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Protein links metabolism and circadian rhythms

Work could lead to drugs to combat obesity, aging and jetlag

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3:04pm, July 24, 2008
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Sirtuin 1 sets clock to
Metabolism

Timing is everything, especially when it comes to basic biological functions such as eating, sleeping and detoxifying. Scientists have known for ages that metabolism is tied to the body’s daily rhythms, but have not known how.

Now, two groups of researchers report in the July 25 Cell the discovery of a molecule that links metabolism to the circadian clock. The missing link turns out to be a protein called sirtuin 1 or SIRT1, which is also a key regulator of aging.

Uncovering the mechanism that links metabolism and circadian rhythms could lead to drugs to combat obesity, aging and jetlag and help shift workers reset their body clocks.

Already, SIRT1 is the target of resveratrol, a molecule found in red wine and other foods and that mimics the health benefits of a nutritious, calorie-restricted diet.

“It’s an interesting connection,” says Herman Wijnen, a circadian geneticist at the University of Virginia in Charlottesville who was not involved in the new studies. “It helps us understand one important aspect of how clocks and metabolism relate to each other.”

Body rhythms are governed by molecular clocks that take about a day to complete a full cycle, hence the name circadian clock. The clocks are composed of proteins whose concentrations or levels of activity rise and fall like the tide.

Most animals have a main pacemaker centered in the brain. Triggered by light, this clock can reset within a couple days.

But almost every cell in the body contains a clock, and these clocks are reset by the introduction of food, by a change in body temperature or through other metabolic signals.

All the cellular clocks need to synchronize with the main clock in the head, says Ueli Schibler of the University of Geneva in Switzerland. But the cellular clocks take longer to reset, a week or more. This mismatch between the cellular clocks and the brain clock is one reason for jetlag.

That’s probably as it should be, Schibler says. “Imagine if you stand up in the middle of the night and eat a sandwich. You don’t want your clock reset just because of one sandwich.”

In 2006, researchers led by Paolo Sassone-Corsi, a molecular biologist at the University of California Irvine, reported that a protein named CLOCK is a component in cellular clocks. It drums out the beat of circadian rhythm by chemically modifying a histone protein, which packages DNA. CLOCK transfers an organic molecule called acetyl to a histone protein. That action causes DNA to open up, helping to turn on the genes contained within the DNA.

Such chemical alterations of DNA and its associated proteins are called epigenetic modifications. They help control development, behavior and metabolic processes in the body.

In order for epigenetic modifications to be most effective they should be reversible, so cells can switch genes off and back on again when needed, such as when a person eats a sandwich and needs to make hormones to tell the brain that the stomach is full or to deal with the sudden influx of energy.

No one knew what CLOCK’s counterpoint — a protein that would remove the acetyl and turn genes off — might be. But Sassone-Corsi and his colleagues suspected that sirtuins might be involved because the proteins respond to a cell’s energy state by plucking acetyl groups from histones and other proteins. The team hypothesized that sirtuins might also interact with cellular clocks.

In one of the new studies, Sassone-Corsi’s group shows that SIRT1 acts as tick to CLOCK’s tock, removing an acetyl group from histones and also from CLOCK’s partner BMAL1.

Schibler and colleagues report similar results in the same issue of Cell, demonstrating that SIRT1 levels rise and fall throughout the day, and that SIRT1, CLOCK and BMAL1 interact in a circadian manner. Schibler’s group also found that SIRT1 is involved in removing acetyl groups from another clock component, a protein called PER2. That action leads to degradation of PER2, driving the clock.

Both groups found that SIRT1 is active in liver clocks. The liver performs many of its functions, such as detoxifying harmful substances and processing fat and cholesterol, on a schedule.

Tying the liver’s clock to metabolic activity makes sense, says Wijnen, and SIRT1’s connection to the clock may be important for timing the organ’s functions. Breakdowns in the body’s clocks could put them out of sync with the brain’s timer, possibly leading to disease.

Metabolic links to gene activity and circadian rhythms may help explain some mysteries of obesity and aging, but the researchers say they still don’t know exactly how SIRT1 keeps clocks ticking.

“The clock really dominates all of our physiology, so it’s not surprising to find these molecules involved in metabolism, aging and obesity” linked to the circadian rhythms, says Sassone-Corsi. “But it is important to find the molecular basis of this mechanism.”

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