569242 | Mgi Jnum | J:196157 |
| Mgi Id | MGI:5486613 | Doi | 10.1073/pnas.1219542110 |
| Citation | Zheng R, et al. (2013) Deficiency of the RIIbeta subunit of PKA affects locomotor activity and energy homeostasis in distinct neuronal populations. Proc Natl Acad Sci U S A 110(17):E1631-40 |
| abstractText | Targeted disruption of RIIbeta-protein kinase A (PKA) in mice leads to a lean phenotype, increased nocturnal locomotor activity, and activation of brown adipose tissue. Because RIIbeta is abundantly expressed in both white and brown adipose tissue as well as the brain, the contribution of neuronal vs. peripheral PKA to these phenotypes was investigated. We used a Cre-Lox strategy to reexpress RIIbeta in a tissue-specific manner in either adipocytes or neurons. Mice with adipocyte-specific RIIbeta reexpression remained hyperactive and lean, but pan-neuronal RIIbeta reexpression reversed both phenotypes. Selective RIIbeta reexpression in all striatal medium spiny neurons with Darpp32-Cre corrected the hyperlocomotor phenotype, but the mice remained lean. Further analysis revealed that RIIbeta reexpression in D2 dopamine receptor-expressing medium spiny neurons corrected the hyperlocomotor phenotype, which demonstrated that the lean phenotype in RIIbeta-PKA-deficient mice does not develop because of increased locomotor activity. To identify the neurons responsible for the lean phenotype, we used specific Cre-driver mice to reexpress RIIbeta in agouti-related peptide (AgRP)-, proopiomelanocortin (POMC)-, single-minded 1 (Sim1)-, or steroidogenic factor 1 (SF1)-expressing neurons in the hypothalamus, but observed no rescue of the lean phenotype. However, when RIIbeta was reexpressed in multiple regions of the hypothalamus and striatum driven by Rip2-Cre, or specifically in GABAergic neurons driven by Vgat-ires-Cre, both the hyperactive and lean phenotypes were completely corrected. Bilateral injection of adeno-associated virus1 (AAV1)-Cre directly into the hypothalamus caused reexpression of RIIbeta and partially reversed the lean phenotype. These data demonstrate that RIIbeta-PKA deficiency in a subset of hypothalamic GABAergic neurons leads to the lean phenotype. |
