Metformin reverses fatty liver disease in obese, leptin-deficient mice.
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.
Lin
H Z
HZ
Department of Medicine, Bldg AA, Room 154-A, 4940 Eastern Ave, Baltimore, Maryland 21224, USA.
Yang
S Q
SQ
Chuckaree
C
C
Kuhajda
F
F
Ronnet
G
G
Diehl
A M
AM
D000255:Adenosine Triphosphate / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002149:Energy Intake / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D005234:Fatty Liver / Q000188:drug therapy*; D006529:Hepatomegaly / Q000188:drug therapy; D006706:Homeostasis / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007333:Insulin Resistance; D008055:Lipids / Q000096:biosynthesis; D008687:Metformin / Q000627:therapeutic use*; D051379:Mice; D008820:Mice, Obese; D009765:Obesity; D000637:Transaminases / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D007004:Hypoglycemic Agents; D008055:Lipids; D014409:Tumor Necrosis Factor-alpha; D000255:Adenosine Triphosphate; D008687:Metformin; D000637:Transaminases