title: Liraglutide increases FGF-21 activity and insulin sensitivity in high fat diet and adiponectin knockdown induced insulin resistance.
abstract: BACKGROUND
  Liraglutide is a glucagon-like peptide-1 analogue that stimulates insulin secretion and improves β-cell function. However, it is not clear whether liraglutide achieves its glucose lowering effect only by its known effects or whether other as yet unknown mechanisms are involved. The aim of this study was to examine the effects of liraglutide on Fibroblast growth factor-21 (FGF-21) activity in High-fat diet (HFD) fed ApoE(-/-) mice with adiponectin (Acrp30) knockdown.
  
  
  METHODS
  HFD-fed ApoE(-/-) mice were treated with adenovirus vectors expressing shAcrp30 to produce insulin resistance. Hyperinsulinemic-euglycemic clamp studies were performed to evaluate insulin sensitivity of the mouse model. QRT-PCR and Western blot were used to measure the mRNA and protein expression of the target genes.
  
  
  RESULTS
  The combination of HFD, ApoE deficiency, and hypoadiponectinemia resulted in an additive effect on insulin resistance. FGF-21 mRNA expressions in both liver and adipose tissues were significantly increased while FGF-21 receptor 1 (FGFR-1) and β-Klotho mRNA levels in adipose tissue, as well as FGFR-1-3 and β-Klotho mRNA levels in liver were significantly decreased in this model. Liraglutide treatment markedly improved insulin resistance and increased FGF-21 expression in liver and FGFR-3 in adipose tissue, restored β-Klotho mRNA expression in adipose tissue as well as FGFR-1-3, β-Klotho levels and phosphorylation of FGFR1 up to the levels observed in control mice in liver. Liraglutide treatment also further increased FGF-21 proteins in liver and plasma. In addition, as shown by hyperinsulinemic-euglycemic clamp, liraglutide treatment also markedly improved glucose metabolism and insulin sensitivity in these animals.
  
  
  CONCLUSIONS
  These findings demonstrate an additive effect of HFD, ApoE deficiency, and adiponectin knockdown on insulin resistance and unveil that the regulation of glucose metabolism and insulin sensitivity by liraglutide may be partly mediated via increased FGF-21 and its receptors action.
authors.affiliation: Key Laboratory of Diagnostic Medicine (Ministry of Education) and Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China.
authors.forename: Mengliu
authors.initials: M
authors.lastname: Yang
authors.forename: Lili
authors.initials: L
authors.lastname: Zhang
authors.forename: Chong
authors.initials: C
authors.lastname: Wang
authors.forename: Hua
authors.initials: H
authors.lastname: Liu
authors.forename: Guenther
authors.initials: G
authors.lastname: Boden
authors.forename: Gangyi
authors.initials: G
authors.lastname: Yang
authors.forename: Ling
authors.initials: L
authors.lastname: Li
mesh_terms: D052242:Adiponectin / Q000235:genetics*; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D001786:Blood Glucose / Q000187:drug effects; D059305:Diet, High-Fat; D005346:Fibroblast Growth Factors / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D005951:Glucose Tolerance Test; D007333:Insulin Resistance / Q000235:genetics*; D000069450:Liraglutide; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D052242:Adiponectin; D001057:Apolipoproteins E; D001786:Blood Glucose; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1