Navigation Links
Coordinating the circadian clock: Molecular pair controls time-keeping and fat metabolism

PHILADELPHIA The 24-hour internal clock controls many aspects of human behavior and physiology, including sleep, blood pressure, and metabolism. Disruption in circadian rhythms leads to increased incidence of many diseases, including metabolic disease and cancer. Each cell of the body has its own internal timing mechanism, which is controlled by proteins that keep one another in check.

One of these proteins, called Rev-erb alpha, was thought to have a subordinate role because the clock runs fairly normally in its absence. New work, published in Genes and Development this month, from the lab of Mitchell Lazar, MD, PhD, director of the Institute for Diabetes, Obesity, and Metabolism at the Perelman School of Medicine, University of Pennsylvania, found that a closely related protein called Rev-erb beta serves as a back-up for Rev-erb alpha. When both are not functioning, the cellular clock loses its time-keeping function.

The two Rev-erbs work together to control fat metabolism, and in their absence, the liver fills with fat. These findings establish the Rev-erbs as major regulators of both clock function and metabolism.

Lazar, postdoctoral fellow Anne Bugge, PhD, and the team knocked out Rev-erb alpha in mice and didn't see a large effect on the liver. When they knocked out both Rev-erb alpha and Rev-erb beta, they saw a loss of the rhythmic cycling of the clock protein Bmal 1's messenger RNA. They concluded that the Rev-erb system is an integral part of the human clock, not ancillary.

Prior to this paper, the Lazar team discovered molecules that act as "shift workers" to maintain the daily rhythm of fat metabolism. When those molecules do not do their jobs, the liver also dramatically fills with fat.

In normal mice, the team of molecules migrates to the genome of liver cells during the daytime. Rev-erb, one of the team members, delivers the molecular workers to thousands of specific locations in the liver genome, many of which are near genes involved in the production of fat. Another team member, histone deacetylase 3 (HDAC3), does construction work on the protein scaffold (the epigenome) surrounding the genome to dampen the activity of the fat-related genes.

During the night, the day shift molecules depart the liver genome, and fat production increases due to other regulatory molecules. The fat production is kept in check when the Rev-erb construction team returns to the genome the next day. However, if HDAC3 is absent, the cycles do not occur, and the liver fills with fat.

The absence of both Rev-erbs prevents HDAC3 from doing its job, since Rev-erbs serve as the shuttle delivering HDAC3 to target genes. Sure enough, fat accumulates in the liver to a much great extent when both Rev-erbs are missing compared to when one is still available.

"This work shows that if we want to manipulate the human clock we would likely need to affect both Rev-erb alpha and Rev-erb beta," explains Lazar. "Circadian rhythm of metabolism is important because disruption of this rhythm leads to a fatty liver. This may explain, in part, why altered circadian rhythms in people who do shift work is associated with metabolic disorders."


Contact: Karen Kreeger
University of Pennsylvania School of Medicine

Related medicine news :

1. How cancer cells loose their (Circadian) rhythm
2. Rising star of brain found to regulate circadian rhythms
3. Study shows new evidence of age-related decline in the brains master circadian clock
4. Circadian clock may impact organ transplant success
5. Molecular pathways linked to sex, age affect outcomes in lung cancer
6. SNMs Conjoint Mid-Winter Meetings continue to advance molecular imaging
7. Scientists Discover Molecular Pathway for Organ Tissue Regeneration and Repair
8. The Association for Molecular Pathology celebrates ruling in DNA patent case
9. USC researchers discover new molecular subtype of brain cancer
10. Molecular discovery points to new therapies for brain tumors
11. Molecular marker could help spot pancreatic cancer early
Post Your Comments:
(Date:12/1/2015)... Angeles, CA (PRWEB) , ... December 01, 2015 , ... ... coalition of obesity groups has filed a discrimination claim against the U.S. Department of ... coverage in their Affordable Care Act (ACA) plans are breaking the clause in the ...
(Date:12/1/2015)... Fla. (PRWEB) , ... December 01, 2015 , ... ... number of leadless pacemakers in the U.S. and is the only hospital in ... from the largest clinical data presentation of transcatheter pacing patients were revealed recently ...
(Date:12/1/2015)... Houston, TX (PRWEB) , ... December 01, 2015 , ... ... owner of Vitenas Cosmetic Surgery, has been named by MedEsthetics magazine as the Best ... best of the best among the many elite aesthetic physicians honored by the industry ...
(Date:12/1/2015)... ... 2015 , ... Growth in medical payments per workers’ compensation claim in Louisiana ... and nonhospital care, according to a recent study by the Workers Compensation Research Institute ... found medical payments per claim with more than seven days of lost time continued ...
(Date:12/1/2015)... York, NY (PRWEB) , ... December 01, 2015 ... ... epidemic in the 1980s we have seen vast improvements in scientific research and ... made significant strides, providing increased hope and relief to those affected by HIV/AIDS. ...
Breaking Medicine News(10 mins):
(Date:12/1/2015)... Va. , Dec. 1, 2015  AccuTEC ... unveiled a new corporate logo and brand identity ... the design and engineering of bladed products where ... --> --> Serving manufacturers ... glass, and auto glass equipment, AccuTEC,s product lines ...
(Date:12/1/2015)... , Dec. 1, 2015 During the ... San Francisco, CA , Medinol ... the coronary marketplace. During a satellite symposium, "The ... Design to Minimize Restenosis", a renowned physician panel ... Medinol NIRxcell™ CoCr Coronary Stent System and the ...
(Date:12/1/2015)... ) has ... and Disposables Market by product, by Animal - ... offering. --> ) has announced ... Disposables Market by product, by Animal - Global ... --> Research and Markets ( ...
Breaking Medicine Technology: