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Genes controlling insulin ‘alter’ body clock

September 19, 2009 By admin Leave a Comment

Washington, Sept 18 (ANI): Scientists at University of California, San Diego have identified certain insulin-regulating genes that can also alter the timing of the body clock.

They said that the findings can lead to new approaches to treating disorders such as metabolic syndrome that can result, at least in part, from chronic disruption of the sleep-wake cycle.

“People knew that the clock regulates many different processes, but what they didn’t realize what that when you tweak those processes, it feeds back and alters the clock,” said Steve Kay, Dean of the Division of Biological Sciences at the University of California, San Diego, who led the study along with John Hogenesch of the University of Pennsylvania.

A molecular clock controls daily physiological rhythms in many types of cells, even cells grown in culture.

By engineering cultured cells to glow yellow when a particular clock gene switched on, the team made the cycle visible. They then interfered with every human gene to see which would shift the clock. They found that hundreds altered the timing.

“We just suddenly discovered 350 new genes that affect the clock that weren’t known before,” Kay said.

However, subsequent screening to confirm the genes’ effect on a second clock gene narrowed the list to 200.

Seven genes involved in insulin control also influenced the rhythms of the clock.

“What came out very strongly was this close relationship between circadian regulation and insulin signalling. There’s a reciprocal relationship between circadian dysfunction and metabolic dysfunction,” said Kay.

The researchers suggest that genetically altered mice with malfunctioning clocks become obese and develop diet-induced diabetes.Understanding this close relationship between circadian regulation and metabolic homeostasis should provide novel ways of identifying new therapies for metabolic disease,” Kay added.

The study appears in journal Cell. (ANI)

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Nighttime alertness probed

August 27, 2009 By admin Leave a Comment

Washington, Aug 27 (ANI): A new study, conducted by researchers in the U.S., has shown that the circadian system is not the only pathway involved in determining alertness at night – red light, which does not stimulate the circadian system, is just as effective at increasing nighttime alertness as blue light, which does.

Mariana Figueiro from Rensselaer Polytechnic Institute, New York, and colleagues examined the effects of the different lighting conditions.

“It is now well accepted that the circadian system is maximally sensitive to short-wavelength (blue) light and is quite insensitive to long-wavelength (red) light. We’ve shown that a moderate level of red light impacts alertness, an effect that must occur via a pathway other than the circadian system,” she said.

Circadian rhythms are roughly 24-hour cycles in various biological processes, such as core body temperature, melatonin synthesis and sleep-wake behavior, that repeat approximately every 24 hours and are synchronized most strongly by the light-dark cycle in the environment.

Bright light is known to increase alertness at night, but it has never been completely clear whether this light-induced alertness can arise from neural pathways other than those involved in the circadian system.

“There is previous compelling evidence that light-induced stimulation of the circadian system increases alertness at night, but our results suggest that this effect is mediated not only by the circadian system, but also through other mechanisms,” Figueiro added.

The research has been described in the open access journal BMC Neuroscience. (ANI)

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Why body clock doesn’t change with temperature

May 17, 2009 By admin Leave a Comment

Washington, May 17 (ANI): Two studies conducted by scientists at Dartmouth Medical School have provided significant insights into why the 24-hour body clock does not change with temperature when metabolism is so affected.

Circadian systems are biological oscillators that orchestrate activities through an elaborate network of interactive proteins and feedback loops. They depend upon transfer of phosphate groups, called phosphorylation, to clock proteins for setting the 24-hour cycle.

Drs. Jay Dunlap and Jennifer Loros, who led both studies, have revealed that both studies looked at phosphorylation of the frequency (FRQ) clock protein, a central feedback cog in the fungal clock system.

They have documented the workings of FRQ and most other components in the Neurospora clock.

“The Cell paper describes how the cell uses phosphorylation of a clock protein to keep the period length of the cycle close to the same across a range of temperatures. This phenomenon, called temperature compensation, is one of the few canonical properties of rhythms that still lack molecular description,” said Dunlap.

The researchers say that their research suggests a new role for the clock-associated enzyme, casein kinase (CK)2, as a key control for temperature compensation. They pursued two uncharacterised circadian protein mutants shown to affect compensation in an unusual way, and identified different subunits of the same enzyme, CK2.

