Leptin stimulates AMPK and p38 MAPK via Rho-dependent actin filament remodeling in primary rat cardiac fibroblasts.

Abstract

Heart failure is a leading cause of morbidity and mortality in obese and diabetic individuals. Hyperleptinemia has been correlated with remodeling events such as cardiomyocyte hypertrophy and cell death, altered metabolism and fibrosis. However, there are paradoxical reports that hyperleptinemia induces myocardial infarction (MI) but protects against progression of heart failure post-MI in obese and diabetic individuals. More recently, the heart has also been shown to be a site of leptin synthesis which may mediate important autocrine and paracrine effects. The cardiac fibroblast plays an important role in the pathophysiology of heart failure and here we specifically investigated the effects of leptin on fibroblast cytoskeletal reorganization and its functional consequences. Our immunofluorescent studies using rhodamine-phalloidin and quantitative analysis of globular:filamentous actin ratios indicated that acute leptin treatment leads to an increase in actin polymerization and reorganization of actin filaments. This was prevented by pretreating cells with a cell permeable inhibitor (exoenzyme C3 transferase from Clostridium botulinum) of Rho-GTPase, an important regulator of cytoskeletal dynamics in the heart. Electron microscopy also revealed alterations in cell morphology as a consequence of leptin-induced actin polymerization. Activation of several signaling pathways, including AMPK and p38 MAPK, by leptin was also attenuated by the Rho inhibitor. Interestingly, these data indicate the permissive role of the cytoskeleton in leptin signaling. In summary, our study demonstrates for the first time that leptin regulates Rho-dependent cytoskeletal remodeling in cardiac fibroblasts which are required for AMPK and p38 MAPK activation. Various cardiac remodeling events known to be mediated by leptin may thus be dependent on changes in the cytoskeleton and these may play an important role in the pathophysiology of heart failure in obese and diabetic individuals.