Obesity and insulin resistance lead to ectopic lipid accumulation and impaired cardiac metabolism, resulting in cardiovascular diseases. Peroxisome proliferator-activated receptor α (PPARα) is highly expressed in the heart and serves as a key regulator of fatty acid metabolism. However, the underlying mechanisms responsible for the development of cardiac dysfunction in these pathologies are still poorly understood. GSK-3α was activated, as evidenced by a decrease in S21 phosphorylation, during insulin resistance with normoglycemia in the hearts of obese mice fed a high-fat diet and
ob/ob
mice. To evaluate the functional significance of GSK-3α upregulation with regard to metabolism, we applied 50 μM of BSA-conjugated palmitic acid to cardiomyocytes
in vitro
for three days. This intervention elicited ectopic lipid accumulation, as evaluated with Oil Red O staining, and a 2.0-fold activation of GSK-3α, similar to lipid-induced insulin resistance and dyslipidemia in the heart
in vivo
. In this condition, downregulation of GSK-3α with shRNA-GSK-3α in cardiomyocytes increased cell viability, ATP synthesis, and fatty acid oxidation, but not glycolysis. Downregulation of GSK-3α also increased the activity of PPRE-luciferase (1.5 fold, p<0.05) and mRNA expression of genes involved in fatty acid metabolism in response to palmitic acid, including
Acox1
and
Cpt1b
. Overexpression of GSK-3α induced a rightward shift of the dose response curve where 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
. Collectively, these results suggest that GSK-3α negatively regulates ligand-dependent activity of PPARα through phosphorylation of PPARα, thereby inhibiting fatty acid metabolism during lipid-induced insulin resistance. GSK-3α may be a novel therapeutic target for metabolic disorders.
PET imaging of glucose and fatty acid metabolism for NAFLD patients
