Given numerous benefits of exercise in preventing metabolic diseases, identification of druggable targets that mimic or boost the molecular cascade of endurance training has been a long‐standing, but elusive, medical goal.[58] Our study identifies IRF4 as the signaling node that regulates metabolic adaptation to extracellular stimuli; this is supported by our findings that IRF4 levels in skeletal muscle were increased by exercise, and that the genetic IRF4 KO mouse model facilitated a reprogramming of glycogen synthesis. This evidence concerns the gene IRF4 and metabolic disease.