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Genes discovered linking circadian clock with eating schedule

For most people, the urge to eat a meal or snack comes at a few predictable times during the waking part of the day. But for those with a rare syndrome, hunger comes at unwanted hours, interrupts sleep and causes overeating. A team in the lab of Satchidananda Panda recently discovered a pair of genes that normally keeps eating schedules in sync with daily sleep rhythms. In mice with mutations in one of the genes, eating patterns are shifted, leading to unusual mealtimes and weight gain. The results were published in Cell Reports.

Satchidananda Panda

“We really never expected that we would be able to decouple the sleep-wake cycle and the eating cycle, especially with a simple mutation,” says Panda, whose work is supported in part by the Joe W. and Dorothy Dorsett Brown Foundation. “It opens up a whole lot of future questions about how these cycles are regulated.”

More than a decade ago, researchers discovered that individuals with an inherited sleep disorder often carry a particular mutation in a protein called PER2, in an area of the protein that can be phosphorylated–the ability to bond with a phosphate chemical that changes the protein’s function. Humans have three PER, or period, genes, all thought to play a role in the circadian clock and all containing the same phosphorylation spot.

Panda’s lab joined forces with a Chinese team led by Ying Xu of Nanjing University to test whether mutations in the equivalent area of PER1 would have the same effect as those in PER2. They bred mice to lack the mouse period genes and added in a human PER1 or PER2 with a mutation in the phosphorylation site. As expected, mice with a mutated PER2 had sleep defects, dozing off earlier than usual. The same wasn’t true for PER1 mutations, though.

Mice with the PER1 phosphorylation defects ate earlier than other mice. The defect caused them to awaken and snack before their sleep cycle was over, and eat more food throughout their normal waking period. When researchers looked at the molecular details of the PER1 protein, they found that the mutated PER1 led to lower protein levels during the sleeping period, higher levels during the waking period and a faster degradation of protein whenever it was produced by cells. Panda and his colleagues hypothesize that normally, PER1 and PER2 are kept synchronized, but a mutation in one of the genes could break this link and cause off-cycle eating or sleeping.

When the team restricted access to food, providing it only at the mice’s normal meal times, they found that even with a genetic mutation in PER1, mice could maintain a normal weight. Over a ten-week follow-up, these mice–with a PER1 mutation but timed access to food–showed no differences compared to control animals. This tells the researchers that the weight gain caused by PER1 is entirely caused by meal mistiming, not other metabolic defects.