Sex differences in obesity in mice are mediated by differential responses of circadian rhythms to high-fat feeding in males and females. Other studies also showed circadian Period genes regulate diet-induced obesity in mice. In this study, we investigated the role of the Period genes in regulating sex differences in obesity. Male and female C57BL/6J wild type, Per1/2 KO, and Per1/2/3 KO mice were housed in 12L:12D and fed high-fat diet for 12 weeks. We found a striking sex difference in obesity

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... such that disabling the Period genes exacerbated adiposity in female, but not male, mice. Increased adiposity in female Period KO mice was not due to increased energy intake since they ate the same number of calories as wild type females. We found the phases of eating and activity rhythms varied from day to day in Period KO, but not wild-type, mice. Per1/2/3 KO females, as well as wild-type and Per1/2/3 KO males, also had disrupted eating rhythms on high-fat diet Therefore, increased interdaily variability and disruption of eating rhythms may contribute to exacerbated diet-induced obesity in Period KO females. Moreover, this study demonstrates that sex is a critical factor when studying the interplay between circadian rhythms and metabolic risk.