Calorie restriction effects on circadian rhythms in gene expression are sex dependent.

The rhythms in the expression of circadian clock genes are affected by calorie restriction (CR), a dietary paradigm known to increase lifespan. Many physiological effects of CR differ between males and females; here we investigated if the sex of animals affects the CR induced changes in the circadian rhythms. The liver expression of some circadian clock genes such as Bmal1 and three Periods (Per1, Per2 and Per3) and the effect of CR on the expression of these genes were sex independent, while the expression of Rev-Erb alpha, Ror gamma and both Cryptochome (Cry1 and Cry2) genes was different between males and females. The effect of CR on Rev-Erb alpha, Ror gamma and Cry1 gene expression was sex dependent. The expression and the effects of CR were sex-specific for several genes previously reported to be regulated by CR: Fmo3, Mup4, Serpina12 and Cyp4a12, while the expression of Cyp4a14a was sex independent. IGF signaling plays an important role in aging and CR effects. Igf-1 expression is regulated by CR and by the circadian clock, we found that rhythms in Igf-1 expression have sexual dimorphism. Our data provide molecular evidence that the sex of animals is an important modulator of circadian rhythms in gene expression and their response to CR.