Abstract


The regulatory subunit IIα of the cAMP-dependent protein kinase (PKA RIIα) is expressed at low levels throughout the body. In brain, RIIα gene expression is highly specific and concentrated primarily in the medial habenula (MHb), a small bilateral structure at the dorsal end of the diencephalon that receives inputs from the limbic forebrain and sends projections to the striatum. Mice deficient in Prkar2a (RIIαKO) resist diet-induced obesity (DIO) and have improved insulin tolerance, yet are phenotypically distinct from genetically lean Prka2b and Prkacb knockout mouse lines. view more

The regulatory subunit IIα of the cAMP-dependent protein kinase (PKA RIIα) is expressed at low levels throughout the body. In brain, RIIα gene expression is highly specific and concentrated primarily in the medial habenula (MHb), a small bilateral structure at the dorsal end of the diencephalon that receives inputs from the limbic forebrain and sends projections to the striatum. Mice deficient in Prkar2a (RIIαKO) resist diet-induced obesity (DIO) and have improved insulin tolerance, yet are phenotypically distinct from genetically lean Prka2b and Prkacb knockout mouse lines. We sought to determine the underlying cause of the observed DIO-resistant phenotype of RIIα mutants by conducting high-sugar high-fat diet (HFD) intake, taste preference and running wheel studies, and by examining PKA activity in several targeted brain regions. Both WT and mutant mice prefered HFD to normal chow, yet RIIαKO mice consistently consumed less than WT mice when provided ad libitum access to HFD over a 10 week period. In brain, PKA activity increased in striatum and hippocampus and HFD feeding caused impressive increases in PKA activity in the mutants. While we detected little or no differences in energy expenditure or total locomotor activity respectively by indirect calorimetry, RIIαKO mice ran twice as much as WT mice when provided access to running wheels. Immunohistochemistry revealed enhanced DARPP-32 in dentate gyrus and MHb as well as alterations in IEGs in MHb of mutant compared to WT mice. We hypothesize that RIIα regulates voluntary exercise and intake via distinct cell populations within the MHb and RIIα deficiency increases motivation for voluntary exercise and sensitizes mice to the rewarding effects of food leading to decreased intake.

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