Nature Medicine
6, 998 - 1003 (2000)
doi:10.1038/79697
Metformin reverses fatty liver disease in obese, leptin-deficient miceHui Zhi Lin1, Shi Qi Yang1, Christine Chuckaree1, Francis Kuhajda2, Gabriele Ronnet3
& Anna Mae Diehl11
Departments of Medicine, Bldg AA, Room 154-A, 4940 Eastern Ave, Baltimore, Maryland 21224
2
Department of Pathology, Bldg AA, Room 154-A, 4940 Eastern Ave, Baltimore, Maryland 21224
3
Department of Neuroscience & Neurology, PCTB 1007, 725 N. Wolfe St., Baltimore, Maryland 21205 The Johns Hopkins University, Baltimore, Maryland
Correspondence should be addressed to Anna Mae Diehl amdiehl@welchlink.welch.jhu.eduThere 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)  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.
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