Conflicting signals: WSU sleep researchers find clues to how night work changes metabolism

Spokane sleep researchers have found clues to how night work disturbs the body’s metabolism over time for higher risk of obesity, diabetes and other health disorders.

The study unlocked mysteries within the body’s organs, finding that instead of the brain’s master clock controlling everything, individual organs like the liver, gut and pancreas have independent biological clocks. This causes conflicting signals in the body as the organs adapt more quickly to shift work.

“We know that shift workers over the long run are at increased risk of diabetes, obesity, metabolic syndrome, cardiovascular disease, kidney disease and various types of cancer, but we never quite understood why,” said study co-senior author Hans Van Dongen, director of the Washington State University Sleep and Performance Research Center in Spokane.

“It’s always been believed that the misalignment between what people do when they’re on night shift and the biological clock in the brain is the primary reason of why all these complications arise.

“We’ve known there are other clocks in the body that are in organs, which we always thought were under the control of the master clock in the brain,” added Van Dongen, a professor at WSU’s Elson S. Floyd College of Medicine in Spokane.

“What we’ve discovered is that the biological clocks in other organs – especially those in the gut, liver and pancreas – are much faster to adapt to a night shift schedule.”

So the body and brain still are on a day schedule during repetitive night work, while the digestive system adapts quickly. Conflicting signals inside the body “affect pretty much every organ in one way or another,” he said.

“All these organs in various ways have trouble dealing with this conflicting information.”

The study’s findings could lead to future treatments – from behavioral interventions such as short napping and eating adjustments to medications. It could help people in jobs where shift work is common, such as health care, law enforcement, emergency aid and the military.

Working with the University of Surrey in England, the WSU researchers received in-depth analysis of metabolites, which are products of chemical reactions involved in digestion, as well as in other metabolic processes in cells and organs.

The blood samples were analyzed in Surrey for 132 different metabolites.

Researchers found that following a night shift schedule, 24-hour rhythms in metabolites related to the digestive system shifted by a full 12 hours, even though the master biological clock in participants’ brains had only moved by about two hours.

Van Dongen said the next step is to find out whether the shifted metabolite rhythms are driven by the shift workers’ altered sleep schedules, the changed timing of when they eat, or both.

Once known, scientists could try to pinpoint any underlying cellular or hormonal issues.

In this study, researchers looked at 14 people who each spent seven days inside the WSU sleep lab in Spokane. Half of them completed a three-day simulated night-shift schedule while the others had three days of a simulated day-shift schedule.

Then, after the simulated shifts, all participants were kept awake for 24 hours in a semi-reclined posture. They received identical snacks every hour and had constant light exposure and room temperature. Every three hours a blood sample was drawn.

“That allowed us to measure the natural rhythms of the body as generated by the body with no interference from anything external,” Van Dongen said.

How can organs have separate biological clocks? Van Dongen said recent separate research by scientists who won a 2017 Nobel Prize explained more about the molecular mechanisms controlling the body’s circadian rhythm, a roughly 24-hour cycle in the physiological processes of living things.

The research discovered how the biological clock works at the cellular level, he said.

“The story is much more complicated, but the basic idea is just about every cell – by having what’s called a negative feedback loop or suppressing its own production of proteins – automatically generates 24-hour rhythms,” Van Dongen said.

“We always thought every one of those cells were under the control of the master clock in the brain. Now, it turns out that the cells that are in organs like the liver and pancreas can actually have these rhythms completely independent of the master clock in the brain.”

The WSU research also could have implications for additional study of the other chronic diseases shift workers are susceptible to, including chronic kidney disease and breast, prostate and skin cancer.

“We believe ours is the first study to suggest a mechanism for the connection between shift work and chronic kidney disease,” said co-senior author Shobhan Gaddameedhi, an assistant professor in the WSU College of Pharmacy and Pharmaceutical Sciences.

He said the simulated night shift group had altered rhythms in two metabolites commonly associated with chronic kidney disease. A cancer biologist, he wants to unravel the link between shift work and cancer.

“It’s possible that changes in the metabolism of shift workers are associated with altered activity of cellular processes that may be involved in cancer development later in life,” Gaddameedhi said.

“Once we understand those cellular processes, we could potentially identify the genes involved and use that knowledge to find ways to prevent cancer in shift workers.”

The WSU sleep research really was the first time its scientists could look at body clocks in organs because of collaboration with the University of Surrey, which has the newer technology to see byproducts generated by organs and rhythms in those byproducts, Van Dongen added.

“They have a new tool that had just became available, which is called targeted metabolomics, a complicated word for doing a lot of analyses on lots of different metabolites very quickly all at once, and it allowed us to look at rhythms in the blood on that scale.”

Looking at so many metabolites in organs at that level would have been impossible a few years ago.

Further research also could benefit international travelers if they frequently cross time zones. Van Dongen added that some people who are classic “night owls” are thought to adapt well to night shift work that better suits them and likely without health concerns.

Work with lab participants finished two to three years ago, he said, then researchers completed further analysis of the results. The study was published July 10 for an online edition of the Proceedings of the National Academy of Sciences.

In addition to Van Dongen, and Gaddameedhi, co-authors included Rajendra Gajula, Brieann Satterfield and Kenneth Porter of WSU; Elena Skornyakov of Eastern Washington University; and Debra Skene, Namrata Chowdhury and Benita Middleton of the University of Surrey.