title: Mitofusin-2 ameliorates high-fat diet-induced insulin resistance in liver of rats.
abstract: OBJECTIVE
  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 9(th) wk. Blood glucose (BG), plasma insulin and insulin sensitivity of rats were determined at end of the 4(th) and 8(th) wk, and after treatment with different amounts of MFN2 expressing adenovirus (10(8), 10(9) or 10(10) 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.
  
  
  CONCLUSIONS
  HFDs induce insulin resistance, and this can be reversed by MFN2 over-expression targeting the insulin signaling pathway.
authors.affiliation: Department of Internal Medicine, Hebei Medical University, Shijiazhuang 050017, Hebei Province, China.
authors.forename: Ke-Xin
authors.initials: KX
authors.lastname: Gan
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.forename: Jin-Hu
authors.initials: JH
authors.lastname: Chen
authors.forename: Chun-Jing
authors.initials: CJ
authors.lastname: Zhu
authors.forename: Guang-Yao
authors.initials: GY
authors.lastname: Song
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D020558:GTP Phosphohydrolases / Q000096:biosynthesis* / Q000235:genetics; D015316:Genetic Therapy; D051273:Glucose Transporter Type 2 / Q000378:metabolism; D007328:Insulin / Q000097:blood; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D024101:Mitochondrial Proteins / Q000096:biosynthesis* / Q000235:genetics; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D051273:Glucose Transporter Type 2; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526299:Irs2 protein, rat; D024101:Mitochondrial Proteins; C495683:Slc2a2 protein, rat; D058539:Phosphatidylinositol 3-Kinase; D011972:Receptor, Insulin; C494923:Akt2 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D020558:GTP Phosphohydrolases
keywords: High-fat diet; Insulin pathway; Insulin resistance; Liver; Mitofusin-2
references.citation: Endocrinology. 2005 Feb;146(2):579-88
references.pmid: 15514089
references.citation: Physiol Rev. 2009 Jul;89(3):799-845
references.pmid: 19584314
references.citation: J Biol Chem. 2000 May 26;275(21):15985-91
references.pmid: 10821852
references.citation: Hypertension. 2004 Feb;43(2):383-7
references.pmid: 14707164
references.citation: J Clin Invest. 1997 Dec 15;100(12):3164-72
references.pmid: 9399964
references.citation: J Biol Chem. 2008 May 16;283(20):13501-5
references.pmid: 18372247
references.citation: J Cell Sci. 2001 Mar;114(Pt 5):867-74
references.pmid: 11181170
references.citation: Proc Natl Acad Sci U S A. 2012 Apr 3;109(14):5523-8
references.pmid: 22427360
references.citation: Diabetologia. 2007 Nov;50(11):2348-55
references.pmid: 17828388
references.citation: Am J Physiol Endocrinol Metab. 2011 Nov;301(5):E749-55
references.pmid: 21862724
references.citation: J Biol Chem. 2002 Nov 1;277(44):42394-8
references.pmid: 12228220
references.citation: Lancet. 2005 Apr 16-22;365(9468):1415-28
references.pmid: 15836891
references.citation: Am J Physiol Endocrinol Metab. 2009 May;296(5):E985-92
references.pmid: 19223655
references.citation: Acta Pharmacol Sin. 2010 Oct;31(10):1293-302
references.pmid: 20711222
references.citation: J Huazhong Univ Sci Technolog Med Sci. 2009 Dec;29(6):689-96
references.pmid: 20037808
references.citation: J Biol Chem. 2005 Jul 15;280(28):26185-92
references.pmid: 15899901
references.citation: Nature. 2001 Dec 13;414(6865):799-806
references.pmid: 11742412
references.citation: Mol Cell Biochem. 1998 May;182(1-2):3-11
references.pmid: 9609109
references.citation: J Mol Endocrinol. 2006 Jun;36(3):485-501
references.pmid: 16720718
references.citation: Proc Natl Acad Sci U S A. 2004 Jul 13;101(28):10422-7
references.pmid: 15240880
references.citation: J Cell Biol. 2003 Jan 20;160(2):189-200
references.pmid: 12527753
references.citation: J Cell Sci. 2005 Jul 15;118(Pt 14):3153-61
references.pmid: 15985463
references.citation: Diabetes. 1997 Jan;46(1):3-10
references.pmid: 8971073
references.citation: J Biol Chem. 2001 Dec 21;276(51):47944-9
references.pmid: 11604392
references.citation: Diabetes Care. 2010 Mar;33(3):645-51
references.pmid: 20032281
references.citation: Int J Obes Relat Metab Disord. 2004 Aug;28(8):1064-71
references.pmid: 15254487
references.citation: J Biol Chem. 2000 Dec 15;275(50):38990-4
references.pmid: 10995761
references.citation: Biochim Biophys Acta. 2010 Jun-Jul;1797(6-7):1028-33
references.pmid: 20175989
references.citation: FASEB J. 2001 Oct;15(12):2099-111
references.pmid: 11641236
references.citation: Int J Biochem Cell Biol. 2009 Oct;41(10):1846-54
references.pmid: 19703653
references.citation: Genes Cells. 2007 Feb;12(2):143-54
references.pmid: 17295835
references.citation: Arch Physiol Biochem. 2009 Feb;115(1):1-12
references.pmid: 19267277
references.citation: Am J Pathol. 2004 Nov;165(5):1499-508
references.pmid: 15509521
references.citation: Ann Surg. 2009 Feb;249(2):277-85
references.pmid: 19212182
references.citation: Neth J Med. 1997 May;50(5):191-7
references.pmid: 9175399
references.citation: Cell. 2010 Apr 16;141(2):280-9
references.pmid: 20403324
references.citation: Circ Res. 2008 Feb 29;102(4):401-14
references.pmid: 18309108