Resetting the Circadian Clock Might Boost Metabolic Health

Consider a quarterback’s passing game: throw the ball too soon and his receiver isn’t in place; throw the ball too late and he risks getting sacked. Either way, he isn’t in sync with his team to move the ball up field. A similar scenario may occur when eating and sleeping habits are out of sync with the body’s circadian clock, leading to metabolic disturbances.

Over the past 20 years, scientists have assembled a clearer picture of the circadian clocks that keep human physiology tuned to the 24-hour light-dark cycle. Now, the basic science is giving way to human studies that reveal how a person’s sleeping habits, eating patterns, and diet may desynchronize the body’s clocks and contribute to metabolic problems like obesity or diabetes.

The findings have led scientists on a hunt for ways to reset the clock and restore healthy metabolism. So far, 2 behavioral interventions—improved sleep and time-restricted eating—show promise in animal and preliminary human studies.

“We are seeing [behaviors that affect] circadian time of day and sleep as human behavior that we can alter,” said Fred Turek, PhD, director of the Center for Sleep and Circadian Biology at Northwestern University in Evanston, Illinois.

Keeping Time

The brain’s suprachiasmatic nucleus (SCN) acts as the central pacemaker for the human circadian system. When the retina processes wavelengths of light typically emitted by the sun, a series of signal transduction events activate the expression of circadian genes within the SCN. In response to these changes in gene expression driven by the light-dark cycle, the SCN also stimulates the release of the hormone cortisol that triggers waking and the hormone melatonin, which signals when it’s time for sleep.

The cyclic expression of circadian genes in the SCN regulates the expression of hundreds—maybe even thousands—of genes throughout the body including many involved in metabolism.

More recently, researchers have discovered that the peripheral organs and tissues have circadian rhythms or “clocks” of their own that are controlled by the cyclic expression of clock genes in their cells, explained Eve Van Cauter, PhD, a professor of medicine at the University of Chicago. These circadian gene oscillations are particularly important for the organs involved in glucose metabolism—the liver, muscles, fat tissue, beta cells, and the gut, she noted. For these internal organs, which aren’t exposed to daylight, food intake is an important marker of the time of day.

“The timing of food synchronizes these peripheral [circadian] oscillators,” Van Cauter said. When food is timed to coincide with the light-dark cycle—as it would have been evolutionarily—the central clocks in the SCN and the peripheral clocks work together to promote healthy metabolism. But if either the central or peripheral clocks are thrown off—for example by eating at off times or having disturbed sleep—it can cause desynchrony between them resulting in metabolic problems.

Although the discovery of peripheral clocks is fairly new, that glucose metabolism is tied to a circadian rhythm and influenced by food timing was realized as far back as the 1970s and 1980s by physicians treating diabetes, noted Satchidananda Panda, PhD, a professor in the Regulatory Biology Laboratory at the Salk Institute in La Jolla, California. He explained that some patients who responded poorly to a glucose challenge at night had no signs of diabetes when given the same challenge in the morning. Even healthy individuals, Panda noted, process sugar from nighttime meals more slowly than they process comparable morning meals.

“This showed there is a beautiful rhythm in glucose metabolism,” Panda said.

Studies involving animals, particularly mice, helped illuminate how disruptions of the body’s circadian clocks may lead to obesity and other metabolic conditions. A seminal study in 2005 showed that mice with mutations in a circadian gene called Clock become obese even when fed a typical mouse chow diet and develop signs of metabolic syndrome, including high cholesterol, high blood glucose, and insufficient production of insulin. They also sleep about 2 hours less and have disturbed eating patterns. While typical mice eat mostly during their active hours at night, the mutant mice split their food consumption almost equally between light and dark hours. Weight gain in the mutant animals is exacerbated when they are fed a high fat diet.

Another study showed typical mice fed a high-fat diet during the day, when they normally sleep, gained much more weight than mice fed the same diet at night during their normal waking hours. When the scientists looked at what was happening to the circadian patterns of gene expression in the mice who ate at odd times of day, they found that the SCN remained tuned to the 24-hour day-night cycle, Turek noted. But changes in sleep and eating behaviors quickly disrupt and dampen the circadian rhythms of gene expression in the peripheral organs, despite the tuned central clocks.

“When the peripheral oscillators are not in sync with the central oscillator, deranged metabolism occurs with weight gain and development of glucose intolerance,” Van Cauter explained.

Humans Out-of-Sync

Humans are not immune to the type of clock disruptions documented in mice.

Decades of epidemiologic studies show workers with overnight shifts or other schedules out of sync with the light-dark cycle have an increased risk of weight gain and diabetes. Genetic mutations in human clock genes have been associated with obesity and metabolic disease. Conversely, a variation in the gene encoding the melatonin receptor has been linked to a higher risk of developing type-2 diabetes.

