The role of TNFα in circadian rhythmic responses and regulation of metabolic regulator SIRT1 in liver

Abstract

A feedback loop exist between the expression of circadian control genes and regulators of metabolic and energy homeostasis, involving the histone deacetylase SIRT1. We show here that TNFα regulates the expression of SIRT1 in liver. Thus, we hypothesize that a relationship exists between hepatic immune response and circadian control genes through the expression of SIRT1. For these experiments C57Bl6/J control mice and mice lacking TNFα receptor (TNFR1−/−) were fasted for 24 hours. Under fed conditions, wild type mice have low SIRT1 expression in liver but SIRT mRNA is increaded 4‐fold after fasting. In TNFR1−/− mice, SIRT1 expression is increased nearly 10‐fold under basal conditions as well as after fasting, suggesting that TNF suppresses SIRT expression. TNFR1−/− mice greater running wheel activity, consume nearly 30% more chow, and exhibit higher respiratory exchange rate than the wild type mice. Importantly, TNFR1−/− mice have altered hepatic circadian Bmal and Per2 expression compared to wild type mice. Most importantly, when the mice were housed in constant darkness, TNFR1−/− mice exhibited greater circadian phase‐shift compared to wild type mice, indicating a faster circadian period in TNFR1−/− mice. In conclusion, these data suggest that TNFα is an important regulator of hepatic circadian gene expression and circadian behavior and may involve the suppression of SIRT.Grant Funding Source: Internal