The Human body's Circadian biological clock: Scientists redraw the blueprint

The discovery of a major gear in the biological clock that tells the body when to sleep and metabolize food may lead to new drugs to treat sleep problems and metabolic disorders, including diabetes.

Scientists at the Salk Institute for Biological Studies, led by Ronald M. Evans, a professor in Salk's Gene Expression Laboratory, showed that two cellular switches found on the nucleus of mouse cells, known as REV-ERBα and REV-ERBβ, are essential for maintaining normal sleeping and eating cycles and for metabolism of nutrients from food.

The findings, reported March 29 in Nature, describe a powerful link between circadian rhythms and metabolism and suggest a new avenue for treating disorders of both systems, including jet lag, sleep disorders, obesity and diabetes.

"This fundamentally changes our knowledge about the workings of the circadian clock and how it orchestrates our sleep-wake cycles, when we eat and even the times our bodies metabolize nutrients," says Evans.

"Nuclear receptors can be targeted with drugs, which suggests we might be able to target REV-ERBα and β to treat disorders of sleep and metabolism."

Nurses, emergency personnel and others who work shifts that alter the normal 24-hour cycle of waking and sleeping are at much higher risk for a number of diseases, including metabolic disorders such as diabetes.

To address this, scientists are trying to understand precisely how the biological clock works and uncover possible targets for drugs that could adjust the circadian rhythm in people with sleep disorders and circadian-associated metabolic disorders.

In mammals, the circadian timing system is orchestrated by a central clock in the brain and subsidiary clocks in most other organs.

The master clock in the brain is set by light and determines the overall diurnal or nocturnal preference of an animal, including sleep-wake cycles and feeding behaviour.

Scientists knew that two genes, BMAL1 and CLOCK, worked together at the core of the clock's molecular machinery to activate the network of circadian genes.

In this way, BMAL1 acts like the accelerator on a car, activating genes to rev up our physiology each morning so that we are alert, hungry and physically active.

Prior to this work REV-ERBα and β were thought to play only a minor role in these cycles, possibly working together to slow CLOCK-BMAL1 activity to make minor adjustments to keep the clock running on time.

However, genetic studies of two genes with similar functions can be very difficult and thus the real importance of REV-ERBα and β remained mysterious.

The Salk scientists got around this hurdle by developing mice in which both genes could be turned off in the liver at any point by giving them an estrogen derivative called tamoxifen.

Now mice could develop normally to adulthood, at which point the scientists could turn off REV-ERBα and REV-ERBβ in their livers, an organ crucial to maintaining the correct balance of sugar and fat in blood, to see what effects it had on circadian rhythms and metabolism.

"When we turned off both receptors, the animal's biological clocks went haywire," says Han Cho, first author on the paper and a postdoctoral researcher in Evan's Salk laboratory.

"The mice started running on their exercise wheels when they should have been resting. This suggested REV-ERBα and REV-ERBβ aren't an auxiliary system that makes minor adjustments, but an integral part of the clock's core mechanism. Without them, the clock can't function properly."

Digging more deeply into the clockworks, the Salk scientists mapped out the genes that the REV-ERBs control to keep the body operating on the right schedule, finding that they overlap with hundreds of the same genes controlled by CLOCK and BMAL1.

This and other findings suggested that the REV-ERBs, act as a break on the genes BMAL1 activates.

"We thought that the core of the clock was an accelerator, and that all REV-ERBα and REV-ERBβ did was to pull the foot off that pedal," says Evans.

"What we've shown is that these receptors act directly as a break to slow clock activity. Now we've got a accelerator and a break, each equally important in creating the daily rhythm of the clock."

The scientists also found that the REV-ERBs control the activity of hundreds of genes involved metabolism, including those responsible for controlling levels of fats and bile.

The mice in which REV-ERBα and REV-ERBβ were turned off had high levels of fat and sugar in their blood, common problems in people with metabolic disorders.

"This explains how our cellular metabolism is tied to daylight cycles determined by the movements of the sun and the earth," says Satchidananda Panda, an associate professor in Salk's Regulatory Biology Laboratory and co-author on the paper.