Even those without genetic mutations or unusual schedules may be at risk of clock disturbances. Thanks to light pollution and growing nighttime use of light bulbs and electronic devices that emit the same wavelengths of light as the sun, many otherwise healthy individuals may experience sleep disturbances or circadian disruptions.

“We live in a society where sleep is not respected,” Van Cauter said.

But sleep, circadian rhythms, and metabolism make up an “inseparable triad,” she noted. Insufficient sleep has been shown to have a harmful impact on glucose tolerance in many populations including healthy adults, children, hospitalized patients, and those with diabetes, she noted. It’s also been shown to reduce resting metabolic rate to a large enough degree that it could translate to a 12.5-pound weight gain in a single year. Sleep restriction also increases hunger, Van Cauter noted. But restoring normal sleep can help reverse these ill effects.

“The work so far suggests that being sleep deprived and losing weight are contradictory,” she said. “To optimize weight loss, you need to sleep.”

A growing appreciation of the importance of circadian biology has led to a push to begin developing clinical interventions that leverage circadian biology to restore metabolic health. In 2015, the National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) held a workshop that brought together top circadian researchers with metabolic researchers. The NIDDK also has partnered with other institutes to request proposals for clinical research on how circadian rhythms impact obesity, diabetes, and other diseases.

“We are trying to encourage investigators to not only do in-depth metabolic work, but also to try out therapeutics,” said Karen Teff, PhD, a program director in NIDDK’s division of diabetes, obesity, and metabolism.

Practical Interventions

Clinicians may be overwhelmed by the prospect of gathering information to assess whether their patients need a clock tune-up. But preliminary clinical studies now under way would provide practical tools for assessment and fairly simple interventions.

Panda and his colleagues have created a mobile phone app called myCircadianClock, which helps people track their eating, sleeping, and activity patterns, as well as when they take medications or supplements. They have begun enrolling participants in a study of the app with the aim of gathering 2 weeks of data from about 10 000 people. They will look for trends in the data to determine whether they can create reference standards physicians could use to identify patients with clock-related disturbances.

“Physicians are used to looking at blood pressure and blood sugar against reference level,” Panda explained. “If you come up with simple rule-of-thumb guidelines for [circadian indicators like eating or sleep] for physicians, that will help patients.”

Eating interval is one factor that the team has looked at. The team found that about half of the 156 participants using the app in an initial study were eating over the course of more than 15 hours each day, with more than one-third of calories consumed after 6 pm. Studies involving mice had shown that restricting eating to 8, 9, or 12 hours during active periods had beneficial effects on weight, metabolism, and circadian rhythms even with a high-fat diet.

So Panda and his colleagues ran a 16-week pilot study with 8 of the app users who had an eating interval greater than 14 hours. The users were asked to restrict eating to a period of 10 to 12 hours each day. Participants did reduce their eating intervals, and on average lost about 7 pounds. They also reported sleeping better, snacking less, and becoming less tolerant to very sweet foods. One participant emailed to say he felt time-restricted eating is “the best diet because it does not deprive him of his favorite foods, and he’s still losing weight.”

“We think timing is something everyone can stick to,” Panda said.

Panda and his colleagues plan to further develop the app to create a “lifestyle report” that can be a starting point for physician-patient discussions. For example, if the report shows that a patient consumes a lot of calories in the form of alcohol and junk food after 8 pm, that person may decide to curtail eating or drinking after 8 pm.

While much work is needed to verify the potential of time-restricted eating and other circadian-targeted interventions, Teff noted that not eating after the evening meal is likely to be beneficial.

“It’s basic dietary and nutritional advice for people with diabetes or obesity, but it potentially fits into circadian theory,” Teff said.

Panda advised that individuals, particularly those at risk of becoming hypoglycemic, not begin any form of fasting without physician supervision. He also suggested that individuals gradually reduce their eating window.

Other efforts are looking at how clinicians might prevent sleep and circadian disruption-related metabolic problems. The Sleep for Inpatients: Empowering Staff to Act (SIESTA) study is currently under way to assess whether training hospital staff to help inpatients sleep better actually will improve the patients’ sleep.

“The hospital itself is an experiment in sleep restriction, sleep deprivation, and sleep disruption,” said Van Cauter.

But hospital staff can take simple steps to help patients sleep, she said. For example, they can batch interventions during the day, talk in lower voices at night, or even set aside time each night when patient disruptions are minimized.

All physicians should spend a few minutes asking patients about their sleep because poor sleep could diminish the effectiveness of therapies, Van Cauter suggested. She noted that short, validated questionnaires on sleep patterns are available.

“Sleep should be considered a pillar of health, with nutrition and exercise,” Van Cauter said. “It’s very important to examine the possibility that optimizing sleep might be a lifestyle intervention that might be more successful than dietary restriction or exercise. It’s one more thing people can do.”


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