Study: Genes link circadian clock to eating schedule

A study found that specific genes link a person's circadian clock to their 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.

Now, Salk scientists have discovered a pair of genes that normally keeps eating schedules in sync with daily sleep rhythms, and, when mutated, may play a role in so-called night eating syndrome. 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 this month's Cell Reports.

"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 senior study author Satchidananda Panda, an associate professor in Salk's Regulatory Biology Laboratory. "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. The mutation is 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 daily circadian clock and all containing the same phosphorylation spot.

The Salk scientists 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 that caused the sleep disorder. So 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.

"In the mice without PER1, there was no obvious defect in their sleep-wake cycles," says Panda. "Instead, when we looked at their metabolism, we suddenly saw drastic changes."

Mice with the PER1 phosphorylation defects ate earlier than other mice -- causing them to wake up and snack before their sleep cycle was over -- and ate more food throughout their normal waking period. When the 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 since they have identical phosphorylation sites -- they are turned on and off at the same times, keeping sleep and eating cycles aligned. But a mutation in one of the genes could break this link, and cause off-cycle eating or sleeping.

"For a long time, people discounted night eating syndrome as not real," says Panda. "These results in mice suggest that it could actually be a genetic basis for the syndrome." The researchers haven't yet tested, however, whether any humans with night eating syndrome have mutations in PER1.

When Panda and Xu's 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 10-week follow-up, these mice -- with a PER1 mutation but timed access to food -- showed no differences to control animals. This tells the researchers that the weight gain caused by PER1 is entirely caused by meal mistiming, not other metabolic defects.

Next, they hope to study exactly how PER1 controls appetite and eating behavior -- whether its molecular actions work through the liver, fat cells, brain or other organs.

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What causes late-night snack cravings?

This article discusses a study on the circadian rhythm and how it influences certain cravings late at night.

A study published in the most recent version of the journal Obesity found that the body's internal clock, the circadian system, increases hunger and cravings for sweet, starchy and salty foods in the evenings. While the urge to consume more in the evening may have helped our ancestors store energy to survive longer in times of food scarcity, in the current environment of high-calorie food, those late night snacks may result in significant weight gain.

"Of course, there are many factors that affect weight gain, principally diet and exercise, but the time of eating also has an effect. We found with this study that the internal circadian system also likely plays a role in today's obesity epidemic because it intensifies hunger at night," said Steven Shea, Ph.D., director for the Center for Research on Occupational and Environmental Toxicology at Oregon Health & Science University and senior author on the study. "People who eat a lot in the evening, especially high-calorie foods and beverages, are more likely to be overweight or obese."

Indeed, eating a lot in the evening can be counterproductive since the human body handles nutrients differently depending on the time of day. For example, sugar tolerance is impaired in the evening. Additionally, consuming more calories in the evening predisposes people to more energy storage; we simply don't expend as much energy after an evening meal in comparison to morning meals.

Furthermore, artificial light enables people to stay up later than they probably should and often people don't get enough sleep. "If you stay up later, during a time when you're hungrier for high-calorie foods, you're more likely to eat during that time," Shea said. "You then store energy and get less sleep, both of which contribute to weight gain."

"If weight loss is a goal, it's probably better to eat your larger, higher-calorie meals earlier in the day," said Shea. "Knowing how your body operates will help you make better choices. Going to bed earlier, getting enough sleep and choosing lower-calorie foods rather than higher-calorie foods in the evening can all help with weight loss."

Conducted by Shea and two Boston-area researchers, Frank Scheer, Ph.D. and Christopher Morris, Ph.D. of Brigham and Women's Hospital and Harvard Medical School, the study examined the appetite and food preference of 12 healthy non-obese adults throughout a 13-day laboratory stay in very dim light in which all behaviors were scheduled, including timing of meals and sleep. Dr. Scheer, first author on the study, explained that "by the end of this long protocol, all of the participants' meals and activities were spaced evenly across the day and night, allowing examination of the true internal circadian effects on appetite, while controlling for other effects on appetite including the amount of food recently consumed."

