Nav: Home

Circadian clock and fat metabolism linked through newly discovered mechanism

May 30, 2019

The enzyme Nocturnin, which governs daily tasks such as fat metabolism and energy usage, works in an entirely different way than previously thought, reported a team of researchers at Princeton University. The newly discovered mechanism reveals the molecular link between the enzyme's daily fluctuations and its energy-regulating role in the body, according to a study published this week in Nature Communications.

"The realization that Nocturnin works in this manner will guide our thinking about sleep, oxidative stress and metabolism, and eventually may serve as a step toward finding better treatments for metabolic diseases," said Alexei Korennykh, an associate professor of molecular biology at Princeton, who led the work.

Nocturnin is part of the circadian clock that alters the metabolism and behavior of living organisms to match the body's needs at different times of the day. For example, Nocturnin levels fluctuate throughout the day, dramatically peaking when the body first awakens. Nocturnin is also a critical regulator of metabolism; compared to regular mice, mice lacking the enzyme make less insulin, are protected from fatty liver disease and are less susceptible to weight gain.

The precise function of Nocturnin inside cells has remained unclear, however. For many years, the enzyme was thought to turn on and off cellular metabolism by degrading certain cellular messages made of ribonucleic acid, or mRNAs. Last year, however, three groups of researchers -- a group from the University of Michigan, a group from the University of Minnesota, and Korennykh's team -- discovered that Nocturnin is incapable of degrading RNAs.

To find out how Nocturnin can have such large effects on the body's metabolism, Korennykh teamed up with Princeton's Joshua Rabinowitz, a professor of chemistry and the Lewis-Sigler Institute for Integrative Genomics, and Paul Schedl, a professor of molecular biology. The study was led by postdoctoral research associate Michael Estrella and graduate student Jin Du in the Alexei lab, and postdoctoral research associate Li Chen in the Rabinowitz lab.

Using methods pioneered by Rabinowitz to screen tissues for the presence of metabolites, the researchers discovered that Nocturnin plays a far more direct role in metabolism than previously appreciated. Rather than degrading mRNAs, the enzyme regulates specific metabolites that help energy production and protect cells from damage. The study determined that Nocturnin is located in the cell's energy-producing structures, the mitochondria, suggesting that this is where the enzyme performs its function.

The team found that Nocturnin removes a phosphate group from two molecules important in metabolism, called NADP+ and NADPH. These molecules allow the cell to modulate the levels of reactive oxygen species, which function both as harmful agents causing damage and as signaling molecules controlling metabolism and fat storage. The researchers conclude that Nocturnin is the first known enzyme to perform this reaction on NADP+ and NADPH inside mitochondria.

Removing phosphate groups from NADP+ and NADPH produces two different but equally important molecules, NAD+ and NADH, which are essential for the function of metabolic enzymes -- the molecular machines that produce energy by breaking down energy-rich biomolecules such as glucose.

Nocturnin upregulation when an animal first awakens might therefore kick the body's energy production into high gear by providing more NAD+ and NADH. "It is tempting to propose that one physiologic function of Nocturnin could be to maximize available NAD+ and NADH for energy generation in a search for food, using the elevated blood sugar that animals have at the time of awakening," Korennykh said.

Korennykh and colleagues also deciphered the crystal structure of human Nocturnin bound to NADPH, showing at the atomic level how the reaction mediated by Nocturnin occurs. NADPH fits perfectly into Nocturnin's active site so that the enzyme can easily remove the molecule's phosphate group.

Finally, the researchers determined that the fruit fly version of Nocturnin, known as Curled, is also unable to cleave RNA. Instead, Curled uses the same mechanism as human Nocturnin and targets NADP+ and NADPH. The Curled gene was first described over 100 years ago by Thomas Hunt Morgan, the pioneering geneticist who won a Nobel Prize for demonstrating that genes are carried on chromosomes. Though Curled has been studied by fruit fly researchers ever since, its biochemical mechanism was a mystery until now.

