GSE63566
Activation of NF-kB Links Nutrition and Inflammation to Circadian Disruption in Mice
The molecular clock synchronizes organismal metabolism by driving transcriptional cycles in anticipation of light, and recent studies have shown that diet itself affects the mammalian clock.  Here, we demonstrate that feeding mice a diet enriched in saturated but not unsaturated fat altered neuronal pacemaker function and behavior, corresponding with activation of the inflammation-signaling transcription complex NF-kB and inhibition of circadian transcription mediated by CLOCK/BMAL1, the forward limb of the clock. Genetic loss of NF-kB signaling increased CLOCK/BMAL1 chromatin binding, up-regulated expression of the clock repressors PER and CRY, and down-regulated the PAR bZIP member E4BP4.  Cistrome analysis showed that activated NF-kB occupied ~36% of BMAL1 sites genome-wide, while inducible NF-kB ablation in adult mice dramatically disrupted circadian activity and light entrainment.  Our results suggest that NF-kB signaling maintains circadian homeostasis in the quiescent state, and that inflammation-induced NF-kB activation leads to circadian disruption independent of overnutrition. Overall design: Identification of NF-kB p65 binding sites in livers from mice treated with intraperitoneal lipopolysaccharide (LPS) or saline control solution at ZT6 and harvested at ZT8.