In our studies investigating the role of autophagy in systemic metabolism, we found that mitochondrial dysfunction due to autophagy deficiency in insulin target tissues, such as skeletal muscle or liver, leads to the induction of fibroblast growth factor (FGF)21 as a mitokine and protection against obesity and insulin resistance. In the following studies, we observed that metformin, one of the most widely used antidiabetic medications, induces mitochondrial stress and induces FGF21 through a PERK–eIF2α–ATF4 pathway, which may contribute to the antidiabetic effect of metformin. Amino acid deprivation also induced ATF4 and FGF21, while the role of mitochondrial dysfunction in this condition is not yet clear. These results suggest the possibility that mitochondrial stress inducing an integrated stress response can induce a mitokine response and affect systemic metabolism in a non‐cell‐autonomous manner, in addition to the well‐recognized cell‐autonomous role of mitochondrial function in metabolism.