August 28, 2008

Protein Links Metabolism to Clock

By Saey, Tina Hesman

Work could lead to drugs for obesity, aging and jet lag Cue stomach rumbles

SIRT1 sets internal clock

To metabolism

Timing is everything, especially when it comes to basic biological functions such as eating, sleeping and liver activity. 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 in mice. 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 for combating obesity, aging and jet lag and for helping shift workers reset their body clocks.

"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."

SIRT1 has also been a source of research interest because of its involvement in the effects of resveratrol, a molecule found in red wine and other foods that mimics the health benefits of a nutritious, calorie-restricted diet.

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

Most animals have a main pacemaker in the brain. Triggered by light, this clock can reset within a couple of 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 by other metabolic signals.

For the body to function normally, all the cellular clocks must synchronize with the main clock in the head, says Ueli Schibler of the University of Geneva in Switzerland and coauthor of one of the studies. 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 jet lag.

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 and coauthor on the other Cell study, 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 in the cell. 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 the new study, Sassone-Corsi's group shows that SIRTl indeed 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, demonstrating that SIRT1 levels rise and fall throughout the day, and that SIRT1, CLOCK and BMALl 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, one of the gears that keeps the clock moving.

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 those clocks 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," says Sassone- Corsi, so it's not surprising to find molecules that are involved in metabolism, aging and obesity linked to the circadian rhythms. "But it is important to find the molecular basis of this mechanism," he adds.

"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."


Copyright Science Service, Incorporated Aug 16, 2008

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