The team developed new ways to manipulate the genome, and showed, by controlling expression, that the level of CK2 dictates the form of compensation through the phosphorylation of the clock protein FRQ.

According to them, the property is unique to CK2 and shared with none of the other similar enzymes implicated in clock function.

The second study traced protein interactions throughout the cycles to show how phosphorylation controls circadian rhythm. It pinpointed a near record number of modifications on FRQ and described how each appears and disappears over the day.

The researchers identified interacting proteins to track and correlate changes in the core circadian network. They determined the clusters and locations of known sites, and through mutational analysis identified novel functional domains to create a dynamic view of a clock protein in action.

The two study have been published in the journal Cell. (ANI)

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The biological basis for the 8-hour work-shift

April 24, 2009 By admin Leave a Comment

Washington, April 24 (ANI): Your usual nine to five office shift has a biological reason behind it, and now scientists have found that some genes in the body are switched on once every 12 or 8 hours, which in turn keeps us actively involved in the work, according to a new study.

The findings by researchers at the University of Pennsylvania School of Medicine and the Salk Institute for Biological Studies indicated that shorter cycles of the circadian rhythm are also biologically encoded.

Already, scientists know that some genes are controlled by the clock and are turned on only one time during each 24-hour cycle.

In the new study, researchers looked at gene activity in the mouse liver every hour for 48 hours using a novel time-sampling approach.

They also found 10-fold more genes controlled by the 24-hour clock than previously reported.

This the first report where researchers have found other periodicities than the 24-hour cycle functioning in a live animal.

According to researchers, these findings have implications for better understanding disruptions to normal circadian rhythms that contribute to a host of pathologies such as cardiovascular and metabolic disease, cancer, and aging-related disorders.

“The principal frequency, which is not a surprise, is the 24-hour cycle, and it is the most prevalent. What was a surprise to us – although we set up the experiment to see exactly this – are the 12-hour and the 8-hour cycles,” said senior author John Hogenesch, PhD, Associate Professor of Pharmacology in the Institute for Translational Medicine and Therapeutics at Penn.

To uncover these shorter oscillations, researchers isolated RNA from the livers of mice every hour for 48 hours.

Microarray analysis showed that more than 3,000 genes were expressed on a circadian rhythm – which account for approximately 4 percent of all of the genes expressed in the liver.

In addition, 260 genes were expressed on a 12-hour cycle and 63 genes were expressed on an 8-hour cycle.

The researchers saw similar 12-hour gene expression patterns in five other tissues.

“There is an obvious biological basis to a 12-hour rhythm. The 12-hour genes predicted dusk and dawn. These are two really, really stressful transitions that your body goes through and your mind goes through. Anybody who has young children realizes that they are more likely to cry around those times – and you’re more likely to cry with them,” said Hogenesch.

The shift in gene expression controlled by these harmonics can help an animal prepare for the behavioural and physiological changes that accompany the shift from light to dark and back.

“We have less of a handle on the 8-hour rhythms, but the fact that we can see them reliably means to me there is the possibility that there could be a biological basis to an 8-hour cycle,” he said.

The study appears in the April issue of PLoS Genetics (ANI)

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Night owls can work longer than early birds

April 24, 2009 By admin Leave a Comment

Washington, Apr 24 (ANI): Early birds may be chirpier in the morning, but it’s the night owls that score over them when it comes to being alert after waking up from sleep, concludes a new brain-scan study.

In the study, researchers monitored the brain activity of self-described early birds and night owls in a sleep lab.

Led by Christina Schmidt of the University of Liege in Belgium, the researchers also took hourly saliva samples to measure the sleepers’ levels of melatonin-a hormone thought to help naturally regulate sleep cycles in mammals.

They allowed both night owls and early birds to stay on their preferred sleep schedules, but each group was awake for the same number of hours each day, reports National Geographic News.

An hour and a half after waking, the groups scored the same on tests that required them to pay attention to a task.

However, it was found that after ten hours of waking up, early birds showed reduced activity in brain areas linked to attention compared with the night owls.

They observed that the “morning people” also felt sleepier and performed more slowly on tests.

