Exendin-4, a Glucagon-Like protein-1 (GLP-1) Receptor Agonist, Reverses Hepatic Steatosis in ob/ob Mice

Hepatology. 2006 Jan;43(1):173-81. doi: 10.1002/hep.21006.

Abstract

Nonalcoholic fatty liver disease (NAFLD) represents a burgeoning problem in hepatology, and is associated with insulin resistance. Exendin-4 is a peptide agonist of the glucagon-like peptide (GLP) receptor that promotes insulin secretion. The aim of this study was to determine whether administration of Exendin-4 would reverse hepatic steatosis in ob/ob mice. Ob/ob mice, or their lean littermates, were treated with Exendin-4 [10 microg/kg or 20 microg/kg] for 60 days. Serum was collected for measurement of insulin, adiponectin, fasting glucose, lipids, and aminotransferase concentrations. Liver tissue was procured for histological examination, real-time RT-PCR analysis and assay for oxidative stress. Rat hepatocytes were isolated and treated with GLP-1. Ob/ob mice sustained a reduction in the net weight gained during Exendin-4 treatment. Serum glucose and hepatic steatosis was significantly reduced in Exendin-4 treated ob/ob mice. Exendin-4 improved insulin sensitivity in ob/ob mice, as calculated by the homeostasis model assessment. The measurement of thiobarbituric reactive substances as a marker of oxidative stress was significantly reduced in ob/ob-treated mice with Exendin-4. Finally, GLP-1-treated hepatocytes resulted in a significant increase in cAMP production as well as reduction in mRNA expression of stearoyl-CoA desaturase 1 and genes associated with fatty acid synthesis; the converse was true for genes associated with fatty acid oxidation. In conclusion, Exendin-4 appears to effectively reverse hepatic steatosis in ob/ob mice by improving insulin sensitivity. Our data suggest that GLP-1 proteins in liver have a novel direct effect on hepatocyte fat metabolism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / metabolism
  • Alanine Transaminase / blood
  • Animals
  • Blood Glucose / analysis
  • Cyclic AMP / biosynthesis
  • Exenatide
  • Fatty Liver / drug therapy*
  • Glucagon-Like Peptide 1 / pharmacology
  • Glucagon-Like Peptide-1 Receptor
  • Insulin Resistance
  • Lipid Peroxidation / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Mice
  • Mice, Obese
  • PPAR alpha / genetics
  • Peptides / therapeutic use*
  • RNA, Messenger / analysis
  • Receptors, Glucagon / agonists*
  • Receptors, Glucagon / analysis
  • Stearoyl-CoA Desaturase / genetics
  • Sterol Regulatory Element Binding Protein 1 / genetics
  • Venoms / therapeutic use*
  • Weight Gain / drug effects

Substances

  • Blood Glucose
  • Glp1r protein, mouse
  • Glp1r protein, rat
  • Glucagon-Like Peptide-1 Receptor
  • PPAR alpha
  • Peptides
  • RNA, Messenger
  • Receptors, Glucagon
  • Sterol Regulatory Element Binding Protein 1
  • Venoms
  • Glucagon-Like Peptide 1
  • Exenatide
  • Cyclic AMP
  • Stearoyl-CoA Desaturase
  • Alanine Transaminase