External seminar: Jerome Menet

External seminar: Jerome Menet (Department of Biology, Interdisciplinary Program of Genetics, Center for Biological Clock Research,Texas A&M University, College Station, TX)

"Role of Food Intake and mTOR in Circadian Biology"

Abstract:

In mammals, virtually every tissue exhibits 24-hour rhythms in gene expression. These rhythms are critical for coordinating the daily activity of nearly every biological function and maintaining cellular homeostasis. While thought to be predominantly driven by the circadian clock present in each cell, accumulating evidence indicates that a large fraction of cycling transcriptomes is also initiated by systemic signals that originate from the daily rhythm of food intake (RFI) and which bypass peripheral clocks to initiate rhythmic transcription. However, the mechanisms through which RFI and systemic signals drive rhythmic gene expression remain largely unknown. Here we show that signaling through the nutrient-sensing kinase mTOR is essential for RFI-driven systemic signals to initiate the rhythmicity of thousands of genes in vivo in mouse liver. Inhibition of mTOR either pharmacologically with rapamycin or genetically by knocking out hepatic mTOR substantially decreases the number of rhythmic genes in the liver of mice fed only at night. This loss is independent of the molecular clock as rhythms in core clock gene expression remain unaltered. Moreover, restoration of rhythmic gene expression in clock-deficient Bmal1 knockout mice by nighttime feeding is almost completely abolished by rapamycin treatment. We further characterized the role of mTOR by treating mice fed arrhythmically (arrhythmic mTOR activity) with the short half-life mTOR inhibitor AZD8055 at either ZT0 or ZT12 to rescue mTOR rhythmic activity at opposite phase-of-day. Remarkably, AZD8055 rescued almost all RFI-driven rhythmic gene expression in a time-of-injection-dependent manner. Interestingly, genes whose rhythmicity is driven by the molecular clock vs. by mTOR belong to the same biological pathways, suggesting that desynchronization between clock and food signals like in shift workers may contribute to desynchronized rhythmic gene expression and, consequently, to disease. We are currently investing this possibility.

In conclusion, our findings indicate that mTOR rhythmic activity is necessary and sufficient to initiate rhythmic systemic signal driven rhythmic gene expression in mouse liver, and suggest that mTOR inhibitors may be used to prevent desynchronization between rhythms driven by the clock and systemic signals.

Host: Kiran Padmanabhan

Monday, January 23rd

Salle Condorcet