Abstract 16729: Glycogen Synthase Kinase-3a Contributes to the Development of Cardiac Dysfunction During Obesity and Insulin Resistance Through Regulation of Peroxisome Proliferator-Activated Receptor a
Obesity and insulin resistance lead to impaired cardiac metabolism, resulting in cardiac dysfunction. PPARα is highly expressed in the heart and serves as a key regulator of fatty acid (FA) metabolism. However, the underlying mechanisms responsible for the development of cardiac hypertrophy and diastolic dysfunction in these pathologies are still poorly understood. GSK-3α, a serine/threonine kinase, was excessively activated, as evidenced by a decrease in S21 phosphorylation, during insulin resistance in the hearts of obese mice fed a high-fat diet (HFD) and ob/ob mice. To evaluate the functional significance of GSK-3α upregulation with regard to cardiac metabolism, we applied 50-300 μM BSA-conjugated palmitic acid to cardiomyocytes in vitro for 3 days. This intervention elicited ectopic lipid accumulation and a 2.0-4.0 fold activation of GSK-3α, similar to lipid-induced insulin resistance and dyslipidemia in the heart in vivo. Under this condition, downregulation of GSK-3α with shRNA-GSK-3α in cardiomyocytes increased cell viability, ATP synthesis and the FA oxidation rate. Downregulation of GSK-3α also increased the activity of a PPAR-luciferase reporter (1.5 fold, p<0.05) and the mRNA levels of some genes involved in FA metabolism, including Acox1 and Cpt1b. Overexpression of GSK-3α induced a rightward shift of the dose response curve when the activity of the PPARα reporter was plotted against the dose of WY14643, a PPARα agonist. GSK-3α, but not GSK-3β, directly interacted with and phosphorylated PPARα in vitro. Next, wild-type (WT) and GSK-3α heterozygous knockout (HKO) mice were fed a HFD for 14 weeks. Cardiac hypertrophy and diastolic dysfunction observed in WT mice were significantly ameliorated in GSK-3α HKO mice after HFD feeding (0.99±0.03 and 0.85±0.06 mm, LVPWDd; 8.1± 0.6 and 6.5±0.5, LVW/TL ratio; 2.36±0.24 and 1.76±0.09, E/A ratio, all p<0.05). Collectively, these results suggest that GSK-3α regulates PPARα activity through phosphorylation of PPARα, thereby controlling FA metabolism. The excessive activation of GSK-3α and phosphorylation of PPARα during obesity and insulin resistance could play an important role in the development of cardiac hypertrophy and diastolic dysfunction.
- © 2013 by American Heart Association, Inc.