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It is well known that exposure to daylight keeps our body clock in check. But what impact does meal timing have? A new study published in Cell helps answer this question and provides new insights on how cells keep a circadian rhythm. The study also has important implications for shift workers and travelers wanting to avoid jet lag.



Anyone who has flown across time zones or pulled an all-nighter will know the powerful side effects of a shift in circadian rhythm, such as a feeling of “grogginess” and messed up sleeping patterns.



While it is difficult to separate a shift in circadian rhythm from other confounding factors (e.g. shift workers are more likely than non-shift workers to be obese), studies suggest that a disrupted body clock can contribute to the development of disease. According to the NHS, shift workers are more likely to report poor health.



In light of this, a collaborative effort was directed at investigating the circadian rhythm mechanisms in more detail. John O’Neill, molecular biologist and principal investigator at the MRC, explains:



“Our main question is, how do individual cells keep time? Because, that’s fascinating, right? In order for their internal clock to be of any use, it needs to be able to be synchronized with the outside world.”



The work led to fresh insights on the intricate control of how cells keep time, which has important implications for shift workers and anyone wanting to avoid jet lag.



The research was published today in Cell and was carried out by researchers from the MRC Laboratory of Molecular Biology (LMB) in Cambridge and the University of Manchester.



An age-old question about circadian rhythms

Guided by “radical research” from the ‘70s

A new role for insulin

The signal would indicate information about feeding

It would have receptors with a very wide distribution

The signal would elicit changes in clock protein levels across different cell types

There had been a few candidates with some evidence to suggest that they played a role (ghrelin, glucose, glucagon), but only in particular cell types. In contrast, insulin was looking to be a strong candidate for directing all cells, says O’Neill:



“The critical thing about the insulin receptor, and also the IGF-1 receptor is that those receptors are expressed in every single cell. The additional observation that it was able to increase the activity of the clock protein period, in every cell type that we tested, as well as in a whole mouse was a really strong piece of evidence that this was the feeding signal that communicates time of feeding to clocks throughout the body.”



Indeed, insulin was shown to reset circadian clocks in vitro and in vivo, by increasing the synthesis of PERIOD proteins (controlled by the Period “clock genes”).



The study was carried out in mice and in cell cultures of different types (mouse-derived fibroblasts, cortical neurons, organotypic liver and kidney slices, and intestinal organoids).



The nitty gritty: insulin-PER signaling requires the perfect trifecta



The circadian entrainment of cells via insulin works through a very clever and coordinated mechanism. For PER levels to be increased by insulin, three things must happen simultaneously:

Activation of MTOR

Inhibition of an enzyme called PTEN, which opposes signaling through the insulin receptor

Reduction in the level of micro-interfering RNAs that would normally destabilize the mRNA of the PERIOD gene

This coordinated detection allows the cell to discriminate this particular type of mTOR-dependent signal from the vast number of other signals that are relayed.



The relative timing of cues from food and light is important

Implications for shift workers and travelers