Cells with a functioning molecular clock are better able to adapt to changes in glucose supply and recover more quickly from long-term starvation, according to a new study published in eLife. This discovery helps explain why changes in the body’s circadian rhythm, such as night shift work and jet lag, may increase the risk of metabolic diseases such as diabetes.

How Glucose Starvation Affects the Circadian Clock

Circadian clocks are closely linked to metabolism: on the one hand, the clock rhythmically modulates many metabolic pathways, on the other hand, nutrients and metabolic stimuli influence the function of the clock. This is achieved through finely tuned feedback loops, where some positive components of the clock activate others, and these then negatively feed back the original activating components. Because glucose affects so many signaling pathways, it is believed that a lack of glucose could challenge the feedback loops in the circadian clock and hamper its ability to maintain a constant rhythm. The researchers wanted to study how chronic glucose deprivation affects the molecular clock and what role the clock plays in adaptation to starvation.

Using the fungus Neurospora crassa as a model, the team first studied how a 40-hour glucose starvation affected two central clock components called the White Collar Complex (WCC), composed of two subunits WC-1 and 2 and Frequency (FRQ). They found that levels of WC1 and 2 gradually decreased to about 15% and 20% of the original pre-starvation levels, respectively, while FRQ levels remained the same but were altered by the addition of many phosphate groups (a process known as hyperphosphorylation referred to as). Normally, hyperphosphorylation prevents FRQ from inhibiting WCC activity—hence the authors speculated that the higher activity might accelerate WCC degradation. When they looked at WCC’s downstream actions, there was little difference between the starved cells and those still growing in glucose. Taken together, this suggests that the circadian clock was still functioning well, driving the rhythmic expression of cellular genes during glucose starvation.

To further investigate the importance of the molecular clock in adaptation to glucose starvation, the team used a Neurospora strain that lacked the WC-1 domain of WCC. They then compared the level of gene expression after glucose starvation with Neurospora that contained an intact molecular clock. They found that long-term glucose starvation affected more than 20% of the coding genes, and that 1,377 of those 9,758 coding genes (13%) showed strain-specific changes, depending on whether the cells had a molecular clock or not. This means that the clock is an important piece of machinery for how cells respond to a lack of glucose.

Internal Clock Regulates Metabolism and Health

Next, the team investigated whether a functioning clock is important for cells to recover after a glucose starvation. They found that Neurospora cells lacking a functional FRQ or WCC grew significantly slower than normal cells when glucose was added, suggesting that a functioning clock helps the cells regenerate. In addition, when they studied the glucose transport system used in Neurospora, they found that cells lacking a functioning clock were unable to dial in the production of a crucial glucose transporter to bring more nutrients into the cell.

According to the researchers, the significant differences between the recovery behavior of fungal strains with and without functioning molecular clocks suggest that adaptation to changing nutrient availability is more efficient when a circadian clock is working in a cell. This suggests that the components of the clock have a major impact on the balance of energy states in cells and underscores the importance of the body clock in regulating metabolism and health.