"Now we want to find ways of leveraging this mechanism to fix a person's metabolic rhythms when they are disrupted by travel, shift work or sleep disorders."

Provided by Salk Institute

Genetic study links body clock receptor to diabetes

A study published in Nature Genetics today has found new evidence for a link between the body clock hormone melatonin and type 2 diabetes.

The study found that people who carry rare genetic mutations in the receptor for melatonin have a much higher risk of type 2 diabetes.

The findings should help scientists to more accurately assess personal diabetes risk and could lead to the development of personalised treatments.

Previous research has found that people who work night shifts have a higher risk of type 2 diabetes and heart disease. Studies have also found that if volunteers have their sleep disrupted repeatedly for three days, they temporarily develop symptoms of diabetes.

The body's sleep-wake cycle is controlled by the hormone melatonin, which has effects including drowsiness and lowering body temperature.

In 2008, a genetic study led by Imperial College London discovered that people with common variations in the gene for MT2, a receptor for melatonin, have a slightly higher risk of type 2 diabetes.

The new study reveals that carrying any of four rare mutations in the MT2 gene increases a person's risk of developing type 2 diabetes six times.

The release of insulin, which regulates blood sugar levels, is known to be regulated by melatonin. The researchers suggest that mutations in the MT2 gene may disrupt the link between the body clock and insulin release, leading to abnormal control of blood sugar.


Professor Philippe Froguel, from the School of Public Health at Imperial College London, who led the study, said: "Blood sugar control is one of the many processes regulated by the body's biological clock.

This study adds to our understanding of how the gene that carries the blueprint for a key component in the clock can influence people's risk of diabetes.

"We found very rare variants of the MT2 gene that have a much larger effect than more common variants discovered before. Although each mutation is rare, they are common in the sense that everyone has a lot of very rare mutations in their DNA. Cataloguing these mutations will enable us to much more accurately assess a person's risk of disease based on their genetics."

In the study, the Imperial team and their collaborators at several institutions in the UK and France examined the MT2 gene in 7,632 people to look for more unusual variants that have a bigger effect on disease risk.

They found 40 variants associated with type 2 diabetes, four of which were very rare and rendered the receptor completely incapable of responding to melatonin. The scientists then confirmed the link with these four variants in an additional sample of 11,854 people.

Professor Froguel and his team analysed each mutation by testing what effect they have on the MT2 receptor in human cells in the lab. The mutations that completely prevented the receptor from working proved to have a very big effect on diabetes risk, suggesting that there is a direct link between MT2 and the disease.

More information: A. Bonnefond et al. 'Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes' Nature Genetics, published online 29 January 2012.

Bipolar Disorder, Depression and Circadian Clock

An off-kilter body clock can throw off our sleep-wake cycle, eating habits, body temperature and hormones—and mounting evidence suggests a malfunctioning clock may also underlie the mood cycles in bipolar disorder.

In a new study led by psychiatrist Alexander Niculescu of Indiana University, researchers found that children with bipolar disorder were likely to have a mutated RORB gene, which codes for a protein crucial to circadian clock function.

The team’s previous work identified alterations to this gene and other clock genes in animal models of the disorder. In the new study, the scientists compared the genomes of 152 bipolar kids with those of 140 typical kids. (Children were studied because their moods cycle more rapidly than the moods of bipolar adults, and a quicker cycle suggests a stronger connection to the circadian clock.)

The team found that the bipolar children were more likely to have one of four alterations to RORB, and the investigators suspect the mu­tations prevent the body from producing the correct amount of the pro­tein to support normal clock function.

Previous studies had shown that strictly regulating a bi­polar patient’s sleep schedule could improve extreme mood cycles, but experts weren’t sure why—until animal studies started showing a connection to circadian clock genes.

“Every time we investigate some [abnormality] of molec­ular machinery linked to the clock genes, we find an associ­ation with bipolar disorder,” says Francesco Benedetti, a neuroscientist at the San Raffaele Scientific Institute in Milan, Italy, who was not involved in the Indiana research.

The ultimate goal, he adds, is to pinpoint the precise mech­anism that links clock function with mood swings, in the hope of designing new drugs and treatments that will restore the clock to working order.