title: Prolonged exposure to insulin suppresses mitochondrial production in primary hepatocytes.
abstract: Insulin is the central regulator of metabolism and is necessary for storing energy as fat efficiently. Mitochondria are primary sites of energy consumption of most cells. Increased plasma insulin level and mitochondrial dysfunction are features of insulin resistance. The exact role of insulin in regulation of mitochondrial production and function remains unestablished. In this study, we observed that mitochondrial production in liver and skeletal muscle gastrocnemius was increased in mice with insulin deficiency (streptozotocin-induced type 1 diabetes). In contrast, prolonged exposure (24 h) of isolated hepatocytes to insulin decreased mitochondrial mass, mitochondrial DNA (mtDNA), intracellular ATP content, and cellular O(2) consumption. Transcript levels of genes associated with mitochondrial production and beta oxidation were decreased, whereas those of lipogenic genes were increased by the prolonged exposure to insulin. Insulin-induced changes in mtDNA, mitochondrial mass, intracellular ATP content, and transcripts of mitochondrion-associated genes were prevented by blockade of Akt activation with the phosphatidylinositol 3-kinase inhibitor LY294002. Conversely, levels of mtDNA, intracellular ATP content, and expression of mitochondrion-associated genes were decreased by overexpression of the constitutively active Akt. Finally, insulin suppression of mtDNA, ATP production, and expression of mitochondrion-related genes was largely prevented by inhibition of cyclic nucleotide phosphodiesterase with isobutylmethylxanthine. Together, our results show prolonged exposure of isolated hepatocytes to insulin suppresses mitochondrial production and function through the classical Akt-dependent insulin signaling pathway.
authors.affiliation: Translational Biology, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Hui-Yu
authors.initials: HY
authors.lastname: Liu
authors.forename: Einav
authors.initials: E
authors.lastname: Yehuda-Shnaidman
authors.forename: Tao
authors.initials: T
authors.lastname: Hong
authors.forename: Jianmin
authors.initials: J
authors.lastname: Han
authors.forename: Jingbo
authors.initials: J
authors.lastname: Pi
authors.forename: Zhenqi
authors.initials: Z
authors.lastname: Liu
authors.forename: Wenhong
authors.initials: W
authors.lastname: Cao