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Gaining control of our circadian rhythms

Posted on behalf of Leila Haghighat.

The woes of those affected by jet lag may soon come to an end. Two papers published today in Nature (here and here) explore how our internal clocks are regulated at the molecular level and how two compounds that alter this regulation could help us readjust to new time zones.

The body’s internal clock is governed by its circadian rhythm, the natural oscillations that occur within a 24-hour period and coincide with natural sleeping and feeding cycles. Each organ maintains its own individual clock, but the master regulator of circadian rhythms lies in the hypothalamus of the brain, more specifically in a structure called the suprachiasmatic nucleus (SCN), which is sensitive to light.

But synchronizing the circadian rhythm with the time of day involves more than just external light cues. Over a decade ago, researchers identified two receptors on the nucleus that also have a key role in the process: REV-ERB-α and REV-ERB-β. At certain times of the day, these receptors suppress the expression of certain genes to send the body into a dormant state. After the molecule that activates REV-ERBs was found in 2007, researchers set their sights on creating synthetic molecules that could mimic it. Turning on REV-ERBs by popping a pill could trick the body into dormancy, thereby adjusting the circadian rhythm.

A team of chemists and biologists led by Thomas Burris at the Scripps Research Institute in Jupiter, Florida, tested two compounds that activate REV-ERB in mice and showed that they change the expression of circadian-associated genes in both the hypothalamus and liver, making the animals less active.

The team kept the mice for 12 days in either constant darkness or alternating 12-hour cycles of light and dark. Constant darkness dampens the master regulator of the circadian rhythm and provides researchers with a look into the “purer rhythms” of individual organs, according to Burris.

The differences found between the two groups make developing a drug for human use more complicated. In the group of mice kept in the dark, those given the maximum dose of either drug could run only half as much as those not given the drug at all. The activity of mice exposed to regular lighting was delayed by only 1–3 hours.

“This suggests that light may in some way be interacting with REV-ERB to control its activity and adds a complication, since from a practical therapeutic point of view, such drugs are going to have to be active in normal lighting cycles,” says Andrew Loudon, a biologist at the University of Manchester, UK, who studies how REV-ERBs regulate immune function.

Beyond jet lag, the two compounds may also hold promise for those looking to lose weight or improve their cholesterol. “Circadian rhythms really have an important role in all types of human disease. Their circuitry controls not just our sleep but also our metabolism,” Burris notes.

Burris’s team fed mice a high-fat diet for 14 weeks and administered the drug twice a day. Mice given the drug lost more weight than controls, and had lower levels of cholesterol and fat in their blood.

Ronald Evans, senior author of the other Nature paper, says: “Together the two papers provide new insights into how clock function and circadian behaviour is established. It shows that the ‘clock’ and indeed our own body rhythm can be considered a therapeutic target.”

Photo courtesy of xlibber via Flickr under Creative Commons.

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