Temporal Control of Metabolic Amplitude by Nocturnin

• Published in: Cell reports (Cambridge) Vol. 22; no. 5; pp. 1225 - 1235
• Main Authors: Stubblefield, Jeremy J., Gao, Peng, Kilaru, Gokhul, Mukadam, Bilal, Terrien, Jeremy, Green, Carla B.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.01.2018; Elsevier
• Subjects: amplitude; Animals; cholesterol; Cholesterol - blood; circadian; Circadian Rhythm - physiology; deadenylation; Life Sciences; lipid; Lipid Metabolism - physiology; Liver - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; nocturnin; Nuclear Proteins - metabolism; obesity; poly(A); RNA, Messenger; Transcription Factors - metabolism; circadian; amplitude; cholesterol; poly(A); lipid; deadenylation; obesity; nocturnin
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.01.011

The timing of food intake and nutrient utilization is critical to health and regulated partly by the circadian clock. Increased amplitude of circadian oscillations and metabolic output has been found to improve health in diabetic and obesity mouse models. Here, we report a function for the circadian deadenylase Nocturnin as a regulator of metabolic amplitude across the day/night cycle and in response to nutrient challenge. We show that mice lacking Nocturnin (Noct−/−) display significantly increased amplitudes of mRNA expression of hepatic genes encoding key metabolic enzymes regulating lipid and cholesterol synthesis, both over the daily circadian cycle and in response to fasting and refeeding. Noct−/− mice have increased plasma triglyceride throughout the night and increased amplitude of hepatic cholesterol levels. Therefore, posttranscriptional control by Nocturnin regulates the amplitude of these critical metabolic pathways, and loss of this activity results in increased metabolic flux and reduced obesity. [Display omitted] •Hepatic mRNAs encoding key metabolic enzymes have increased amplitude in Noct−/− mice•Hepatic Nocturnin mRNA expression is responsive to nutrient status•Lipid and cholesterol levels are increased after a meal in Noct−/− mice•mRNAs with increased amplitude in Noct−/− mice have lengthened poly(A) tails Stubblefield et al. find that Nocturnin is a key regulator of metabolic amplitude. Nocturnin expression depends on the circadian clock and nutrient status. In the absence of Nocturnin, mRNAs encoding lipid and cholesterol metabolic enzymes display increased amplitudes of expression, resulting in increased circulating metabolites.