Research Paper Volume 11, Issue 18 pp 7510—7524

MiR-27a promotes insulin resistance and mediates glucose metabolism by targeting PPAR-γ-mediated PI3K/AKT signaling

Tianbao Chen 1, *, , Yi Zhang 2, *, , Yilan Liu 2, , Dexiao Zhu 1, , Jing Yu 2, , Guoqian Li 1, , Zhichun Sun 2, , Wanru Wang 1, , Hongwei Jiang 3, , Zhenzhen Hong 2, ,

  • 1 Department of Cardiology, The First Affiliated Hospital of Quanzhou, Fujian Medical University, Quanzhou, Fujian, China
  • 2 Department of Endocrinology, The First Affiliated Hospital of Quanzhou, Fujian Medical University, Quanzhou, Fujian, China
  • 3 Department of Endocrinology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan, China
* Equal contribution and Co-first authors

received: March 21, 2019 ; accepted: September 2, 2019 ; published: September 28, 2019 ;

https://doi.org/10.18632/aging.102263
How to Cite

Copyright © 2019 Chen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

This study aimed to establish a high-fat diet (HFD)-fed obese mouse model and a cell culture model of insulin resistance (IR) in mature 3T3-L1 adipocytes. A dual-luciferase reporter assay (DLRA) was confirmed interaction between miR-27a and the 3′-untranslated region (UTR) of Peroxisome proliferator-activated receptor (PPAR)-γ. The inhibition of PPAR-γ expression by microRNA (miR)-27a in IR cells at both the protein and mRNA levels was confirmed by a mechanistic investigation. Moreover, the 3′-UTR of PPAR-γ was found to be a direct target of miR-27a, based on the DLRA. Furthermore, antagomiR-27a upregulated the activation of PI3K/Akt signaling and glucose transporter type 4 (GLUT4) expression at the protein and mRNA levels. Additionally, the PPAR inhibitor T0070907 repressed the insulin sensitivity upregulated by antagomiR-27a, which was accompanied by the inhibition of PPAR-γ expression and increased levels of AKT phosphorylation and GLUT4. The PI3K inhibitor wortmannin reduced miR-27a-induced increases in AKT phosphorylation, glucose uptake, and GLUT4. miR-27a is considered to be involved in the PPAR-γ-PI3K/AKT-GLUT4 signaling axis, thus leading to increased glucose uptake and decreased IR in HFD-fed mice and 3T3-L1 adipocytes. Therefore, miR-27a is a novel target for the treatment of IR in obesity and diabetes.

Abbreviations

HFD: High-fat diet; DLRA: Dual-luciferase reporter assay; UTR: 3′-untranslated region; T2DM: Type 2 diabetes mellitus; Mirnas: Micrornas; GLUT4: Glucose transporter type 4; MAPK: Mitogen-activated protein kinase; PPAR: Peroxisome proliferator-activated receptor; HFD: High-fat diet; TGF: Transforming growth factor; TNF: Tumor necrosis factor; qrt-PCR: Quantitative real-time PCR; WB: Western blot; FBS: Fetal bovine serum; DMEM: Dulbecco’s modified Eagle’s medium; AD-mir-27a: Adenovirus expressing a mir-27a inhibitor; AD-NC: Adenovirus vector; PBST: PBS-Tween-20; BSA: Bovine serum albumin; GAPDH: Glyceraldehyde 3-phosphate dehydrogenase.