Resetting the metabolic clock

January 29, 2014 by Sonia Fernandez
Circadian rhythms are affected by things like travel over time zones, diet and light exposure. Credit: Peter Allen illustration

We've all heard about circadian rhythm, the roughly 24-hour oscillations of biological processes that occur in many living organisms. Yet for all its influence in many aspects of our lives—from sleep to immunity and, particularly, metabolism—relatively little is understood about the mammalian circadian rhythm and the interlocking processes that comprise this complex biological clock.

Through intensive analysis and computer modeling, researchers at UC Santa Barbara have gained insight into factors that affect these oscillations, with results that could lend themselves to circadian regulation and pharmacological control. Their work appears in the early edition of the Proceedings of the National Academy of Sciences.

"Our group has been fascinated with for over 10 years now, as they represent a marvelous example of robust control at the molecular scale in nature," said Frank Doyle, chair of UCSB's Department of Chemical Engineering and the principal investigator for the UCSB team. "We are constantly amazed by the mechanisms that nature uses to control these clocks, and we seek to unravel their principles for engineering applications as well as shed light on the underlying cellular mechanisms for medical purposes."

"Focus is often given to metabolism, cell division and other generic cell processes, but circadian oscillations are just as central to how life is organized," said Peter St. John, a researcher in the Department of Chemical Engineering and lead author of the study.

Blood pressure, he noted, varies with time of day, as do visual acuity, smell and taste. Certain hormones are released at certain times to do their tasks. We get sleepy or become more alert at different hours. All these various highs and lows, rises and falls are the result of our circadian rhythm.

"There are genes and proteins that are expressed in a cell and their activity, or expression level, changes with time of day," explained St. John. "These oscillations are caused by genetic circuits. So you'll have a gene that's produced, and when it's in its finished form, it will turn itself off." The proteins and genes get cleared away, after which production starts all over again, in a cycle that takes roughly 24 hours to complete.

While genetics plays a role in these rhythms—for instance if your parents were night owls, it's likely you will be one too—environment, habits and lifestyles also affect the clock.

"It's not just this free-running oscillator," said St. John. "It gets these inputs from light. For instance if you get light early in the morning, it'll speed up something so your phase is adjusted to the time of day." Other influences include food (not so much what you eat but when), drugs, shift work and frequent travel across time zones.

The healthiest circadian rhythms are the ones that are considered to be "high-amplitude"—where different and complementary processes occur in the body during distinct and regular daytime and nighttime phases.

"We're very different animals during the night and the day," said St. John. "If you're fasting at night and you're asleep, the demands on your cells will be very different than if you're awake and running around. There's this temporal separation between the genes that you need during the day and those you need at night."

Problems occur when the amplitude gets repressed, often because of modern-day schedules and lifestyles. Too much light at night, insufficient or irregular sleep hours, and eating or exercising too late in the evening are all habits that don't allow for the necessary nighttime-phase cellular activity. This in turn can lead to disorders such as diabetes, heart disease and obesity. In very preliminary studies, Alzheimer's disease and certain liver conditions are also associated with low-amplitude rhythms.

Establishing high-amplitude circadian rhythms could be as simple as modifying our schedules, but for some people—those with sleep disorders, for example, or those whose work requires long and irregular hours—it can be difficult, if not impossible.

By studying the regulation of the clock proteins called Period (PER) and Cryptochrome (CRY)—proteins that are thought to be involved with metabolism—St. John and Doyle were able to model the mechanisms of two small-molecule drugs—Longdaysin and KL0001—that regulate the expression of the clock proteins. The insight they gained could lead to therapies that can help those with repressed circadian rhythms.

"Everybody thought that these were very similar proteins," said St. John. "They bind to each other. They enter the nucleus together." The assumption was that perturbations to those proteins would produce similar results. "But when we analyzed the data," St. John continued, "it turned out that when you stabilize PER you get these higher-amplitude rhythms, but when you stabilize CRY you get these lower-amplitude rhythms."

These results—obtained by studying cultured human cells that glow depending on their circadian phase, as well as through computer modeling—shed light on the mechanisms behind the metabolic aspect of circadian rhythms and pave the way for drug therapies that could decrease the risk of disease for those with disrupted rhythms. The UCSB researchers worked in collaboration with experimental scientists Tsuyoshi Hirota and Steve Kay from UC San Diego and USC, respectively.

"These collaborative partnerships with life scientists are crucial to the success of a project like this," said Doyle, "and this kind of collaborative research team can implement the paradigm of systems biology with combined mathematical modeling and high-throughput experimental biology."

Future modeling studies will try to determine if there is an optimal phase for taking one drug or the other to improve the amplitude of circadian rhythms. Experimental work will focus on improving specificity and bioavailability—the amount of drug that actually reaches the target tissues before being discharged by the body.

Explore further: Nutrition influences metabolism through circadian rhythms

More information: Spatiotemporal separation of PER and CRY posttranslational regulation in the mammalian circadian clock, Peter C. St. John, DOI: 10.1073/pnas.1323618111

Related Stories

Nutrition influences metabolism through circadian rhythms

December 19, 2013
A high-fat diet affects the molecular mechanism controlling the internal body clock that regulates metabolic functions in the liver, UC Irvine scientists have found. Disruption of these circadian rhythms may contribute to ...

Researchers identify key molecular components linking circadian rhythms and cell division cycles

January 14, 2014
(Medical Xpress)—Researchers at the University of Cincinnati (UC) have identified key molecular components linking circadian rhythms and cell division cycles in Neurospora crassa, providing insights that could lead to improved ...

The internal clock and feeding rhythm set the pace of the liver

January 15, 2014
Living organisms have adapted to the day-night cycle and, in most cases, they have evolved a "circadian clock". Its effects are not completely known yet but its functioning has been shown to have important metabolic consequences ...

New study reveals links between alcoholic liver disease and the circadian clock

January 17, 2014
Researchers from the University of Notre Dame and the Indiana University School of Medicine have revealed a putative role for the circadian clock in the liver in the development of alcohol-induced hepatic steatosis, or fatty ...

Recommended for you

Molecular hitchhiker on human protein signals tumors to self-destruct

July 24, 2017
Powerful molecules can hitch rides on a plentiful human protein and signal tumors to self-destruct, a team of Vanderbilt University engineers found.

New vaccine production could improve flu shot accuracy

July 24, 2017
A new way of producing the seasonal flu vaccine could speed up the process and provide better protection against infection.

Researchers develop new method to generate human antibodies

July 24, 2017
An international team of scientists has developed a method to rapidly produce specific human antibodies in the laboratory. The technique, which will be described in a paper to be published July 24 in The Journal of Experimental ...

A sodium surprise: Engineers find unexpected result during cardiac research

July 20, 2017
Irregular heartbeat—or arrhythmia—can have sudden and often fatal consequences. A biomedical engineering team at Washington University in St. Louis examining molecular behavior in cardiac tissue recently made a surprising ...

Want to win at sports? Take a cue from these mighty mice

July 20, 2017
As student athletes hit training fields this summer to gain the competitive edge, a new study shows how the experiences of a tiny mouse can put them on the path to winning.

'Smart' robot technology could give stroke rehab a boost

July 19, 2017
Scientists say they have developed a "smart" robotic harness that might make it easier for people to learn to walk again after a stroke or spinal cord injury.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.