PKA RIIα Knockout Mice Are Resistant to Diet-induced Obesity

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 708-722-Obesity: Response to Interventions
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-711
Edra London*, Eva Szarek and Constantine A Stratakis
National Institutes of Health (NIH), Bethesda, MD
PKA RIIα Knockout Mice Are Resistant to Diet-induced Obesity

Edra London, PhD; Eva Szarek, PhD; and Constantine A. Stratakis, MD, DMedSci

Section on Endocrinology and Genetics, Program on Developmental Endocrinology & Genetics (PDEGEN) Eunice Kennedy ShriverNational Institute of Child Health & Human Development (NICHD), National Institutes of Health, Bethesda, MD

The prevalence of obesity in the U.S. has reached a staggering 35.7% for adults and over 17% for children. Similar trends are observed worldwide. Changes in lifestyle and diet over the past few decades  are believed to be important contributing factors to the obesity epidemic, yet it remains unclear why certain individuals are susceptible and others resist obesity in an “obesogenic environment”. The interaction between genes and diet is one area of particular interest. The Protein kinase A (PKA) signaling system is widely expressed in humans and mice and in addition to being a regulator of cellular metabolism, PKA is important in nearly all organ systems affected by obesity. Therefore, PKA is a good potential therapeutic target for obesity. PKA has four regulatory subunit isoforms (RIα, RIIα, RIβ, RIIβ) and four catalytic subunit isoforms (Cα, Cβ, Cγ, Prkx). Knockout (KO) of RIIβ, which is highly expressed in brain as well as in brown and white adipose tissue, results in a genetically lean mouse. The basis for this is not completely understood, but RIIβ deficiency is known to cause a compensatory increase in RIα and increase basal PKA activity. We report that the RIIα KO mouse resists diet-induced obesity (DIO), glucose intolerance, and fatty liver when challenged with chronic high-fat diet (HFD) feeding. After only 2 week exposure to HFD, both female and male RIIα KO mice weighed significantly less than WT littermates. Interestingly, over time this effect was more pronounced in females.  RIIα KO mice with ad libitum access to control diet and HFD were significantly leaner than their WT counterparts as determined by Echo-MRI.  In WT mice, mRNA expression of PKA subunits decreased after long-term HFD; these changes were not observed in RIIα KO mice. Intake studies revealed that RIIα KO mice consumed significantly less HFD than their weight-matched WT controls when given free access to the same HFD. Locomotor activity assessment is needed to determine the contribution of energy expenditure to this model of DIO resistance.  In conclusion, PKA RIIα represents a new potential target for therapeutic interventions in obesity. Future studies will investigate how peripheral PKA signaling is affected by RIIα deficiency and whether the observed phenotype is driven by central or peripheral regulatory mechanisms.

Nothing to Disclose: EL, ES, CAS

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