THE ROLE OF LYSOPHOSPHATIDIC ACID AND AUTOTAXIN IN OBESITY-INDUCED CARDIAC INSULIN RESISTANCE

Abstract

The metabolic changes to adipose tissue during obesity can induce cardiac insulin resistance. During obesity and diabetes, cardiac metabolic flexibility is reduced, which may lead to impaired ATP production, elevated reactive oxygen species production, mitochondrial dysfunction and apoptosis. The adipokine, autotaxin (ATX), which generates bioactive lipids called lysophosphatidic acids (LPA), has been linked to obesity-induced insulin resistance in both mouse models and humans. This study is the first to examine the role of ATX/LPA in obesity-induced cardiac insulin resistance, cardiac dysfunction and in palmitate-induced lipotoxicity. Pre-incubation with LPA reduced the magnitude of insulin stimulation of AKT compared to baseline. In the presence of palmitate, LPA exacerbated cardiac insulin resistance in H9C2 cells and neonatal rat cardiomyocytes. Lastly, a reduction in ATX/LPA levels protected against obesity-induced cardiac insulin resistance and cardiac dysfunction. Collectively, these results suggest increasing levels of ATX/LPA aide in the progression of cardiomyopathy during obesity and insulin resistance/diabetes.