Not Like Clockwork: High-fat diet disrupts daily routines of mice

Most mice sleep, eat, and exercise on a predictable 24-hour cycle, thanks to their precise internal clocks. But mice fed a fatty diet have trouble sticking to their schedule, new research shows. Genetic activity, not just behavior, drives the changes.

Understanding this novel link between daily cycles, known as circadian rhythms, and the metabolic system could help reveal the mechanism behind some cases of obesity and diabetes in humans, scientists say.

Earlier research had shown a connection between circadian rhythm and eating behavior. For example, mutations in mouse genes that help maintain the internal clock’s rhythm cause the animals to overeat and gain weight. Studies have also shown that people who work night shifts are at higher risk for obesity than their day-shift counterparts, and that getting too little sleep can raise a child’s risk of developing diabetes later in life.

Joseph Bass of Northwestern University in Evanston, Ill., suspected that diet and sleep/wake cycles are linked in other ways. So he and his colleagues fed male mice diets high in fat and recorded their daily behavior.

“We don’t normally wake up during the middle of the night hungry,” says Bass. “Our clock controls that.” But after only 2 weeks on the fatty diet, the usually nocturnal mice began waking up and eating during the day.

To get at the root of how diet was changing the mice’s circadian rhythms, the researchers tracked hormone and gene expression in different tissues of the animals for 24 hours. A high-fat diet altered the daily activity cycle of genes involved in appetite and metabolism, the team reports in the November Cell Metabolism.

The diet dampened the usual cyclic variation in the activity of some genes. For other genes, the frequency or amplitude of the cycle changed. The changes varied among tissues, says Bass, because circadian rhythms play different roles in different organs. Mice that got only 16 percent of their calories from fat, instead of 45 percent, did not exhibit the changes.

Bass says that understanding the two-way link between circadian rhythms and diet in mice could help explain sleep and metabolic disorders in people. “Maybe a very common perturbation, high-fat feeding, is one of the factors that disrupts the circadian rhythm,” he says. “And disrupting the circadian rhythm, in turn, affects appetite. It’s a vicious cycle.”

Tamas Horvath of Yale University calls the new findings “incredibly novel” and says that the next step is to probe exactly how, at a molecular level, a high-fat diet alters the expression of “clock genes.” Future studies could test how different diets change circadian rhythms, Horvath says.

“Is it the combination of fat and carbohydrate that matters?” ponders Horvath. “What if you put the mice on an Atkinslike diet with more protein? Would that be different?”