Molecular Clock Might Be Key to Metabolic Adaptation

A study published in eLife suggests that cells with a functioning molecular clock can better adapt to changes in glucose supply and recover faster from long-term starvation. The discovery helps to explain why changes to the body's circadian rhythms — such as night shift work and jetlag — can increase the risk of metabolic diseases such as diabetes. Circadian clocks are closely linked to metabolism, and this study provides insights into the molecular mechanisms behind this relationship.

The study, led by researchers at the Department of Physiology, Semmelweis University, Budapest, Hungary, used the fungus Neurospora crassa as a model to investigate how chronic glucose deprivation affects the molecular clock and what role the clock plays in adaptation to starvation. 

The team found that when the fungus was starved of glucose for 40 hours, two core clock components, the White Collar Complex (WCC) and Frequency (FRQ), were affected. WCC levels decreased gradually to about 15% and 20% of initial levels, whereas FRQ levels remained the same but were altered by adding many phosphate groups (i.e., hyperphosphorylation).

When they looked at the downstream actions of WCC, the researchers found little difference between the starved cells and those still growing in glucose, suggesting that the circadian clock was still functioning robustly and driving the rhythmic expression of cellular genes during glucose starvation.

To further investigate the importance of the molecular clock in adapting to glucose deprivation, the team used a Neurospora strain lacking the WC-1 domain of WCC and compared the levels of gene expression after glucose starvation to Neurospora containing an intact molecular clock. They found that long-term glucose starvation affected more than 20% of coding genes and that 1,377 of these 9,758 coding genes (13%) showed strain-specific changes depending on whether or not the cells had a molecular clock. This implies that the clock is an important piece of machinery for the cells' response to a lack of glucose.

The team also found that the growth of Neurospora cells lacking a functional FRQ or WCC was significantly slower than normal cells when glucose was added, implying that a functional clock supports the cells' regeneration. Additionally, they found that cells lacking a functional clock were unable to dial up the production of a crucial glucose transporter to get more nutrients into the cell.

"The marked differences between the recovery behavior of fungus strains with and without functional molecular clocks suggests that adaptation to changing nutrient availability is more efficient when a circadian clock operates in a cell," said senior author Krisztina Káldi, Associate Professor at Semmelweis University. "This suggests that the clock components have a major impact on balancing energy states within cells and highlights the importance of the clock in regulating metabolism and health."

These findings provide new insights into how a functional molecular clock supports the adaptation and recovery of cells during changes in glucose supply, which may have implications for understanding how changes to the body's circadian rhythms can lead to metabolic diseases such as diabetes.