The researchers found that the internal circadian system regulated hunger, with participants feeling the least hungry in the morning (8 a.m.) and most hungry in the evening (8 p.m.). Similar rhythms were found in appetite for types of food, such as sweet, starchy and salty, and the estimate of how much food participants could eat. The study concludes that the internal circadian system causes an evening peak in appetite that may promote larger, higher-calorie meals before the fasting period necessitated by sleep.

"Our study suggests that because of the internal circadian regulation of appetite, we have a natural tendency to skip breakfast in favor of larger meals in the evening. This pattern of food intake across the day is exactly what Sumo wrestlers do to gain weight." said Steven Shea. "So, it seems likely that the internal circadian system helps with efficient food storage. While this may have been valuable throughout evolution, nowadays it is likely to contribute to the national epidemic of obesity."

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Excess holiday eating has same effect as jet lag

This article discusses how excess holiday eating disturbs your "food clock" and has effects similar to jet lag or working the graveyard overnight shift at work. It also discusses how to reset your "food clock."

If the sinful excess of holiday eating sends your system into butter-slathered, brandy-soaked overload, you are not alone: People who are jet-lagged, people who work graveyard shifts and plain-old late-night snackers know just how you feel.

All these activities upset the body's "food clock," a collection of interacting genes and molecules known technically as the food-entrainable oscillator, which keeps the human body on a metabolic even keel. A new study by researchers at the University of California, San Francisco (UCSF) is helping to reveal how this clock works on a molecular level.

Published this month in the journalProceedings of the National Academy of Sciences, the UCSF team has shown that a protein called PKCγ is critical in resetting the food clock if our eating habits change.

The study showed that normal laboratory mice given food only during their regular sleeping hours will adjust their food clock over time and begin to wake up from their slumber, and run around in anticipation of their new mealtime. But mice lacking the PKCγ gene are not able to respond to changes in their meal time -- instead sleeping right through it.

The work has implications for understanding the molecular basis of diabetes, obesity and other metabolic syndromes because a desynchronized food clock may serve as part of the pathology underlying these disorders, said Louis Ptacek, MD, the John C. Coleman Distinguished Professor of Neurology at UCSF and a Howard Hughes Medical Institute Investigator.

It may also help explain why night owls are more likely to be obese than morning larks, Ptacek said.

"Understanding the molecular mechanism of how eating at the "wrong" time of the day desynchronizes the clocks in our body can facilitate the development of better treatments for disorders associated with night-eating syndrome, shift work and jet lag," he added.

Resetting the Food Clock

Look behind the face of a mechanical clock and you will see a dizzying array of cogs, flywheels, reciprocating counterbalances and other moving parts. Biological clocks are equally complex, composed of multiple interacting genes that turn on or off in an orchestrated way to keep time during the day.

In most organisms, biological clockworks are governed by a master clock, referred to as the "circadian oscillator," which keeps track of time and coordinates our biological processes with the rhythm of a 24-hour cycle of day and night.

Life forms as diverse as humans, mice and mustard greens all possess such master clocks. And in the last decade or so, scientists have uncovered many of their inner workings, uncovering many of the genes whose cycles are tied to the clock and discovering how in mammals it is controlled by a tiny spot in the brain known as the "superchiasmatic nucleus."

Scientists also know that in addition to the master clock, our bodies have other clocks operating in parallel throughout the day. One of these is the food clock, which is not tied to one specific spot in the brain but rather multiple sites throughout the body.

The food clock is there to help our bodies make the most of our nutritional intake. It controls genes that help in everything from the absorption of nutrients in our digestive tract to their dispersal through the bloodstream, and it is designed to anticipate our eating patterns. Even before we eat a meal, our bodies begin to turn on some of these genes and turn off others, preparing for the burst of sustenance -- which is why we feel the pangs of hunger just as the lunch hour arrives.

Scientist have known that the food clock can be reset over time if an organism changes its eating patterns, eating to excess or at odd times, since the timing of the food clock is pegged to feeding during the prime foraging and hunting hours in the day. But until now, very little was known about how the food clock works on a genetic level.

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