Furthermore, as the day wore on, early birds showed less activity in a region deep in the brain involved in the so-called circadian master clock, which regulates our daily cycles of alertness.

Thus, they concluded that people tend to favour mornings or nights based at least in part on how they react to a kind of competition in the brain.

Circadian hormones, which keep us alert while awake, can get overridden by sleep pressure, a physiological pull that causes us to get sleepier the longer we’re awake.

Study co-author Philippe Peigneux, also of the University of Liege, said that while night owls seem to handle sleep pressure better, the late-to-bed strategy might backfire outside the lab.

He said: “Morning types may be at an advantage, because their schedule is fitting better with the usual work schedule of the society.

“It may represent a problem for evening types obliged to wake up early while having difficulties going to bed in the evening, eventually leading to a sleep debt.”

The findings of the study have been published in the latest issue of the journal Science. (ANI)

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Missing or mutated ‘clock’ gene ‘ups vascular disease risk’

March 26, 2009 By admin Leave a Comment

Washington, Mar 26 (ANI): Researchers at Medical College of Georgia have found that circadian clocks that set the rhythmic motion of our bodies for wakeful days and sleepy nights can also set us up for vascular disease when broken.

During the study, they found that mice with mutated or missing ‘clock’ genes were prone to thick, inflexible blood vessels with narrow passageways, unhealthy changes typically associated with risk factors such as smoking, high blood pressure and cholesterol.

“Having a bad or broken clock seems to promote vascular disease,” said Dr. Daniel Rudic, vascular biologist in the MCG Schools of Medicine and Graduate Studies and the study’s corresponding author.

The findings suggest increased disease risk for those with mutated clocks, shift workers whose schedule are routinely in conflict with their natural rhythms, as well as others with poor sleep patterns. They also support the merit of developing time-released meds that are in sync with circadian rhythms.

Inside blood vessels, researchers found that clocks regulate key signaling that enables blood vessel dilation and remodeling.

Mice with missing or mutated clock genes have significantly less AKT, an enzyme that promotes the blood-vessel relaxing molecule nitric oxide, and less of nitric oxide precursor eNOS.

In animal models of vascular disease, the altered or missing clocks dramatically accelerated the unhealthy vascular response. In aged mice, the response is even worse, including a predisposition for developing clots.

Yet mice with mutated rather than missing clock gene fared much better in normal light-dark cycles than those in constant darkness. It was only in constant darkness that vascular injury occurred.

“The dysfunction is clearly light-cycle dependent, demonstrating these effects are related to circadian rhythm,” Dr. Rudic said.

The study is published in this week’s issue of Circulation. (ANI)

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How the body clock controls metabolism and ageing

March 20, 2009 By admin Leave a Comment

Washington, Mar 20 (ANI): In a study on mice, a team of scientists have found how the biological circadian clock mechanism in animals corresponds with processes that control aging and metabolism.

The findings by researchers at Washington University School of Medicine in St. Louis and Northwestern University can explain why the weakening of the circadian rhythm with age could contribute to age-related disorders, such as insulin resistance and type 2 diabetes.

“Our study establishes a detailed scheme linking metabolism and aging to the circadian rhythm. This opens the door to new avenues for treating age-related disorders and ways to restore a healthy daily circadian rhythm. It could also yield new interventions to alleviate metabolic disorders such as obesity and diabetes,” said one of the lead authors, Dr. Shin-ichiro Imai.

In an earlier study, Imai demonstrated that a gene called SIRT1 was at the centre of a network that regulates aging.

SIRT1 coordinates metabolic reactions throughout the body and manages the body’s response to nutrition. The gene is activated when calories are restricted below normal, which has been shown to extend the life spans of some laboratory animals.

“Under nutritional scarcity, SIRT1 may delay aging and extend life span to assure survival until food becomes more readily available,” explained Imai.

The researcher had earlier shown that interfering with the circadian clock of mice led to metabolic complications, including obesity and type 2 diabetes.

The new research has linked the circadian clock to SIRT1 through a key metabolite that serves as the energy currency of the body.

Thus, the researchers have defined a biochemical mechanism by which the body’s metabolic and nutritional status can directly drive the oscillation of the body’s daily clock as well as influence aging and longevity.

