Metformin reverses fatty liver disease in obese, leptin-deficient mice

Nat Med. 2000 Sep;6(9):998-1003. doi: 10.1038/79697.


There is no known treatment for fatty liver, a ubiquitous cause of chronic liver disease. However, because it is associated with hyperinsulinemia and insulin-resistance, insulin-sensitizing agents might be beneficial. To evaluate this possibility, insulin-resistant ob/ob mice with fatty livers were treated with metformin, an agent that improves hepatic insulin-resistance. Metformin improved fatty liver disease, reversing hepatomegaly, steatosis and aminotransferase abnormalities. The therapeutic mechanism likely involves inhibited hepatic expression of tumor necrosis factor (TNF) alpha and TNF-inducible factors that promote hepatic lipid accumulation and ATP depletion. These findings suggest a mechanism of action for metformin and identify novel therapeutic targets in insulin-resistant states.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Adipose Tissue / drug effects
  • Animals
  • Body Weight / drug effects
  • Energy Intake / drug effects
  • Energy Metabolism / drug effects
  • Fatty Liver / drug therapy*
  • Hepatomegaly / drug therapy
  • Homeostasis / drug effects
  • Hypoglycemic Agents / therapeutic use*
  • Insulin Resistance
  • Lipids / biosynthesis
  • Metformin / therapeutic use*
  • Mice
  • Mice, Obese
  • Obesity*
  • Transaminases / drug effects
  • Tumor Necrosis Factor-alpha / biosynthesis*


  • Hypoglycemic Agents
  • Lipids
  • Tumor Necrosis Factor-alpha
  • Adenosine Triphosphate
  • Metformin
  • Transaminases