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Beneficial Effects of Metformin in Diet-Induced Obesity Associated Non-Alcoholic Fatty Liver Disease
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Non-alcoholic fatty liver disease (NAFLD) is closely associated with obesity and insulin resistance. To better understand the pathophysiology of obesity-associated NAFLD, the present study examined the involvement of liver and adipose tissues in metformin actions on reducing hepatic steatosis and inflammation during obesity. Also, the importance of AMPK in regulating the anti-steatosis and anti-inflammatory properties of metformin was examined. C57BL/6J mice were fed a high-fat diet (HFD) for 12 weeks to induce obesity-associated NAFLD and treated with metformin (150 mg/kg/d) orally for the last four weeks of HFD feeding. Compared with HFD-fed control mice, metformin-treated mice showed improvement in both glucose tolerance and insulin sensitivity, but also a decrease in hepatic steatosis and liver inflammation associated with an increase in the phosphorylation of liver AMP-activated protein kinase (AMPK). However, metformin treatment did not significantly alter adipose tissue AMPK phosphorylation and inflammatory responses. In vitro studies showed that metformin directly decreased steatosis in hepatocytes and inflammation in both hepatocytes and macrophages, and is AMPK associated. Further in vitro studies confirmed the importance of AMPK in regulating the anti-steatosis and anti-inflammatory effects of metformin in hepatocytes and macrophages. Taken together, these results suggest that metformin protects against obesity-associated NAFLD largely through direct effects on decreasing hepatocyte fat deposition and on inhibiting inflammatory responses in both hepatocytes and macrophages.
Woo, Shih Lung (2016). Beneficial Effects of Metformin in Diet-Induced Obesity Associated Non-Alcoholic Fatty Liver Disease. Doctoral dissertation, Texas A & M University. Available electronically from