Time out. Scientists found that mice with a faulty internal Clock (right) gained more body fat than normal mice (left).

Obesity is All in the Timing

A faulty internal clock can alter the body's metabolism, leading to such problems as diabetes and obesity, suggests a new study. Mice with a disrupted biological clock slept less, ate more, and gained more body fat than normal mice, indicating that, when it comes to understanding the molecular basis of obesity, timing may be key.

Much of the body's biological rhythms--when to eat, when to sleep, etc.--are set by a 24-hour circadian clock, a biological timing system linked to the rising and setting of the sun. The system relies on several genes, but one in particular seems to be a primary driver of the circadian machinery. Called Clock, the gene was discovered in 1997 by neurobiologists Fred Turek and Joseph Takahashi of Northwestern University in Evanston, Illinois. Several years later, Turek's team noticed that mice that lacked a functioning Clock gene were heavier than normal mice. Intrigued, Turek joined with endocrinologist Joseph Bass, also at Northwestern, to study the effects of regular and high-fat diets in normal mice and mice with a dysfunctional Clock gene.

The researchers found that the Clock mice were unable to control their weight, regardless of which diet they were on. When fed a regular diet, the mutant mice showed a 35% increase in body fat compared to normal mice; on a high-fat diet mutant mice had an alarming 75% increase in body fat relative to normal mice. The scientists also noticed that Clock mice slept about one to two hours less than normal mice, and when they weren't sleeping, they were eating. The irregular eating patterns may have been related to a decrease in the production of appetite-regulating hypothalamic peptides, such as leptin and ghrelin, say the researchers.

"The disruption of the circadian clock machinery seems to affect not only the rhythm of appetite regulation, but also the expression of the genes and proteins at their absolute level," says Turek, whose team reports its findings online today in Science. Because humans have the "identical circadian clock machinery" as mice, adds Bass, the work has important implications for scientists studying obesity and diabetes in people.

The findings also may have relevance for understanding other health problems, says neurobiologist Emmanuel Mignot at Stanford University, who studies sleep disorders. "This offers one more piece of evidence that circadian rhythm, sleep regulation, and metabolic regulation are tightly integrated."

Related sites
Turek's Web site
Bass's Web site
Center for Sleep and Circadian Biology
Circadian rhythm interactive graphic