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 used state-of-the-art genetic technology to map thousands of positions where a molecular “master regulator” of fat-cell biology is nestled in DNA to control genes in these cells. The findings appear online this week in Genes & Development.
The international obesity epidemic is leading to major health risks, including increased rates of diabetes, heart disease, and cancer. Obesity is caused by increased numbers of fat cells that store more fat than normal. “This research has the potential to lead to new ways to think about therapies aimed at reducing the number of fat cells or altering fat cell function in ways that reduce the complications of obesity,” says Lazar.
The master molecule is called PPAR gamma, a gene regulator that is also the target of a major class of antidiabetic drugs, which include Actos® and Avandia. PPAR gamma binds directly to DNA, regulating the production of proteins by turning genes on or off. Actos® and Avandia are effective in treating diabetes, but their side effects, which include weight gain, prevent them from being recommended as a first-line therapy. The drugs bind to PPAR gamma in the nucleus of fat cells, which affects the expression of many genes, about twenty of which were previously known.
New biocomputing methods allowed first author Martina I. Lefterova, a PhD candidate in the Lazar lab, to discover roughly 5,300 additional sites that PPAR gamma targets in fat-cell DNA. The amount of data is enormous, and may allow additional insights into how fat-cell genes are regulated.
“Until now, we were looking at how PPAR gamma works one gene at a time,” says Lazar. “It’s like we were peering at the pieces of a jigsaw puzzle in isolation. Now we can look at the full picture.” Analysis of the data has already led the Penn team to understand how different factors, including one called C/EBP, cooperate with PPAR gamma to fulfill fat cell functions.
Lefterova used a new technology called Chip on Chip that, in its first step, employs an antibody to isolate the segments of DNA attached to PPAR gamma. Then in the second step, a microarray chip is used to determine the genetic sequences of the isolated DNA.
Decreasing the side effects associated with antidiabetic drugs is the main clinical goal of this work. The major side effects related to the mechanisms of these drugs is increased fat and increased edema, or water weight gain, so understanding exactly where and how these drugs affect gene regulators like PPAR gamma—whether their binding to PPAR gamma turns genes on or off—is important.
“We want to be able to determine which genes we want to affect in one case, but not the other, in order to eliminate unwanted side effects, but keep the positive anti-diabetic effects,” says Lazar.
In addition to Lazar, Penn co-authors are David Steger, Michael Schupp, Ana Cristancho, Jonathan Schug, Dan Feng David Zhuo, and Christian Stoeckert, Jr. This was a collaboration with Shirley Liu and Yong Zhang of the Dana-Farber Cancer Institute in Boston. The National Institute of Diabetes, Digestive, and Kidney Diseases and the National Cancer Institute provided funding for this research.
PENN Medicine is a $3.6 billion enterprise dedicated to the related missions of medical education, biomedical research, and excellence in patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.
Penn's School of Medicine is currently ranked #4 in the nation in U.S.News & World Report's survey of top research-oriented medical schools; and, according to most recent data from the National Institutes of Health, received over $379 million in NIH research funds in the 2006 fiscal year. Supporting 1,700 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.
The University of Pennsylvania Health System (UPHS) includes its flagship hospital, the Hospital of the University of Pennsylvania, rated one of the nation’s top ten “Honor Roll” hospitals by U.S.News & World Report; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center. In addition UPHS includes a primary-care provider network; a faculty practice plan; home care, hospice, and nursing home; three multispecialty satellite facilities; as well as the Penn Medicine at Rittenhouse campus, which offers comprehensive inpatient rehabilitation facilities and outpatient services in multiple specialties.
Karen Kreeger | EurekAlert!
How brains surrender to sleep
23.06.2017 | IMP - Forschungsinstitut für Molekulare Pathologie GmbH
A new technique isolates neuronal activity during memory consolidation
22.06.2017 | Spanish National Research Council (CSIC)
An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.
Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...
Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.
Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...
Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.
As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...
Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.
With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...
Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine
Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...
19.06.2017 | Event News
13.06.2017 | Event News
13.06.2017 | Event News
23.06.2017 | Physics and Astronomy
23.06.2017 | Physics and Astronomy
23.06.2017 | Information Technology