mTOR signaling contributes to system-driven rhythmic gene expression in mouse liver

Area of Science:

• Molecular Biology
• Chronobiology
• Metabolism

Background:

• Rhythmic gene expression orchestrates daily biological functions.
• Circadian clocks regulate daily rhythms, but food-driven signals also play a role.
• Mechanisms linking nutrient sensing to rhythmic gene expression are largely unknown.

Purpose of the Study:

• To investigate the role of mechanistic target of rapamycin (mTOR) signaling in mediating food-driven rhythmic gene expression in the liver.
• To determine if mTOR signaling is necessary and sufficient for rhythmic liver gene expression, metabolome, and endoplasmic reticulum stress response.

Main Methods:

• Utilized acute inhibition of mTOR signaling in vivo.
• Analyzed hepatic gene expression patterns.
• Assessed liver metabolome and endoplasmic reticulum stress markers.

Main Results:

• mTOR signaling is necessary and sufficient for food-driven hepatic rhythmic gene expression and metabolic rhythms.
• mTOR inhibition desynchronizes mTOR-driven rhythmic genes but not clock-controlled genes.
• Alignment of rhythmic mTOR activity with the circadian cycle is critical for overall rhythmic gene expression.

Conclusions:

• Nutrient-sensing mTOR pathway mediates food-driven liver rhythms independently of the circadian clock.
• Misalignment between circadian and systemic signals contributes to disease.
• mTOR inhibitors may help resynchronize rhythms and treat circadian rhythm disorders.