Fig. 8: The protective mechanism of FGF21 on type 2 diabetes-induced cardiomyopathy.

Heart is a special organ that predominantly consumes fatty acid to generate energy. Compared to glucose, more oxygen is required for generating an equal amount of adenosine triphosphate. Under diabetic conditions, glucose metabolism is impaired that forces the heart to consume more fatty acid to generate energy. During this period, excessive ROS is produced and accumulates in the cardiac cells that induce oxidative stress. Oxidative stress will cause cardiac cell injury and apoptosis followed by cardiac remodeling and finally leads to cardiac dysfunction and heart failure. The present study showed that both exogenous and endogenous FGF21 induces the preventive effect on type 2 diabetes-induced cardiomyopathy. Further study reveals that the cardiac protection of FGF21 was mediated by AMPK. First, AMPK activates AKT2–GSK3β pathway that enhances NRF2 nuclear translocation via inhibition of nuclear accumulation of Fyn to induce antioxidant genes expression. Second, AMPK also actives fatty acid β-oxidation via ACC–CPT-1 pathway to specifically reduce lipid accumulation in the myocardium. Therefore, both antioxidative and lipid-lowering pathways regulated by AMPK mediate FGF21’s prevention on DCM