Navigation Links
Coordinating the circadian clock: Molecular pair controls time-keeping and fat metabolism
Date:4/6/2012

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
karen.kreeger@uphs.upenn.edu
215-349-5658
University of Pennsylvania School of Medicine
Source:Eurekalert

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:
*Name:
*Comment:
*Email:
(Date:6/25/2016)... ... June 25, 2016 , ... "With 30 hand-drawn hand gesture animations, FCPX users ... - CEO of Pixel Film Studios. , ProHand Cartoon’s package transforms over 1,300 ... Pro X . Simply select a ProHand generator and drag it above media or ...
(Date:6/25/2016)... Montreal, Canada (PRWEB) , ... June 25, 2016 , ... ... the pursuit of success. In terms of the latter, setting the bar too high ... low, risk more than just slow progress toward their goal. , Research from ...
(Date:6/24/2016)... Texas (PRWEB) , ... June 24, 2016 , ... ... International Conference and Scientific Sessions in Dallas that it will receive two significant ... of the grants came as PHA marked its 25th anniversary by recognizing patients, ...
(Date:6/24/2016)... Plano, TX (PRWEB) , ... June 24, 2016 , ... ... taking part in Genome magazine’s Code Talker Award, an essay contest in which patients ... for an award to be presented at the 2016 National Society of Genetic Counselors ...
(Date:6/24/2016)... ... June 24, 2016 , ... National recruitment firm ... sciences executive with extensive sequencing and genomics experience, as Vice President of North American ... Hill will be responsible for leading the sales team in the commercialization of the ...
Breaking Medicine News(10 mins):
(Date:6/24/2016)... -- Research and Markets has announced the addition ... report to their offering. ... The World Market for Companion Diagnostics covers the world ... in the report includes the following: , ... by Region (N. America, EU, ROW), 2015-2020 , World ...
(Date:6/23/2016)... June 23, 2016  MedSource announced today that ... e-clinical software solution of choice.  This latest decision ... value to their clients by offering a state-of-the-art ... relationship establishes nowEDC as the EDC platform of ... full-service clients.  "nowEDC has long been a preferred ...
(Date:6/23/2016)... June 23, 2016 Roche (SIX: RO, ROG; ... for its Elecsys BRAHMS PCT (procalcitonin) assay as a ... septic shock. With this clearance, Roche is the first ... integrated solution for sepsis risk assessment and management. ... infection and PCT levels in blood can aid clinicians ...
Breaking Medicine Technology: