Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice.

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.

• Authors: Xiaokun Ding, Neeraj K Saxena, Songbai Lin, Nitika Arora Gupta, Narita Gupta, Frank A Anania
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 43 Issue 1 Pg. 173-81 (Jan 2006) ISSN: 0270-9139 [Print] United States
• PMID: 16374859 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• 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, pathology)
• Male
• Mice
• Mice, Obese
• PPAR alpha (genetics)
• Peptides (therapeutic use)
• RNA, Messenger (analysis)
• Receptors, Glucagon (agonists, analysis)
• Stearoyl-CoA Desaturase (genetics)
• Sterol Regulatory Element Binding Protein 1 (genetics)
• Venoms (therapeutic use)
• Weight Gain (drug effects)