Original Article
Copyright ©2013 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Mar 14, 2013; 19(10): 1572-1581
Published online Mar 14, 2013. doi: 10.3748/wjg.v19.i10.1572
Mitofusin-2 ameliorates high-fat diet-induced insulin resistance in liver of rats
Ke-Xin Gan, Chao Wang, Jin-Hu Chen, Chun-Jing Zhu, Guang-Yao Song
Ke-Xin Gan, Chun-Jing Zhu, Department of Internal Medicine, Hebei Medical University, Shijiazhuang 050017, Hebei Province, China
Chao Wang, Jin-Hu Chen, Department of Endocrinology, the General Hospital of Hebei Province, Shijiazhuang 050051, Hebei Province, China
Guang-Yao Song, Department of Internal Medicine, Hebei Medical University, Shijiazhuang 050017, Hebei Province, China
Author contributions: Song GY, Wang C, Chen JH, Gan KX and Zhu CJ designed the research; Gan KX and Zhu CJ performed the research and analyzed the data; Gan KX wrote the paper; all authors have read and approved the final manuscript.
Supported by Grants from the National Natural Science Foundation of China, No. 30971391, No. 81170742; and Natural Science Foundation of Hebei Province, China, No. C2010001638, No. C2011307008
Correspondence to: Guang-Yao Song, Professor, Department of Internal Medicine, Hebei Medical University, 361 East Zhongshan Road, Shijiazhuang 050017, Hebei Province, China. sguangyao@sohu.com
Telephone: +86-311-85988267 Fax: +86-311-85988318
Received: August 12, 2012
Revised: November 13, 2012
Accepted: December 27, 2012
Published online: March 14, 2013
Processing time: 214 Days and 17.7 Hours
Abstract

AIM: To investigate the effects of mitofusin-2 (MFN2) on insulin sensitivity and its potential targets in the liver of rats fed with a high-fat diet (HFD).

METHODS: Rats were fed with a control or HFD for 4 or 8 wk, and were then infected with a control or an MFN2 expressing adenovirus once a week for 3 wk starting from the 9th wk. Blood glucose (BG), plasma insulin and insulin sensitivity of rats were determined at end of the 4th and 8th wk, and after treatment with different amounts of MFN2 expressing adenovirus (108, 109 or 1010 vp/kg body weight). BG levels were measured by Accu-chek Active Meter. Plasma insulin levels were analyzed by using a Rat insulin enzyme-linked immunosorbent assay kit. Insulin resistance was evaluated by measuring the glucose infusion rate (GIR) using a hyperinsulinemic euglycemic clamp technique. The expression or phosphorylation levels of MFN2 and essential molecules in the insulin signaling pathway, such as insulin receptor (INSR), insulin receptor substrate 2 (IRS2), phosphoinositide-3-kinase (PI3K), protein kinase beta (AKT2) and glucose transporter type 2 (GLUT2) was assayed by quantitative real-time polymerase chain reaction and Western-blotting.

RESULTS: After the end of 8 wk, the body weight of rats receiving the normal control diet (ND) and the HFD was not significantly different (P > 0.05). Compared with the ND group, GIR in the HFD group was significantly decreased (P < 0.01), while the levels of BG, triglycerides (TG), total cholesterol (TC) and insulin in the HFD group were significantly higher than those in the ND group (P < 0.05). Expression of MFN2 mRNA and protein in liver of rats was significantly down-regulated in the HFD group (P < 0.01) after 8 wk of HFD feeding. The expression of INSR, IRS2 and GLUT2 were down-regulated markedly (P < 0.01). Although there were no changes in PI3K-P85 and AKT2 expression, their phosphorylation levels were decreased significantly (P < 0.01). After intervention with MFN2 expressing adenovirus for 3 wk, the expression of MFN2 mRNA and protein levels were up-regulated (P < 0.01). There was no difference in body weight of rats between the groups. The levels of BG, TG, TC and insulin in rats were lower than those in the Ad group (P < 0.05), but GIR in rats infected with Ad-MFN2 was significantly increased (P < 0.01), compared with the Ad group. The expression of INSR, IRS2 and GLUT2 was increased, while phosphorylation levels of PI3K-P85 and AKT2 were increased (P < 0.01), compared with the Ad group.

CONCLUSION: HFDs induce insulin resistance, and this can be reversed by MFN2 over-expression targeting the insulin signaling pathway.

Keywords: Mitofusin-2, High-fat diet, Insulin resistance, Insulin pathway, Liver