Jet lag is a bothersome reminder that the human body is set to a 24-hour, or circadian, clock. The master clock resides in the brain and regulates various behaviours, including sleeping and waking, taking its cues from the rhythm of daylight. Many metabolic functions — such as release of glucose by the liver and fat-burning by muscles — also follow daily patterns of activity. “There is a clear metabolic clock in the body,” says Jiandie Lin of the Life Sciences Institute at the University of Michigan in Ann Arbor. He wanted to determine the relationship between this metabolic clock and the circadian clock.

While working in Bruce Spiegelman's lab at Harvard Medical School, Lin studied a protein known as PGC-1α, a master regulator of energy-producing mitochondria. “We knew that PGC-1α is highly regulated in response to the environment and also regulates several major metabolic pathways,” says Lin. Because of this, he wondered whether PGC-1α might provide the molecular link between metabolic and circadian clock pathways.

Two years ago, Lin set up his own lab in Michigan and focused on this question. His group isolated mouse tissues at several times of day and found that PGC-1α expression in both the liver and skeletal muscle pulsed with a circadian rhythm. In addition, PGC-1α production increased the expression of several 'clock' genes, suggesting that rhythmic PGC-1α activity provides a signal to coordinate metabolism and the circadian clock. This conclusion was supported by the fact that transgenic mice lacking PGC-1α had abnormal daily rhythms of activity, body temperature and metabolic rate.

But Lin's group couldn't tell whether the loss of daily rhythms in the knockout mice was due to disruption of the circadian clock in the brain or a defect in the cells and tissues lacking PGC-1α. To determine at what level PGC-1α functioned, the researchers knocked down PGC-1α expression using an adenoviral vector carrying an interfering RNA molecule directed toward PGC-1α. “When injected through the tail vein adenoviruses almost exclusively infect the liver, so we essentially created a tissue-specific knockout mouse,” explains Lin. When liver PGC-1α expression was perturbed, circadian control over energy metabolism in the organ was lost. Thus, PGC-1α exerts its effects on circadian rhythm from within the confines of the liver (see page 477).

“The circadian clock was thought to affect physiology through downstream output mechanisms. Our findings support a mechanism that allows energy metabolism in peripheral tissues to be directly synchronized to the clocks in our bodies,” says Lin. In other words, PGC-1α responds to light and nutritional cues, and prompts specific tissue clocks and metabolic activities to follow the same pattern. Lin says the finding that a single molecule can regulate both circadian and metabolic pathways is not entirely unexpected. “We knew a lot about PGC-1α and that it could integrate and regulate multiple pathways,” he says.

Lin now plans to examine this new molecular link between metabolism and clock pathways in metabolic diseases. It is known that obese people and those with type 2 diabetes, who store more fat than they burn, often have perturbed circadian cycles. By targeting PGC-1α, it may be possible to synchronize metabolic functions to daily cues in these individuals.