title: High-fat-fed obese glutathione peroxidase 1-deficient mice exhibit defective insulin secretion but protection from hepatic steatosis and liver damage.
abstract: OBJECTIVE
  Reactive oxygen species (ROS) such as H2O2 can promote signaling through the inactivation of protein tyrosine phosphatases (PTPs). However, in obesity, the generation of ROS exceeds the antioxidant reserve and can contribute to the promotion of insulin resistance. Glutathione peroxidase 1 (Gpx1) is an antioxidant enzyme that eliminates H2O2. Here, we have used Gpx1(-/-) mice to assess the impact of oxidative stress on glucose homeostasis in the context of obesity.
  
  
  RESULTS
  Gpx1(-/-) mice fed an obesogenic high-fat diet for 12 weeks exhibited systemic oxidative stress and hyperglycemia, but had unaltered whole-body insulin sensitivity, improved hepatic insulin signaling, and decreased whole-body glucose production. High-fat-fed Gpx1(-/-) mice also exhibited decreased hepatic steatosis and liver damage accompanied by decreased plasma insulin and decreased glucose-induced insulin secretion. The decreased insulin secretion was associated with reduced islet β cell pancreatic and duodenal homeobox-1 (Pdx1) and insulin content, elevated pancreatic PTP oxidation (including PTPN2 oxidation), and elevated signal transducer and activator of transcription 1 (STAT1) Y701 phosphorylation.
  
  
  CONCLUSIONS
  Taken together, these results are consistent with H2O2 inactivating pancreatic PTPs (such as the STAT1 phosphatase PTPN2) for the promotion of STAT-1 signaling to suppress Pdx1 expression and differentiation and, consequently, reduce β cell insulin secretion. We propose that the decreased insulin secretion, in turn, results in decreased hepatic lipogenesis and steatosis, attenuates liver damage, and improves hepatic insulin signaling to suppress hepatic glucose production. Limiting insulin secretion may help combat the development of hepatic steatosis and liver damage in diet-induced obesity.
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, Monash University , Victoria, Australia .
authors.forename: Troy L
authors.initials: TL
authors.lastname: Merry
authors.forename: Melanie
authors.initials: M
authors.lastname: Tran
authors.forename: Maria
authors.initials: M
authors.lastname: Stathopoulos
authors.forename: Florian
authors.initials: F
authors.lastname: Wiede
authors.forename: Barbara Christianne
authors.initials: BC
authors.lastname: Fam
authors.forename: Garron T
authors.initials: GT
authors.lastname: Dodd
authors.forename: Iain
authors.initials: I
authors.lastname: Clarke
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Watt
authors.forename: Sofianos
authors.initials: S
authors.lastname: Andrikopoulos
authors.forename: Tony
authors.initials: T
authors.lastname: Tiganis
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D005234:Fatty Liver / Q000473:pathology* / Q000517:prevention & control*; D005979:Glutathione Peroxidase / Q000172:deficiency* / Q000378:metabolism; D006943:Hyperglycemia / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D008099:Liver / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism; D018384:Oxidative Stress; D000094765:Glutathione Peroxidase GPX1
chemical_list: D001786:Blood Glucose; D007328:Insulin; D005979:Glutathione Peroxidase; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse