Liraglutide increases FGF-21 activity and insulin sensitivity in high fat diet and adiponectin knockdown induced insulin resistance

PLoS One. 2012;7(11):e48392. doi: 10.1371/journal.pone.0048392. Epub 2012 Nov 12.

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.

Method: 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.

Conclusion: 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.

MeSH terms

  • Adiponectin / genetics*
  • Adipose Tissue / drug effects
  • Adipose Tissue / metabolism
  • Animals
  • Apolipoproteins E / genetics
  • Blood Glucose / drug effects
  • Diet, High-Fat*
  • Fibroblast Growth Factors / blood
  • Fibroblast Growth Factors / genetics
  • Fibroblast Growth Factors / metabolism*
  • Gene Expression Regulation / drug effects
  • Gene Knockdown Techniques
  • Glucagon-Like Peptide 1 / administration & dosage
  • Glucagon-Like Peptide 1 / analogs & derivatives*
  • Glucagon-Like Peptide 1 / pharmacology
  • Glucose Tolerance Test
  • Insulin Resistance / genetics*
  • Liraglutide
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • RNA Interference
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Fibroblast Growth Factor / genetics
  • Receptors, Fibroblast Growth Factor / metabolism

Substances

  • Adiponectin
  • Apolipoproteins E
  • Blood Glucose
  • RNA, Messenger
  • Receptors, Fibroblast Growth Factor
  • fibroblast growth factor 21
  • Fibroblast Growth Factors
  • Liraglutide
  • Glucagon-Like Peptide 1

Grant support

This work was supported by grants from the National Natural Science Foundation of China (30871199, 30771037, 30971388 and 81070640), and the Doctoral Fund of the Ministry of Education of China (20105503110002). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.