Cellular clocks throughout the body are precisely synchronized by tiny fluctuations in body temperature.

Clock genes in the suprachiasmatic nucleus in the brain of a mouse wax and wane to regulate the body's circadian rhythms.

Video: Joe Takahashi

Every 24 hours, millions of 'clocks' inside of our cells reset, helping to tune sleep patterns, blood pressure and metabolism. These clocks—which are actually sets of genes that turn on and off in a cyclical rhythm—are precisely synchronized thanks to tiny fluctuations in body temperature, according to a new study.

Scientists knew that internal clocks in plants, bacteria, and cold-blooded animals such as lizards and fish are extremely sensitive to temperature. But this is the first study to show that the body's thermostat also controls mammalian body clocks, suggesting that temperature resets are "evolutionarily ancient," the researchers say.

"If you look very broadly across all living systems, it appears that the ability to use temperature to synchronize clocks is ubiquitous," notes Howard Hughes Medical Investigator Joseph S. Takahashi, who led the new work, which was published October 15, 2010 in Science. "Light and temperature seem to be the major universal cues."

Sorting out the complex molecular interplay that regulates the body’s internal clock is crucially important because broken clocks can cause more than a fitful night’s sleep. Disrupted circadian rhythms have been linked to cancer, psychiatric disorders, and metabolic syndrome.

If you look very broadly across all living systems, it appears that the ability to use temperature to synchronize clocks is ubiquitous.

Joseph S. Takahashi

The suprachiasmatic nucleus (SCN), a tiny structure deep in the mammalian brain, is known as the body's 'master clock.' It receives light input from the eyes and sends out chemical and electrical signals to the rest of the body to keep it set on a 24-hour schedule.

Since it was localized in the 1970s, the SCN has garnered lots of scientific attention. But in the past few years, Takahashi's team and others have discovered that clock genes are expressed in just about every cell in the body. These peripheral clocks seem to have different physiological roles depending on their location. For example, in July, Takahashi and his colleague Joe Bass at Northwestern University reported in Nature that disrupting clock genes in mouse pancreatic cells gives the critters diabetes.

The master clock of the SCN holds the puppet strings of the myriad peripheral clocks, but scientists are only beginning to understand how. Takahashi's new study shows that the SCN controls body temperature, which in turn regulates the peripheral clocks.

The team took advantage of an enzyme called firefly luciferase, so named because the insects use it to glow green. Using tricks of genetic engineering, the researchers manipulated mouse cells so that the luciferase gene was fused with Per2, an important clock gene. Then, by recording the cells with a supersensitive camera, the researchers could see—literally—how Per2 expression waxed and waned over time.

The researchers applied the technique to cultured mouse cells from the lung and pituitary gland and then tweaked the temperature from 36 to 38.5 degrees Celsius (the normal range of body temperature in mice). Surprisingly, even tiny changes in temperature affected the cycle of Per2 expression. "It's not a weak effect—it's an extremely robust effect," says Takahashi, chair of the department of neuroscience at the University of Texas Southwestern Medical Center, in Dallas.

In contrast, temperature did not reset Per2 expression in tissue from the SCN.

The master clock's resistance to temperature fluctuations makes sense for two reasons, Takahashi says. Imagine if your clock reset every time you walked outside in the cold. "You don’t want your clock to be sensitive to inappropriate cues," he says. Second, because the SCN controls body temperature, if it did show this sensitivity, "it would be constantly getting a feedback signal that it itself is generating," he says.

The researchers also showed that peripheral clocks lost their temperature sensitivity when they used a drug to block a signaling network known as the heat shock pathway, which influences aging and longevity. That's intriguing because many kinds of cellular insults, such as stress hormones and appetite signals, are also known to activate heat shock proteins. "In a way, that's analogous to how many different kinds of signals can impinge upon the circadian clock," Takahashi says. "We think that this pathway helps us to understand how all these different kinds of signals might be integrated."

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