Metformin ameliorates diet‐induced hepatic steatosis and inflammation without altering adipose phenotype (37.1)

Abstract

Non‐alcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis and inflammation, and is closely associated with obesity. We examined the effects of metformin on hepatic steatosis and inflammation to elucidate the possible protective mechanisms of metformin actions. Wild‐type C57BL/6J mice were fed a high‐fat diet (HFD) for 12 weeks and treated with metformin (150 mg/kg/d) orally for the last four weeks of HFD feeding. We found that metformin improved glucose tolerance and insulin sensitivity, and decreased liver weight and hepatic steatosis but not adiposity of HFD‐fed mice compared with controls. Additionally, metformin increased the phosphorylation of liver AMP‐activated protein kinase (AMP) and decreased the phosphorylation of liver c‐Jun N‐terminal kinase 1 (JNK1) and the mRNA levels of lipogenic enzymes and proinflammatory cytokines. These changes were not observed in adipose tissue. In cultured hepatocytes, metformin increased AMPK phosphorylation and decreased fat deposition and inflammatory responses. In cultured macrophages, metformin partially blunted the stimulatory effects of lipopolysaccharide on JNK1 and nuclear factor kappa B p65 phosphorylation and cytokine expression. Thus, metformin protects against NAFLD largely through direct effects on decreasing hepatocyte fat deposition and on inhibiting inflammatory responses in both hepatocytes and macrophages.Grant Funding Source: Supported by ADA, AHA, NIH