The prevalence of metabolic syndrome, obesity and insulin resistance has become an epidemic in the world. A strong association exists between metabolic syndrome and non-alcoholic fatty liver disease (NAFLD), though the etiology of NAFLD is still unclear. This close association leads to numerous clinical studies to investigate the effects of insulin sensitizers, thiazolidinediones (TZDs), on hepatic fat accumulation. Thiazolidinediones affect glucose and lipid metabolism in insulin-sensitive tissues, which in turn reduces the lipid content in the liver by modulating several mediators. In the present review, we discuss key modulators – adiponectin and sirtulin-adenosine monophosphate activated protein kinase signaling – as the mechanisms responsible for NAFLD related to metabolic syndrome.