To identify the differential effects of mitokines, GDF15 and FGF21 on the metabolic phenotype of adipocyte-specific Crif1 (also known as Gadd45gip1) knockout (AdKO) AdKO mice, we generated AdKO mice with global Gdf15 knockout (AdGKO) or global Fgf21 knockout (AdFKO). Under high-fat diet conditions, AdKO mice were resistant to weight gain and exhibited higher EE and improved glucose tolerance. In vivo genetic inhibition of OxPhos in adipocytes significantly upregulated mitochondrial unfolded protein response-related genes and secretion of mitokines such as GDF15 and FGF21. We evaluated the metabolic phenotypes of AdGKO and AdFKO mice, revealing that GDF15 and FGF21 differentially regulated energy homeostasis in AdKO mice. Both mitokines had beneficial effects on obesity and insulin resistance in the context of decreased adipocyte OxPhos, but only GDF15 regulated EE in AdKO mice. Our data from AdGKO mice fed an HFD for 8 weeks revealed that long-term induction of GDF15 in AdKO mice attenuated progression of obesity in this context through increased EE. Our findings in AdFKO mice suggested that prolonged induction of FGF21 in AdKO mice did not affect EE, but remarkably ameliorated HFD-induced obesity and insulin resistance. The present study demonstrated that the muscle and adipose tissue adaptive mitochondrial stress response affected systemic energy homeostasis via cell-autonomous and non-cell-autonomous pathways.