Hepatocyte-specific reduction of mitochondrial oxidative phosphorylation improve whole body insulin sensitivity and energy expenditure
Seul Gi Kang1,2, Hyon Seung Yi1, Saetbyel Jung1, Min Jeong Choi1,2, Seong Eun Lee1, Joon Young Chang1,2, Hyo Kyun Chung1, Minho Shong1
1Research Center for Endocrine and Metabolic Diseases, 2Department of Medical Science, Chungnam National University School of Medicine, Daejeon, Republic of Korea
The reduction of mitochondrial respiratory function has long been considered to be a cause of metabolic disease and T2DM. However, recent studies revealed that inhibition of mitochondrial oxidative phosphorylation (OXPHOS) increased longevity in C. elegans and improved insulin sensitivity in mice respectively. The liver is a major metabolic organ, and its function is controlled by insulin and other metabolic hormones. The metabolic phenotype induced by liver mitochondrial dysfunction is still not fully understand. CR6-interacting factor 1 (CRIF1) is interacts with large subunit (LSU) of mitochondrial-ribosome and essential for insertion of OXPHOS polypeptides into the inner mitochondrial membrane. To determine which metabolic phenotypes are induced by reduction of hepatic mitochondrial respiratory, we generated liver-specific Crif1 deficient mice (LivKO). As a Crif1 deletion cause reduced OXPHOS functions, we measured oxygen consumption and glycolysis rate. The ability of adaptation to increased oxygen demand is lower in primary hepatocytes of LivKO, whereas glucose uptake and glycolytic capacity is remarkably higher than wild-type (WT) primary hepatocytes. These perturbations of mitochondrial OXPHOS function were associated with enhanced expression of the genes-related mitochondrial biogenesis, such as PGC1α/β and TFAM level. To evaluate whole body energy metabolism in LivKO mice, we conducted glucose and insulin tolerance test in WT and LivKO mice fed normal chow or high fat diet. LivKO mice exhibited the improvement of insulin sensitivity and resistance to diet-induced obesity compared to WT mice. Energy expenditures assessed using indirect calorimetry were also increased in LivKO mice. These findings suggest that hepatocyte-specific reduction of mitochondrial oxidative phosphorylation alter not only liver metabolism but also whole body insulin sensitivity and energy expenditure in mice.
Keywords: mitochondria, Crif1, oxidative phosphorylation, insulin sensitivity, energy expenditure