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Exendin‐4, a glucagon‐like protein‐1 (GLP‐1) receptor agonist, reverses hepatic steatosis in ob / ob mice
Author(s) -
Ding Xiaokun,
Saxeeeraj K.,
Lin Songbai,
Gupta Narita,
Anania Frank A.
Publication year - 2006
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.21006
Subject(s) - medicine , endocrinology , steatosis , insulin resistance , adiponectin , agonist , insulin , glucagon like peptide 1 receptor , exenatide , nonalcoholic fatty liver disease , glucose homeostasis , fatty liver , receptor , chemistry , type 2 diabetes , diabetes mellitus , disease
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 μg/kg or 20 μg/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. (H EPATOLOGY 2006;43:173–181.)