The cJun NH2-terminal kinase (JNK) stress signaling pathway is implicated in the metabolic response to the consumption of a high-fat diet, including the development of obesity and insulin resistance. These metabolic adaptations involve altered liver function. Here, we demonstrate that hepatic JNK potently represses the nuclear hormone receptor peroxisome proliferator-activated receptor alpha (PPARalpha). Therefore, JNK causes decreased expression of PPARalpha target genes that increase fatty acid oxidation and ketogenesis and promote the development of insulin resistance. We show that the PPARalpha target gene fibroblast growth factor 21 (Fgf21) plays a key role in this response because disruption of the hepatic PPARalpha-FGF21 hormone axis suppresses the metabolic effects of JNK deficiency. This analysis identifies the hepatokine FGF21 as a critical mediator of JNK signaling in the liver.