eLife: Even in the case of hunger, the cell's biological clock continues to run

According to a study published in the journal eLife, cells with a functioning molecular clock adapt better to changes in glucose supply and recover more quickly from chronic starvation
.

The finding helps explain why changes in the body's circadian rhythm — such as night shifts and jet lag — increase the risk of
metabolic diseases such as diabetes.

The circadian clock is closely related to metabolism: on the one hand, the circadian clock rhythmically regulates many metabolic pathways, on the other hand, nutrients and metabolic cues affect the function of
the circadian clock.
This is achieved through a finely tuned feedback loop where some positive component of the clock activates other components, and then these negative feedback primitive activating components
.

"Since glucose affects so many signaling pathways, it is thought that glucose deficiency may challenge the feedback loop of the circadian clock, hindering its ability to maintain a constant rhythm, and we wanted to explore how chronic glucose deprivation affects the molecular clock, and what role
the molecular clock plays in adapting to hunger.
"

Using the fungus Choderma rugatus as a model, the team first investigated how 40 hours of glucose starvation affected two core clock components, WCC, a complex consisting of two subunits, WC-1 and 2, and frequency (FRQ).

They found that before starvation, WC1 and w2 levels gradually dropped to 15 and 20 percent of initial levels, while FRQ levels remained the same but changed due to the addition of many phosphate groups (a process known as overphosphorylation).

In general, excessive phosphorylation prevents FRQ from inhibiting WCC activity – so the authors speculate that higher activity may accelerate WCC degradation
.
When they looked at the downstream activity of WCC, there was little difference
between the starved cells and those still growing in glucose.
Taken together, this suggests that the circadian clock is still running robustly during glucose starvation and drives rhythmic expression
of cellular genes.

To further investigate the importance of the molecular clock in accommodating glucose deprivation, the team used a strain
of Veolia that lacks the WC-1 domain of WCC.
They then compared gene expression levels
after glucose starvation.
They found that chronic glucose starvation affected more than 20 percent of the coding genes, and of those 9758 coding genes, 1377 (13 percent) showed strain-specific changes, depending on whether the cells had a molecular clock
.
This means that the circadian clock is an important mechanism
for cells to respond to a lack of glucose.

Next, the team investigated whether having a functional clock was important
for cells to recover after glucose starvation.
They found that when glucose was added, cells lacking FRQ or WCC function were significantly slower than normal cells, meaning the functional clock supported cell regeneration
.
In addition, when they studied the glucose transport system, they found that cells that lacked a functional clock were unable to produce a key glucose transporter that would transport more nutrients into the cell
.

Senior author Krisztina Káldi, associate professor at Semmelweis University, concludes: "The significant difference in recovery behavior between fungal strains with and without functional molecular clocks suggests that adaptation to changing nutrient availability is more effective
when the circadian clock operates in cells.
This suggests that the clock component has a significant impact on balancing the energy state within the cell and underscores the importance of
the clock in regulating metabolism and health.
”