The new finding points potentially to innovative ways to correct metabolic disorders and improve health as people age.

In the study on laboratory mice, the researchers found a daily oscillation of the metabolite NAD (nicotinamide adenine dinucleotide), an important compound that is the body’s way of exchanging energy and moving it where it’s needed.

“Seeing this striking abnormality in the NAD levels was like discovering the cause of a disease in a patient after running a blood test,” said one of the co-authors of the study.

The researchers found that the NAD rhythm was linked to the daily rise and fall of the activity of “clock” genes, the genes that serve as the gears that run the body’s internal clock.

Also, they discovered that the clock genes directly interact with a biochemical process that produces NAD.

NAD is required for SIRT1 to function, suggesting that SIRT1 activity increased and decreased along with NAD oscillation in the mice.

Studying the mice under controlled conditions of light and dark, the researchers established the details of the NAD-SIRT1-clock gene loop and showed that it functions in liver and fat cells.

“We showed that this feedback cycle is driven by NAD. Because NAD levels reflect nutrition and energy levels, NAD’s link to the circadian and aging mechanisms makes them sensitive to the nutritional status of the organism,” said Imai.

The study has been published in the online edition of the journal Science. (ANI)

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Body clock, metabolism link could lead to cancer treatment

March 13, 2009 By admin Leave a Comment

Washington, Mar 13 (ANI): Researchers at University of California, Irvine, have found that circadian rhythms, our own body clock, regulate energy levels in cells.

According to researchers, the findings could provide greater insights into the bond between the body’s day-night patterns and metabolism. They said that the discovery could help create new ways to treat cancer, diabetes, obesity and a host of related diseases.

Also, Paolo Sassone-Corsi, Distinguished Professor and Chair of Pharmacology, and his colleagues found that the proteins involved with circadian rhythms and metabolism are intrinsically linked and dependent upon each other.

“Our circadian rhythms and metabolism are closely partnered to ensure that cells function properly and remain healthy. This discovery opens a new window for us to understand how these two fundamental processes work together, and it can have a great impact on new treatments for diseases caused by cell energy deficiencies,” Sassone-Corsi said.

Sassone-Corsi had already identified that the enzyme protein CLOCK is an essential molecular gear of the circadian machinery and interacts with a protein, SIRT1, which senses cell energy levels and modulates aging and metabolism.

In the new study, Sassone-Corsi and his colleagues show that CLOCK works in balance with SIRT1 to direct activity in a cell pathway by which metabolic proteins send signals called the NAD+ salvage pathway.

In turn, a key protein in that pathway, NAMPT, helps control CLOCK levels, creating a tightly regulated codependency between our circadian clock and metabolism.

“When the balance between these two vital processes is upset, normal cellular function can be disrupted. And this can lead to illness and disease,” Sassone-Corsi said.

He said that the findings suggest that proper sleep and diet may help maintain or rebuild this balance, and also help explain why lack of rest or disruption of normal sleep patterns can increase hunger, leading to obesity-related illnesses and accelerated aging.

The specific interaction between CLOCK and SIRT1 and the NAD+ salvage pathway also presents a starting point for drug development aimed at curbing cell dysfunction and death, thereby helping to solve major medical problems such as cancer and diabetes.

Their study appears online in Science Express. (ANI)

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Sleep-wake rhythm implicated in diabetes

January 17, 2009 By Rajesh Leave a Comment

London, Jan 17 (ANI): An international team of researchers has identified a genetic variant associated with increased fasting glucose levels and a high risk for type 2 diabetes.

The new genetic variant controls fasting glucose levels via the release of melatonin, which implicates a link between the sleep-wake rhythm.

The MTNR1B gene stalls the release of insulin via the neural hormone melatonin.

The melatonin level in the body is high at night and declines in daylight, whereas the insulin level is higher during the day than in the night, reports Nature Genetics.

This implicates an association between the sleep-wake rhythm, the so-called circadian rhythm, and fasting glucose levels.

The researchers hope that the new findings may open up new avenues for developing effective treatments, which go far beyond the primarily symptomatic therapy approaches to diabetes used today. (ANI)

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