Although several previous studies have suggested a relationship between sleep and the stress response, the mechanism underlying this relationship remains largely unknown. Here, we show that fibroblast growth factor 21 (FGF21), a lipid metabolism-related hormone, may play a role in this relationship. In this study, we examined differences in the stress response between FGF21 knockout (KO) mice and wild-type (WT) mice after social defeat stress (SDS). When the amount of non-rapid eye movement (NREM) sleep, rapid eye movement (REM) sleep and wakefulness were averaged over the dark period after SDS, only KO mice showed significant differences in NREM sleep and wakefulness. In the social interaction test, KO mice seemed to be more prone to social avoidance. Our real-time (RT) -PCR results revealed that the mRNA expression of the stress- and sleep-related gene gamma-aminobutyric acid A receptor subunit alpha 2 was significantly lower in WT mice than in KO mice. Moreover, KO mice showed lower plasma levels of ketone bodies, which also affect sleep/wake regulation, than WT mice. These results suggested that FGF21 might influence sleep/wake regulation by inducing production of an anti-stress agent and/or ketone bodies, which may result in resilience to social stress.
