['Piperonal is an important flavor additive with antibacterial and anxiolytic properties. We investigated the effects and possible mechanisms of piperonal protection against high-fat diet (HFD)-induced hepatic steatosis and insulin resistance.', 'C57BL/6 J mice were fed with a normal diet (ND; based on the AIN-76 rodent diet), HFD (20% fat and 1% cholesterol), or piperonal-supplemented diet (POD; HFD supplemented with 0.05% piperonal) for 10 weeks.', 'Piperonal supplementation reduced hepatic lipid concentrations, liver dysfunction and plasma levels of insulin and glucose in HFD-fed mice. Piperonal significantly enhanced mRNA expression and secretion of adiponectin in 3T3-L1 adipocytes. Dietary piperonal significantly increased circulating adiponectin levels and hepatic AMP-activated protein kinase (AMPK) activation in HFD-fed mice; these were associated with the suppression of sterol regulatory element binding protein-1c and activation of glucose transporter-2 translocation in the livers. Piperonal also significantly reduced the expression of endoplasmic reticulum (ER) stress markers in the livers of HFD-fed mice.'] Does piperonal prevent high-fat diet-induced hepatic steatosis and insulin resistance in mice via activation of adiponectin/AMPK pathway?