Navigation Links
Molecular partnership controls daily rhythms, body metabolism

PHILADELPHIA - A research team led by Mitchell Lazar, MD, PhD, Director of the Institute for Diabetes, Obesity, and Metabolism at the University of Pennsylvania School of Medicine, has discovered a key molecular partnership that coordinates body rhythms and metabolism.

Lazar and his colleagues, including the study's first author Penn Veterinary Medicine doctoral student Theresa Alenghat, studied a protein called NCoR that modulates the body's responses to metabolic hormones. They engineered a mutation into mice that prevents NCoR from working with an enzyme that is normally its partner, HDAC3. These animals showed changes in the expression of clock and metabolic genes, and were leaner, more sensitive to insulin, and on different sleep-wake cycles than controls.

The role of the NCoR-HDAC3 partnership in regulating the body's internal clock was previously unknown. HDAC3 is an enzyme that affects gene expression by binding to receptors in the cell nucleus to affect gene activity, but not by directly changing DNA. The findings suggest that HDAC via NCoR controls the body's internal clock, and therefore metabolism, through this epigenetic change. Their findings are reported in this week's issue of Nature.

"In the fight against the obesity and diabetes epidemics, disruption of NCoR and its enzyme partner, might be a valuable new weapon," says Lazar.

Most physiological processes cycle every day and night, and the most well-known of these circadian rhythms is the sleep-wake cycle. Abnormal sleep patterns, such as those of shift-workers, can be risk factors for metabolic disorders such as obesity and diabetes. "These diseases have reached epidemic proportions, so scientists are urgently seeking to understand the connections between biological rhythms and metabolism," notes Lazar.

The daily rhythm of mice with the disrupted molecular partnership was shortened by almost half an hour. Over time, this added up to a shifted daily rhythm.

The mice were also leaner (not gaining as much weight when put on a high-fat diet), and they were protected from developing resistance to the action of insulin, which is a hallmark of the most common form of diabetes in people. Expression of several metabolic genes was also altered in the engineered mice.

"The molecular partnership regulates hormone action as well as clock genes that coordinate circadian rhythms," says Lazar. "It's extraordinary that, despite their abnormal sleep-wake cycle, which might have been predicted to cause metabolic problems, the mice were actually healthier metabolically.

"However this finding doesn't mean people should start changing their sleep patterns because this is really evidence that there is coordination between metabolism and circadian activities, including sleep," cautions Lazar. "It's not that the mice are sleeping less, it's that their sleep cycle is shifted, when compared to mice maintained on a normal sleep-wake cycle."

Companies are currently targeting enzymes like HDAC with drugs called histone deacetylase (HDAC) inhibitors. "However there are dozens of HDACs, which do not all have the same molecular target," says Lazar. "If we target all of them we will get unwanted side effects related to the other HDACs. Our results suggest that HDAC3, and especially its partnership with NCoR, could be a specific target for diabetes and obesity."


Contact: Karen Kreeger
University of Pennsylvania School of Medicine

Related medicine news :

1. Molecular Switch in Brain May End Smokers Cravings
2. Cepheid Receives Health Canada License for First Molecular Diagnostic Test for MRSA and S. aureus Soft Tissue Infections
3. Four of Molecular Medicine's Thought Leaders will Keynote at Cambridge Healthtech Institute's Molecular Medicine Tri-Conference
4. Thinking Systems Corporation Announces Integration of Its ThinkingPACS(TM) for Molecular Imaging Into Fujifilms Synapse(R) PACS
5. Cepheid Launches First On-Demand Molecular Diagnostic Test for Clostridium Difficile Into European Market
6. Penn scientists map molecular regulation of fat-cell genetics
7. SNM to showcase the latest research in molecular imaging and nuclear medicine
8. Transplantation: molecular miscegenation blurs the boundary between self and non-self
9. Battelle to Perform Verification Studies of IntelligentMDxs Proprietary Molecular Diagnostic Assay Process
10. Preliminary Clinical Data Presented at the 20th EORTC-NCI-ACR Symposium on Molecular Targets and Cancer Therapeutics Demonstrate Superior Profile of S*BIOs Novel Anti-Cancer Drug SB939
11. Bio-imaging mass spectrometry techniques reveal molecular details about complex systems
Post Your Comments:
(Date:6/25/2016)... ... June 25, 2016 , ... ... and applications at AcademyHealth’s Annual Research Meeting June 26-28, 2016, at the Hynes ... important health care topics including advance care planning, healthcare costs and patient and ...
(Date:6/25/2016)... ... June 25, 2016 , ... As a lifelong Southern Californian, Dr. ... his M.D from the David Geffen School of Medicine at UCLA. He trained in ... to complete his fellowship in hematology/oncology at the UCLA-Olive View-Cedars Sinai program where he ...
(Date:6/24/2016)... ... 2016 , ... Those who have experienced traumatic events may suffer from a ... such as drug or alcohol abuse, as a coping mechanism. To avoid this pain ... following a traumatic event. , Trauma sufferers tend to feel a range of emotions, ...
(Date:6/24/2016)... Francisco, CA (PRWEB) , ... June 24, 2016 ... ... CitiDent, is now offering micro-osteoperforation for accelerated orthodontic treatment. Dr. Cheng has extensive ... self-ligating Damon brackets , AcceleDent, and accelerated osteogenic orthodontics. , Micro-osteoperforation ...
(Date:6/24/2016)... ... June 24, 2016 , ... The ... recognize Dr. Barry M. Weintraub as a prominent plastic surgeon and the network’s ... the world, and the most handsome men, look naturally attractive. Plastic surgery should ...
Breaking Medicine News(10 mins):
(Date:6/23/2016)... -- Research and Markets has announced the ... (Organic Chemical (Sugar, Petrochemical, Glycerin), Inorganic Chemical), Functionality (Filler, ... Global Forecast to 2021" report to their offering. ... pharmaceutical excipients market is projected to reach USD 8.1 ... the forecast period 2016 to 2021. ...
(Date:6/23/2016)... Capricor Therapeutics, Inc. ... company focused on the discovery, development and commercialization ... in its ongoing randomized HOPE-Duchenne clinical trial (Halt ... its 24-patient target. Capricor expects the trial to ... 2016, and to report top line data from ...
(Date:6/23/2016)... and INDIANAPOLIS , June 23, 2016 ... Lilly Diabetes Tomorrow,s Leaders Scholarship is any indication, the ... announced today online at by the ... diabetes stand in the way of academic and community ... Foundation,s scholarship program since 2012, and continues to advocate ...
Breaking Medicine Technology: