The Circadian Protein Nocturnin Regulates Metabolic Adaptation in Brown Adipose Tissue

Fine-tuning of transcriptional responses can be critical for long-term outcomes in response to an environmental challenge. The circadian protein Nocturnin belongs to a family of proteins that include exonucleases, endonucleases and phosphatases and is most closely related to the CCR4 family of deadenylases that regulate the cellular transcriptome via control of polyA tail length of RNA transcripts. In this study, we investigate the role of Nocturnin in regulating the transcriptional response and downstream metabolic adaptations during cold exposure in brown adipose tissue. We find that Nocturnin exhibits dual localization within the cytosol and mitochondria, and loss of Nocturnin causes changes in expression of networks of mRNAs involved in mitochondrial function. Furthermore, Nocturnin-/- animals display significantly elevated levels of TCA cycle intermediates indicating that they have distinct metabolic adaptations during a prolonged cold exposure. We conclude that cold-induced stimulation of Nocturnin levels can regulate long-term metabolic adaptations to environmental challenges. Overall design: We performed mRNA-seq analysis on brown fat (BAT) isolated from wild-type and Nocturnin-/- littermates at room temperature or after a 4-hour cold exposure. For cold exposure experiments, age-matched 10-20 week old young adult WT and Nocturnin-/- mice were randomly assigned to cold (6C) or room temperature (22C) groups. Mice were single housed for the duration (4hrs) of the experiment and food was removed in order to minimize individual variation. N=4-5 mice per condition.