FTO modulates circadian rhythms and inhibits the CLOCK-BMAL1-induced transcription

Abstract Variations in the human fat mass and obesity-associated gene, which encodes FTO, an 2-oxoglutarate-dependent nucleic acid demethylase, are associated with increased risk of obesity. These FTO variations were recently shown to affect IRX3 and the exact function of FTO is still controversial. Obesity is closely linked to circadian rhythm. To understand the role of FTO in circadian rhythm, we analyzed the circadian rhythm of FTO deficient mice. FTO deficient mice had robust circadian locomotor activity rhythms with prolonged periods. The light-induced phase shifts of circadian rhythms were also significantly affected in FTO deficient mice. Tissue explants of FTO deficient mice maintained robust peripheral rhythms with prolonged period. Overexpress of FTO represses the transcriptional activation by CLOCK and BMAL1. Core clock genes expression of mRNA and protein were also altered in FTO deficient mice. Furthermore, FTO co-immunoprecipitated with CRY1/2 in a circadian manner. These results indicate a fundamental link between the circadian rhythm and FTO and extend the function of FTO to the core clockwork machinery.