MicroRNA-26a regulates insulin sensitivity and metabolism of glucose and lipids
Xianghui Fu, … , David D. Moore, Wendong Huang
Xianghui Fu, … , David D. Moore, Wendong Huang
Published May 11, 2015
Citation Information: J Clin Invest. 2015;125(6):2497-2509. https://doi.org/10.1172/JCI75438.
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Research Article Metabolism

MicroRNA-26a regulates insulin sensitivity and metabolism of glucose and lipids

Abstract

Type 2 diabetes (T2D) is characterized by insulin resistance and increased hepatic glucose production, yet the molecular mechanisms underlying these abnormalities are poorly understood. MicroRNAs (miRs) are a class of small, noncoding RNAs that have been implicated in the regulation of human diseases, including T2D. miR-26a is known to play a critical role in tumorigenesis; however, its function in cellular metabolism remains unknown. Here, we determined that miR-26a regulates insulin signaling and metabolism of glucose and lipids. Compared with lean individuals, overweight humans had decreased expression of miR-26a in the liver. Moreover, miR-26 was downregulated in 2 obese mouse models compared with control animals. Global or liver-specific overexpression of miR-26a in mice fed a high-fat diet improved insulin sensitivity, decreased hepatic glucose production, and decreased fatty acid synthesis, thereby preventing obesity-induced metabolic complications. Conversely, silencing of endogenous miR-26a in conventional diet–fed mice impaired insulin sensitivity, enhanced glucose production, and increased fatty acid synthesis. miR-26a targeted several key regulators of hepatic metabolism and insulin signaling. These findings reveal miR-26a as a regulator of liver metabolism and suggest miR-26a should be further explored as a potential target for the treatment of T2D.

Authors

Xianghui Fu, Bingning Dong, Yan Tian, Philippe Lefebvre, Zhipeng Meng, Xichun Wang, François Pattou, Weidong Han, Xiaoqiong Wang, Fang Lou, Richard Jove, Bart Staels, David D. Moore, Wendong Huang

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Figure 5

miR-26a regulates fatty acid metabolism and gluconeogenesis.

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miR-26a regulates fatty acid metabolism and gluconeogenesis. (A) Venn di...
(A) Venn diagram comparing hepatic proteins in WT and Alb-Mir26a mice fed a HFD for 16 weeks, as identified by proteomic analysis. The numbers of proteins that are similarly or differentially expressed are shown. (B) Heat map of protein levels of genes involved in fatty acid metabolism, as indicated in Supplemental Figure 12. (C) Heat map of mRNA levels of genes involved in lipid and cholesterol metabolism. (D) Plasma triglycerides, cholesterol, and HDL levels in WT and Alb-Mir26a Tg mice fed a HFD. (E) Heat map of protein levels of genes involved in glycolysis/gluconeogenesis. (F) Expression of gluconeogenic genes in livers of Alb-Mir26a Tg and WT mice fed a HFD for 16 weeks. (G) PTT analysis of Alb-Mir26a Tg and WT mice fed a HFD for 16 weeks. (H) Glucose production in primary hepatocytes isolated from Alb-Mir26a Tg and WT mice fed either a CD or a HFD for 16 weeks. Results are normalized to the level in hepatocytes isolated from WT mice fed a CD. Data are shown as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.005, 2-tailed Student’s t test.