title: Liver-specific inducible nitric-oxide synthase expression is sufficient to cause hepatic insulin resistance and mild hyperglycemia in mice.
abstract: Inducible nitric-oxide synthase (iNOS), a major mediator of inflammation, plays an important role in obesity-induced insulin resistance. Inhibition of iNOS by gene disruption or pharmacological inhibitors reverses or ameliorates obesity-induced insulin resistance in skeletal muscle and liver in mice. It is unknown, however, whether increased expression of iNOS is sufficient to cause insulin resistance in vivo. To address this issue, we generated liver-specific iNOS transgenic (L-iNOS-Tg) mice, where expression of the transgene, iNOS, is regulated under mouse albumin promoter. L-iNOS-Tg mice exhibited mild hyperglycemia, hyperinsulinemia, insulin resistance, and impaired insulin-induced suppression of hepatic glucose output, as compared with wild type (WT) littermates. Insulin-stimulated phosphorylation of insulin receptor substrate-1 (IRS-1) and -2, and Akt was significantly attenuated in liver, but not in skeletal muscle, of L-iNOS-Tg mice relative to WT mice without changes in insulin receptor phosphorylation. Moreover, liver-specific iNOS expression abrogated insulin-stimulated phosphorylation of glycogen synthase kinase-3β, forkhead box O1, and mTOR (mammalian target of rapamycin), endogenous substrates of Akt, along with increased S-nitrosylation of Akt relative to WT mice. However, the expression of insulin receptor, IRS-1, IRS-2, Akt, glycogen synthase kinase-3β, forkhead box O1, protein-tyrosine phosphatase-1B, PTEN (phosphatase and tensin homolog), and p85 phosphatidylinositol 3-kinase was not altered by iNOS transgene. Hyperglycemia was associated with elevated glycogen phosphorylase activity and decreased glycogen synthase activity in the liver of L-iNOS-Tg mice, whereas phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, and proliferator-activated receptor γ coactivator-1α expression were not altered. These results clearly indicate that selective expression of iNOS in liver causes hepatic insulin resistance along with deranged insulin signaling, leading to hyperglycemia and hyperinsulinemia. Our data highlight a critical role for iNOS in the development of hepatic insulin resistance and hyperglycemia.
authors.affiliation: Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Shriners Hospitals for Children, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Shohei
authors.initials: S
authors.lastname: Shinozaki
authors.forename: Cheol Soo
authors.initials: CS
authors.lastname: Choi
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Shimizu
authors.forename: Marina
authors.initials: M
authors.lastname: Yamada
authors.forename: Minhye
authors.initials: M
authors.lastname: Kim
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.forename: Goshi
authors.initials: G
authors.lastname: Shiota
authors.forename: H Henry
authors.initials: HH
authors.lastname: Dong
authors.forename: Young-Bum
authors.initials: YB
authors.lastname: Kim
authors.forename: Masao
authors.initials: M
authors.lastname: Kaneki
mesh_terms: D000418:Albumins / Q000235:genetics; D000818:Animals; D005260:Female; D005951:Glucose Tolerance Test; D022781:Hepatocytes / Q000378:metabolism; D006943:Hyperglycemia / Q000378:metabolism*; D007333:Insulin Resistance; D008099:Liver / Q000201:enzymology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
chemical_list: D000418:Albumins; D014280:Triglycerides; D052247:Nitric Oxide Synthase Type II; D051057:Proto-Oncogene Proteins c-akt