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New job for old protein: Controlling the body clock

Most life on Earth, whether simple or complex, flows with the universal hum of circadian rhythms. Our sleeping, eating and the way we burn energy all are governed by the ticking of our body clocks in relation to light and dark cycles.
(Photo by Peter Smith Photography)

Besides making us feel alternatively tired or wakeful, this 24-hour rhythm pulses with biochemical reactions throughout the body, turning on and off genes that instruct the liver to pump glucose, synthesize cholesterol or burn fat. The means by which these processes are coordinated, however, has been a mystery—until now.

A team led by Jiandie Lin, research assistant professor at the Life Sciences Institute (LSI), wanted to find how metabolic pathways worked in concert with the circadian clock to create the predictable daily patterns of energy storage or usage. What they found could give further insight into the origins of obesity and diabetes.

By creating genetically altered "knockout" mice, they uncovered a new job for an old protein called PGC-1 (alpha). PGC-1 is best known as a master regulator of genes that control energy production in the cell; it ramps up the activity of mitochondria, the microscopic generators that provide power for muscles and nerve cells.

Lin and his colleagues found that mice lacking this protein had abnormal daily rhythms of activity, body temperature and metabolic rate. Their studies also revealed that it controls genes that coordinate circadian rhythms, and in the process, synchronize clockwork in the body using tissue metabolic activities. Acting as an energy rheostat, the protein enables real time adjustment of metabolic activities with light and dark cycles, and thus serves as a key coordinator of metabolic functions with the minute-by-minute ticking of the clock.

"Our body maintains constant blood glucose levels by balancing appetite, production of glucose by the liver, its storage as glycogen (or starch) and its usage for energy. The liver continuously pumps out glucose, which does not occur at a steady rate, but rather, the rate oscillates with the circadian rhythm," Lin says.

"We also know that obese people, who store more fat than they burn, often have perturbed circadian cycles. Looking at this new molecular link between metabolism and the role of the clock pathway in metabolism in both normal and obese people may give us new insights into the beginnings of obesity and diabetes," says Lin, who also is an assistant professor in the Department of Cell & Developmental Biology at the Medical School.

The paper, "Transcriptional coactivator PGC-1 integrates the mammalian clock and energy metabolism" by Chang Liu, Siming Li, Tiecheng Liu, Jimo Borjigin and Lin appeared online May 2 in the journal Nature.

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