Deletion of Prkar2a, with its exclusive habenular brain expression, confers obesity resistance through decreased hedonic drive and increased voluntary exercise

Authors

• E London
• J Wester
• CA Stratakis

Abstract

The cAMP-dependent protein kinase (PKA) system is crucial in regulating energy balance and numerous cellular functions as it mediates the effects of hormones, neurotransmitters and catecholamines that bind G-protein coupled receptors. Prkar2a codes for PKA regulatory subunit RIIa, that unlike other PKA subunits, has minimal expression throughout the brain except in the habenula where it is highly expressed. The habenula has been implicated in regulating hedonic state, depression, voluntary exercise, and primary reinforcement. Here we show that RIIa knockout (KO) mice resist diet-induced obesity, and this phenomenon cannot be explained by enhanced metabolic rate. Instead, RIIa KO consistently consumed less palatable high fat (HF) chow than wild type (WT) mice, despite their comparable preference for HF over regular chow. RIIa KO mice also consistently consumed less 10% sucrose solution during a two-week sucrose preference test. Alternatively, when provided home cage running wheels, RIIa KO mice ran two to three times more than WT littermates. Observed differences were more profound in females. Pkrar2a colocalizes with Chrna3 and Chrnb3 in the medial habenula, and with Mor1 in the lateral habenula, yet it is not known how it might regulate nicotinic or mu opioid receptor pathways. Enzymatic activity assays revealed decreased habenular PKA activity in RIIa KO compared to WT mice; PKA activity was unchanged in striatum, a region that provides input to the habenula. Others have shown that mice with dorsal medial habenula lesions have blunted sucrose preference as well as poor performance in voluntary wheel running. These data combined suggest that Prkar2a has diverse roles in modulating behaviors related to reward reinforcement and motivation for voluntary exercise, likely by affecting downstream targets such as ventral tegmental area or substantia nigra. Ongoing studies involve virus-mediated reexpression of Prkar2a in the habenula and habenula-specific KO of Prkar2a using a Gpr151-cre/floxed Prkar2a mouse line. The study of Prkar2a in brain may provide a new approach for better understanding the role of the habenula in regulating behaviors involved in obesity, addiction, and depression.

Scientific Focus Area: Molecular Biology and Biochemistry

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