Objective: Disruption of mitochondrial protein homeostasis activates the cytosolic signal pathway and subsequently alter the nuclear gene expression related to homeostasis. The liver is the largest organs and releases tremendous protein to the blood. Moreover, hepatic mitochondria have the higher metabolic flexibility to adjust to the altered energy demand, which can be a good model to investigate the adaptive response to the reduced function of mitochondria on systemic energy metabolism. Methods: We generated mice lacking CRIF1, a key component for OXPHOS complex maturation and insertion into the mitochondrial inner membrane, in hepatocytes using Cre-LoxP recombination. We have characterized the liver-specific Crif1 knockout mice (LKO) on hepatic adaptive response and systemic metabolism. Results: Deletion of hepatic Crif1 caused reduced OXPHOS function and abnormal mitochondrial morphology. As an adaptive response, there was increased expression of mitochondrial protease. Glycolytic capacity and glucose uptake in the Crif1-deficient hepatocytes were remarkably higher than control. LKO mice showed improved glucose clearance and energy expenditure in high-fat diet conditions with resistance to weight gain. More interestingly, genes associated with PPAR signaling and UCP1 were remarkably elevated in the inguinal adipose tissue of LKO mice. Transcriptomic analysis suggested an alteration of systemic metabolisms, such as fatty acid metabolism and steroid biosynthesis, and representative hepatokines, such as Gdf15 and Fgf21. The metabolic phenotype of the double knockout mice (LKO/Gdf15^-/- or LKO/Fgf21^-/-) manifested that GDF15 and FGF21 were dispensable for glucose clearance and energy expenditure, but GDF15 was required for lower weight gain and hepatic fat accumulation in LKO mice. Conclusion: These findings suggested that disruption of mitochondrial proteostasis in liver induced not only hepatic adaptive response but also systemic metabolism especially in inguinal adipose tissue, leading to protection from obesity and insulin resistance. Moreover, we observed the concrete relevance of hepatokines on system metabolism, which can be a useful therapeutic strategy for obesity.