A team led by Joseph Besharse of the Medical College of Wisconsin and Carla Green of the University of Virginia report in this week's Proceedings of the National Academy of Sciences USA that when the clock gene Nocturnin was disabled in mice, the animals did not plump up when fed fatty fare.
"We show evidence that the clock itself is behaving correctly in the mutant mouse," Besharse says, "but various aspects of lipid ands glucose metabolism are disrupted."
Besharse and Green discovered Nocturnin more than a decade ago. The gene codes for a protein produced in a number of mammalian tissues—including the liver. During the day the liver manufactures relatively low levels of the protein, but at night it ramps up its production a hundredfold.
The researchers knocked out the function of Nocturnin in a group of mice. They then fed some of the mice normal diets, while others received high-fat meals. The animals on standard diets looked and acted a lot like normal mice: They were slim, spent time running on a wheel and were active at the same times of the day.
The Nocturnin-deficient mice on high-fat diets, however, showed only slight weight gain, whereas normal mice on the same diet ballooned to twice the size of their mutant counterparts. In addition, wild mice had large stores of fat around their livers, but the gene-deficit animals did not.
"They're better off without the gene, I guess, if you're just looking at obesity," says Besharse. However, "the mutant mice have altered glucose metabolism on a standard diet. It is likely that the Nocturnin [protein], which is produced in multiple tissues—liver, fat cells, pancreas and gut—is affecting glucose and lipid metabolism at multiple levels." This, he adds, triggers resistance to the hormone insulin secreted by the pancreas, which ferries glucose from the blood into individual cells, where it is converted to energy. People with low insulin production or resistance may develop type 2 diabetes.
Besharse says his team will continue to research the gene's molecular mechanism in the liver as well as in other tissues where its protein is produced, including the eyes, brain and kidneys. "Certainly it has crossed our minds that [a drug] that would inhibit the activity of Nocturnin might influence lipid [fat] storage," Besharse says. "But that's way down the road, in terms of research."