Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, PO Box 802010, New Haven, CT 06520-8020, USA.
Diabetologia. 2011 Apr;54(4):935-44. doi: 10.1007/s00125-010-1984-5. Epub 2010 Dec 29.
AIMS/HYPOTHESIS: 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.
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.
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/INTERPRETATION: 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.
目的/假设：据称，胰岛素作用受果蝇 tribbles 同源物 3（TRIB3）调节，TRIB3 在体外可阻止胸腺瘤病毒原癌基因（AKT）和过氧化物酶体增殖物激活受体-γ（PPAR-γ）的激活。然而，TRIB3 在体内的生理作用仍存在争议。
我们研究了用对照或 Trib3 反义寡核苷酸（ASO）处理的大鼠中 TRIB3 的作用。使用正葡萄糖-高胰岛素钳夹技术在体内评估组织特异性胰岛素敏感性。另一组用 PPAR-γ 拮抗剂双酚 A 二缩水甘油醚（BADGE）治疗，以评估 PPAR-γ 在介导对 Trib3 ASO 反应中的作用。
Trib3 ASO 处理可使肝脏和白色脂肪组织中的 Trib3 表达分别特异性降低 70%至 80%。空腹血糖、胰岛素浓度和内源性葡萄糖产生率保持不变。然而，Trib3 ASO 在正葡萄糖-高胰岛素钳夹期间使胰岛素刺激的全身葡萄糖摄取增加了约 50%。这归因于骨骼肌葡萄糖摄取的改善。尽管 Trib3 表达减少，但 AKT2 活性没有增加。Trib3 ASO 增加了白色脂肪组织的质量，并增加了 Ppar-γ 及其关键靶基因的表达，这表明 Trib3 ASO 主要通过 PPAR-γ 依赖的方式改善胰岛素敏感性。与 BADGE 共同治疗减弱了白色脂肪组织的扩张，并消除了 Trib3 ASO 的胰岛素增敏作用。最后，Trib3 ASO 还增加了血浆高密度脂蛋白胆固醇，这一变化在与 BADGE 共同治疗时仍然存在。
结论/解释：这些数据表明，TRIB3 抑制在体内主要通过 PPAR-γ 依赖的方式改善胰岛素敏感性，而 AKT2 活性没有变化。
