title: Knockdown of the gene encoding Drosophila tribbles homologue 3 (Trib3) improves insulin sensitivity through peroxisome proliferator-activated receptor-γ (PPAR-γ) activation in a rat model of insulin resistance.
abstract: OBJECTIVE
  Insulin action is purportedly modulated by Drosophila tribbles homologue 3 (TRIB3), which in vitro prevents thymoma viral proto-oncogene (AKT) and peroxisome proliferator-activated receptor-γ (PPAR-γ) activation. However, the physiological impact of TRIB3 action in vivo remains controversial.
  
  
  METHODS
  We investigated the role of TRIB3 in rats treated with either a control or Trib3 antisense oligonucleotide (ASO). Tissue-specific insulin sensitivity was assessed in vivo using a euglycaemic-hyperinsulinaemic clamp. A separate group was treated with the PPAR-γ antagonist bisphenol-A-diglycidyl ether (BADGE) to assess the role of PPAR-γ in mediating the response to Trib3 ASO.
  
  
  RESULTS
  Trib3 ASO treatment specifically reduced Trib3 expression by 70% to 80% in liver and white adipose tissue. Fasting plasma glucose, insulin concentrations and basal rate of endogenous glucose production were unchanged. However, Trib3 ASO increased insulin-stimulated whole-body glucose uptake by ~50% during the euglycaemic-hyperinsulinaemic clamp. This was attributable to improved skeletal muscle glucose uptake. Despite the reduction of Trib3 expression, AKT2 activity was not increased. Trib3 ASO increased white adipose tissue mass by 70% and expression of Ppar-γ and its key target genes, raising the possibility that Trib3 ASO improves insulin sensitivity primarily in a PPAR-γ-dependent manner. Co-treatment with BADGE blunted the expansion of white adipose tissue and abrogated the insulin-sensitising effects of Trib3 ASO. Finally, Trib3 ASO also increased plasma HDL-cholesterol, a change that persisted with BADGE co-treatment.
  
  
  CONCLUSIONS
  These data suggest that TRIB3 inhibition improves insulin sensitivity in vivo primarily in a PPAR-γ-dependent manner and without any change in AKT2 activity.
authors.affiliation: Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, PO Box 802010, New Haven, CT 06520-8020, USA.
authors.forename: D
authors.initials: D
authors.lastname: Weismann
authors.forename: D M
authors.initials: DM
authors.lastname: Erion
authors.forename: I
authors.initials: I
authors.lastname: Ignatova-Todorava
authors.forename: Y
authors.initials: Y
authors.lastname: Nagai
authors.forename: R
authors.initials: R
authors.lastname: Stark
authors.forename: J J
authors.initials: JJ
authors.lastname: Hsiao
authors.forename: C
authors.initials: C
authors.lastname: Flannery
authors.forename: A L
authors.initials: AL
authors.lastname: Birkenfeld
authors.forename: T
authors.initials: T
authors.lastname: May
authors.forename: M
authors.initials: M
authors.lastname: Kahn
authors.forename: D
authors.initials: D
authors.lastname: Zhang
authors.forename: X X
authors.initials: XX
authors.lastname: Yu
authors.forename: S F
authors.initials: SF
authors.lastname: Murray
authors.forename: S
authors.initials: S
authors.lastname: Bhanot
authors.forename: B P
authors.initials: BP
authors.lastname: Monia
authors.forename: G W
authors.initials: GW
authors.lastname: Cline
authors.forename: G I
authors.initials: GI
authors.lastname: Shulman
authors.forename: V T
authors.initials: VT
authors.lastname: Samuel
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D004195:Disease Models, Animal; D004852:Epoxy Compounds / Q000494:pharmacology; D015309:Glucose Clamp Technique; D015151:Immunoblotting; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008297:Male; D016376:Oligonucleotides, Antisense / Q000235:genetics; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D004852:Epoxy Compounds; D016376:Oligonucleotides, Antisense; D047495:PPAR gamma; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; C502443:Trib3 protein, rat; C019273:bisphenol A diglycidyl ether; D000098826:Bisphenol A Compounds