FGF21 is a PPARα-regulated gene elucidated in the liver of PPARα-deficient mice or PPARα agonist-treated mice. Mice globally lacking adipose triglyceride lipase (ATGL) exhibit a marked defect in triglyceride (TG) catabolism associated with impaired PPARα-activated gene expression in the heart and liver including a drastic reduction in hepatic FGF21 mRNA expression. Here we show that FGF21 mRNA expression is markedly increased in the heart of ATGL-deficient mice accompanied by elevated expression of endoplasmic reticulum (ER) stress markers which can be reversed by reconstitution of ATGL expression in cardiac muscle. In line with this assumption, the induction of ER stress increases FGF21 mRNA expression in H9C2 cardiomyotubes. Interestingly, cardiac FGF21 expression was also induced upon fasting of healthy mice implicating a role of FGF21 in cardiac energy metabolism. To address this question we generated and characterized mice with cardiac-specific overexpression of FGF21 (CM-Fgf21). FGF21 was efficiently secreted from cardiomyocytes of CM-Fgf21 mice which moderately affected cardiac TG homeostasis indicating a role for FGF21 in cardiac energy metabolism. Together, we show that FGF21 expression is activated upon cardiac ER stress linked to defective lipolysis and that a persistent raise in circulating FGF21 levels interferes with cardiac and whole body energy homeostasis.