The continued functioning of circadian clock of cells even after starvation

According to a study that was just published in eLife, cells that have a functioning molecular clock are better able to adapt to changes in glucose supply and can recover from long-term starvation more quickly.

The finding sheds light on why disruptions to the circadian rhythms of the body, like night shift work and jet lag, can raise the risk of metabolic diseases like diabetes.

The relationship between circadian clocks and metabolism is complex. On the one hand, the clock rhythmically regulates a number of metabolic pathways, and on the other, dietary factors and metabolic cues affect the clock’s operation.

This is accomplished by carefully crafted feedback loops in which some positive clock components activate others, and those latter components then negatively feedback the initial activating components.

Because glucose affects so many signaling pathways, it is thought that glucose deficiency might challenge the feedback loops in the circadian clock and hinder its ability to maintain a constant rhythm. We wanted to explore how chronic glucose deprivation affects the molecular clock and what role the clock plays in adaptation to starvation.”

Anita Szöke, PhD Student, Department of Physiology, Semmelweis University

Using the fungus Neurospora crassa as a model, the team first investigated the impact of 40 hours of glucose starvation on two central clock elements known as the White Collar Complex (WCC), which is made up of two subunits WC-1 and 2, and Frequency (FRQ).

They discovered that levels of WC1 and 2 gradually dropped to 15% and 20% of initial levels prior to starvation, whereas levels of FRQ remained constant but were changed by the addition of numerous phosphate groups (a process called hyperphosphorylation).

The authors hypothesized that since hyperphosphorylation typically prevents FRQ from inhibiting WCC activity, the increased activity might hasten WCC degradation. There was not much of a difference between the starved cells and those still gaining glucose when they examined the downstream effects of WCC.

All of this suggests that even during glucose deprivation, the circadian clock was still active and regulating the rhythmic expression of cellular genes.

The team used a Neurospora strain deficient in the WC-1 domain of WCC to examine the role of the molecular clock in adaptation to glucose deprivation. They next compared Neurospora with an intact molecular clock to the levels of gene expression following glucose starvation.

More than 20% of the coding genes were found to be affected by prolonged glucose deprivation, and 1,377 of the 9,758 coding genes (13% of them) displayed strain-specific variations depending on whether the cells contained a molecular clock. This suggests that the clock plays a crucial role in the cells’ reaction to a glucose shortage.

The team then investigated whether cells' ability to recover from glucose starvation required a functional clock. It was discovered that when glucose was added, the growth of Neurospora cells lacking a functional FRQ or WCC was noticeably slower than that of normal cells, suggesting that a functional clock supports the cells’ regeneration.

Additionally, they discovered that cells lacking a functional clock were unable to increase the production of a critical glucose transporter, which is required to bring in more nutrients when they investigated the glucose transport system used in Neurospora.

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. 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.”

Krisztina Káldi, Study Senior Author and Associate Professor, Semmelweis University