Nonalcoholic steatohepatitis is prevalent among obese individuals with excessive caloric intake, insulin resistance, and type II diabetes. However, no animal models exist that recapitulate this important association. This study produced and characterized steatohepatitis (SH) caused by intragastric overfeeding in mice. C57BL/6, tumor necrosis factor (TNF) type I receptor-deficient, and genetically matched wild type mice were fed via an implanted gastrostomy tube a high-fat diet for 9 weeks in the increasing amount up to 85% in excess of the standard intake. Animals were examined for weight gain, insulin sensitivity, and histology and biochemistry of liver and white adipose tissue (WAT). Overfed C57BL/6 mice progressively became obese, with 71% larger final body weights. They had increased visceral WAT, hyperglycemia, hyperinsulinemia, hyperleptinemia, glucose intolerance, and insulin resistance. Of these mice, 46% developed SH with increased plasma alanine aminotransferase (121 ± 27 vs. 13 ± 1 U/L), neutrophilic infiltration, and sinusoidal and pericellular fibrosis. Obese WAT showed increased TNFα and leptin expression and reciprocally reduced adiponectin expression. The expression of lipogenic transcription factors (SREBP-1c, PPARγ, LXRα) was increased, whereas that of a lipolytic nuclear factor PPARα was reduced in SH. SH was associated with reduced cytochrome P450 (Cyp)2e1 but increased Cyp4a. TNF type I receptor deficiency did not prevent obesity and SH. In conclusion, forced overfeeding with a high-fat diet in mice induces obesity, insulin resistance, and SH in the absence of TNF signaling or Cyp2e1 induction.
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