To assess the effect of adiponectin on the circadian rhythm disturbances associated with metabolic syndrome, we generated a KK/Ta mouse line expressing the human adiponectin transgene in the liver. Locomotor activity of control C57BL/6 mice was highest during the beginning of the dark period and low during the light period. Under constant darkness, the length of locomotor activity rhythm of control mice was slightly shorter than 24 h. In KK/Ta mice the peak of locomotor activity was blunted and significant activity was observed during the light period. Furthermore, KK/Ta mice showed shorter average period length of free-running locomotor activity rhythm when compared with control mice. However, the transgenic expression of adiponectin in the liver significantly altered the circadian rhythm of locomotor activity and the length of free-running rhythm of KK/Ta mice towards those of C57BL/6 mice. In the liver and skeletal muscles from control mice, mRNA levels of Arntl and Cry1 were increased during the dark period, whereas those of Dbp, Cry2, Per1 and Per2 were elevated during the light period. KK/Ta mice exhibited phase advances in circadian rhythms of Arntl, Dbp, Cry2 and Per2 in both tissues. The phase shifts of the circadian clock gene expression in the liver were attenuated in adiponectin-transgenic mice. These results suggest that adiponectin is a peripheral regulator of the circadian clocks in the brain and peripheral organs, and may be a novel target for the treatment of obesity-associated disorders of circadian rhythms.