Food-Driven Liver Clock Could Point to New Ways to Help Shift Work, Jet Lag

Anyone who has pulled an all-nighter, flown across time zones, or eaten a 2 a.m. burrito after a late shift knows the strange feeling of the body being out of sync with itself. Scientists have long blamed this on the circadian clock, the internal timekeeper found in nearly every cell. But new research on mice suggests that another player, a protein already targeted by widely used cancer drugs, may be just as responsible for keeping the liver’s daily rhythms on schedule.

Researchers at Texas A&M University found that a nutrient-sensing protein called mTOR acts almost like a second clock in the liver, one that is closely tied to feeding and can drive the liver’s daily rhythms on its own, separate from the molecular circadian clock. When the team blocked mTOR’s activity in mice, more than half of the liver’s normal daily gene-activity patterns collapsed, even though the animals’ actual circadian clock kept ticking along just fine. Flip that around, and resetting mTOR’s rhythm with a precisely timed blocking drug restored rhythms lost when mice ate around the clock instead of on a set schedule.

Published in Science Advances, the study matters beyond rodent biology labs. Shift workers, frequent flyers, and anyone who eats at irregular hours are exposed to the kinds of mismatched timing signals this research helps explain. If a food-driven system like mTOR can fall out of step with the body’s master clock, it may help explain why disrupted eating patterns are linked to metabolic problems, and it hints that drugs already used to target mTOR could someday help realign the body’s rhythms.

How Scientists Uncovered the Liver’s Second Clock

To understand how food timing shapes gene activity in the liver, the researchers worked with two types of mice: normal mice with fully functioning body clocks, and genetically altered mice that lacked a working circadian clock entirely. Both groups were fed only at night, a schedule known to produce strong, predictable daily patterns in liver gene activity.

Some mice then received rapamycin, a well-known drug that blocks mTOR, while others got a placebo shot. After two weeks, the team collected liver samples every four hours across a full day to track which genes were switching on and off, and when. They confirmed the drug was working by checking a direct marker of mTOR activity in the liver tissue.

Results here were hard to miss. In normal mice, blocking mTOR erased more than half of the liver’s normal daily gene-activity patterns compared to untreated animals. Even more telling, the same thing happened in mice that had no working circadian clock at all. Since those mice don’t have a functioning internal clock to begin with, any rhythm they still showed had to be coming from food intake itself. When mTOR was blocked in these clock-less mice, that food-driven rhythm mostly disappeared too. That result showed something important: mTOR was not simply helping the circadian clock along. It was running its own separate rhythm-generating operation.

Researchers then flipped the experiment. Instead of feeding mice on a strict schedule, they let some mice eat at random times throughout the day and night, a setup known to flatten out normal liver rhythms. Next, they gave these randomly fed mice a fast-acting mTOR-blocking drug called AZD8055, timed to hit either at the start of the day or right before the mice’s active nighttime period. Unlike rapamycin, which lingers in the body for a long time, this drug clears out within a few hours, making it possible to test how a brief, precisely timed dose of mTOR blocking affects the system.

Surprisingly, both timing strategies restored the liver’s daily gene-activity patterns to levels similar to mice on a strict feeding schedule, even though the mice were still eating at random times. That pattern pointed to something simple: resetting mTOR activity at the right moment could kick-start the liver’s rhythms, no matter when the animals actually ate.

But timing also produced an unexpected side effect. When the drug was given right before the mice’s active period, right when mTOR activity would normally be ramping up, it pushed the timing of mTOR-related genes several hours later, while leaving clock-related genes completely untouched. In other words, the researchers could pull these two systems apart simply by hitting mTOR at the wrong moment. The paper describes this as evidence that “alignment of rhythmic mTOR activity to the circadian cycle is critical for overt cycling transcriptomes,” meaning the two systems normally need to stay in step for the liver’s rhythms to look normal and coordinated.

Beyond gene activity, the researchers also looked at the liver’s broader chemistry using a large-scale scan of its metabolic compounds. They found that random-time feeding sharply reduced the number of body chemicals that showed daily rhythms, and that resetting mTOR activity restored many of those rhythms. They also examined how the liver responds to a form of cellular stress caused by misfolded proteins building up, and found that this stress response, too, depended heavily on rhythmic mTOR activity rather than on the circadian clock itself.

What the Liver’s Second Clock Means for Jet Lag and Shift Work

None of this means the circadian clock is unimportant. Genes directly tied to the clock’s core machinery stayed on schedule no matter what happened to mTOR, and the study makes clear that many biological pathways rely on contributions from both systems working together. What the findings add is a second, previously overlooked dial that the body uses to time its internal processes, one tuned to food rather than to light and darkness.

That distinction has real-world stakes. Modern life is full of situations where eating patterns drift away from the body’s natural light-dark cycle: overnight shifts, jet lag, late-night snacking. If a food-sensitive system like mTOR can fall out of step with the circadian clock under these conditions, that mismatch could ripple through liver function in ways that add to the risk of metabolic disease over time. Because drugs targeting mTOR already exist and are used in medicine, the authors suggest this pathway could eventually be a lever for realigning disrupted body rhythms rather than just a mechanism to understand. This research was conducted in mice and focused specifically on the liver, so it’s a foundational finding rather than a treatment ready for the clinic.

Still, it reframes a basic question about the body. The clock in each cell may set the beat, but what and when someone eats appears to run its own rhythm alongside it; when the two fall out of time, the liver seems to feel it.