Leptin induces cardiac fibrosis through galectin-3, mTOR and oxidative stress: potential role in obesity

Objective: Leptin acts as a cardiac profibrotic factor. However, the mechanisms underlying this effect are unclear. Therefore, we sought to elucidate the mediators involved in this process and the potential role of leptin in cardiac fibrosis associated with obesity. Methods: Male Wistar rats were fed either a high-fat diet (HFD; 33.5% fat), or a standard diet (3.5% fat) for 6 weeks. Results: HFD animals show cardiac hypertrophy, fibrosis and an increase in O-2(-) production as evaluated by dihydroethidium. Echocardiographic parameters of cardiac structure and systolic function were similar in both groups. Cardiac levels of leptin, collagen I, galectin-3 and transforming growth factor beta (TGF-beta) were higher in HFD than in controls. In cardiac myofibroblasts, leptin (10-100 ng/ml) increased O-2(-), collagen I, galectin-3, TGF-beta and connective tissue growth factor production (CTGF). These effects were prevented by the presence of either melatonin (10(-3) mmol/l) or the inhibitor of mTOR, rapamycin (10(-4) mmol/l). Blockage of galectin-3 activity by N-acetyllactosamine (LacNac 10(-3) mmol/l) reduced both collagen I and O-2(.-) production induced by leptin. The p70S6 kinase activation/phosphorylation, the downstream mediator of mTOR, induced by leptin was not modified by melatonin. Leptin reduced the metalloproteinase (MMP) 2 activity and the presence of melatonin, rapamycin or LacNac were unable to prevent it. Conclusion: The data suggest that leptin locally produced in the heart could participate in the fibrosis observed in HFD by affecting collagen turnover. Collagen synthesis induced by leptin seems to be mediated by the production of galectin-3, TGF-beta and CTGF through oxidative stress increased by activation of mTOR pathway.