"Our work shows that even in the age of genomics and personalized medicine, basic biology still remains to be understood," Korennykh said. "In the example of Nocturnin and Curled, a pathway regulating some of the most important molecules in metabolism was hidden in plain sight for the past 100 years."
-end-
This study was funded by Princeton University, the National Institutes of Health, the Burroughs Wellcome Foundation, the Vallee Foundation, the Stand Up to Cancer-Cancer Research UK-Lustgarten Foundation Pancreatic Cancer Dream Team collective, and the U.S. Department of Energy.

The study, "The Metabolites NADP+ and NADPH are the Targets of the Circadian Protein Nocturnin (Curled)," by Michael A Estrella, Jin Du, Li Chen, Sneha Rath, Eliza Prangley, Alisha Chitrakar, Tsutomu Aoki, Paul Schedl, Joshua Rabinowitz and Alexei Korennykh, was published online in Nature Communications on May 30, 2019.

Princeton University

Related Circadian Clock Articles:

U of M research discovers link between stress and circadian clock health
New research from the University of Minnesota Medical School found a little stress can make the circadian clock run better and faster.
The role of GABA neurons in the central circadian clock has been discovered
Temporal order of physiology and behavior is regulated by the central circadian clock located in the SCN.
Researchers take aim at circadian clock in deadly brain cancer
Scientists at USC and UC San Diego have discovered a potential novel target for treating glioblastoma, the deadly brain cancer that took the life of Sen.
The circadian-hypoxia link in cardioprotection
Throughout the evolutionary time, all organisms and species on Earth evolved with an adaptation to consistent oscillations of sunlight and darkness, now recognized as circadian rhythm.
Circadian clock and fat metabolism linked through newly discovered mechanism
Princeton University researchers found that the enzyme Nocturnin, known for its role in fat metabolism and circadian rhythm, acts on two well-established molecules in metabolism.
Dead zones in circadian clocks
Circadian clocks of organisms respond to light signals during night but do not respond in daytime.
Circadian clock plays unexpected role in neurodegenerative diseases
Northwestern University researchers induced jet lag in a fruit fly model of Huntington disease and found that jet lag protected the flies' neurons.
Researchers locate circadian clock that controls daily rhythms of aggression
Synchronized by light and darkness, the circadian clock exerts control over wake/sleep cycles, body temperature, digestion, hormonal cycles and some behavior patterns.
The rhythm of genes: How the circadian clock regulates 3-D chromatin structure
EPFL biologists and geneticists have uncovered how the circadian clock orchestrates the 24-hour cycle of gene expression by regulating the structure of chromatin, the tightly wound DNA-protein complex of the cell.
The circadian clock controls the cell cycle and tumor growth in plants
Biological rhythms are ubiquitous in nature, from the beating of the heart to the rhythms of flowering plants.
More Circadian Clock News and Circadian Clock Current Events

Top Science Podcasts

We have hand picked the top science podcasts of 2019.
Now Playing: TED Radio Hour

Risk
Why do we revere risk-takers, even when their actions terrify us? Why are some better at taking risks than others? This hour, TED speakers explore the alluring, dangerous, and calculated sides of risk. Guests include professional rock climber Alex Honnold, economist Mariana Mazzucato, psychology researcher Kashfia Rahman, structural engineer and bridge designer Ian Firth, and risk intelligence expert Dylan Evans.
Now Playing: Science for the People

#541 Wayfinding
These days when we want to know where we are or how to get where we want to go, most of us will pull out a smart phone with a built-in GPS and map app. Some of us old timers might still use an old school paper map from time to time. But we didn't always used to lean so heavily on maps and technology, and in some remote places of the world some people still navigate and wayfind their way without the aid of these tools... and in some cases do better without them. This week, host Rachelle Saunders...
Now Playing: Radiolab

Dolly Parton's America: Neon Moss
Today on Radiolab, we're bringing you the fourth episode of Jad's special series, Dolly Parton's America. In this episode, Jad goes back up the mountain to visit Dolly's actual Tennessee mountain home, where she tells stories about her first trips out of the holler. Back on the mountaintop, standing under the rain by the Little Pigeon River, the trip triggers memories of Jad's first visit to his father's childhood home, and opens the gateway to dizzying stories of music and migration. Support Radiolab today at Radiolab.org/donate.