Getting from point A to B may sound simple, but not so in the formation of fat cells.
In a finding with potential drug-development implications, Mitchell A. Lazar, M.D., Ph.D., director of the Institute for Diabetes, Obesity, and Metabolism at the University of Pennsylvania School of Medicine, and colleagues report in the current issue of Genes & Development the discovery of an intermediate state between early-stage fat cells and fully mature ones that is only present transiently during the fat-cell formation process. This intermediate state is induced by hormones related to cortisol, which are known to contribute to obesity and metabolic disturbances in people.
New therapies for obesity or metabolic diseases such as diabetes could potentially target this transition state toward a maturing fat cell.
The transition state – present within 24 hours of the start of the fat-cell differentiation process – is defined by chemical changes to genetic material called chromatin, which package a cell’s DNA. These changes kick start the expression of regulatory proteins and provide a cellular memory that allows the cell to continue developing even after the signal to undergo this transition has waned.Probing the Genome
Using a cell culture system, the team, led by postdoctoral researcher David Steger, PhD, probed genes involved in fat-cell development and function for chromatin changes that were associated with the start of mature fat-cell formation. They found chromatin changes near a gene encoding the master regulator of differentiation, PPAR-gamma, which is also a target of anti-diabetic drugs.
"That gave us confidence to interrogate the whole genome," Lazar says.
The team scanned the genome for regions that were modified within 24 hours of the onset of fat-cell differentiation and analyzed those regions for potential binding sites for proteins that induce the expression of other genes. These proteins activate the genes whose proteins cause changes in cellular behavior and function.Complex Control System
That the glucocorticoid receptor is part of this transition state is remarkable, Lazar says, in that the growth factor complex required to induce fat-cell formation includes dexamethasone, one type of gluococorticoid hormone. No one had ever considered why dexamethasone was required to make this transition happen, Lazar says. "The dexamethasone is stimulating the hormone receptor to bind transiently at this site and create the transition state.” This happens at dozens of sites in the cell genome, and the hormone is the coordinating signal.
On the basis of their findings, Lazar and his colleagues propose a model in which, upon stimulation of pre-fat cells, CEBP-beta, GR, and other proteins assemble near the PPAR-gamma gene and activate it. Once that happens, the circuit is on, even if the fat-cell-forming stimulus should disappear. In what the investigators call a “feedforward loop,” the PPAR-gamma protein induces its own expression, as well as that of another master regulatory gene, CEBP-alpha. CEBP-alpha, in turn, activates its expression as well as that of PPAR-gamma. More importantly, both proteins also induce the expression of fat-cell genes, thereby committing the cell to its ultimate fate.
“The idea that a transient hormone signal coordinates many locations throughout the genome in the process of making a fat cell is surprising and informative," Lazar says.
And that state – or rather, the molecular players that comprise it -- could provide a useful target for anti-obesity drug development, he adds.
The study was supported by the National Institutes for Diabetes, Digestive and Kidney Diseases, the George S. Cox Medical Research Institute, and by the Picower Foundation.
Penn Medicine is one of the world’s leading academic medical centers, 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, which together form a $3.6 billion enterprise.
Penn’s School of Medicine is currently ranked #2 in U.S. News & World Report’s survey of research-oriented medical schools, and is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $367.2 million awarded in the 2008 fiscal year.
Penn Medicine’s patient care facilities include:The Hospital of the University of Pennsylvania – the nation’s first teaching hospital, recognized as one of the nation’s top 10 hospitals by U.S. News & World Report.
Additional patient care facilities and services include Penn Medicine at Rittenhouse, a Philadelphia campus offering inpatient rehabilitation and outpatient care in many specialties; as well as a primary care provider network; a faculty practice plan; home care and hospice services; and several multispecialty outpatient facilities across the Philadelphia region.
Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2009, Penn Medicine provided $733.5 million to benefit our community.
Karen Kreeger | EurekAlert!
Zap! Graphene is bad news for bacteria
23.05.2017 | Rice University
Discovery of an alga's 'dictionary of genes' could lead to advances in biofuels, medicine
23.05.2017 | University of California - Los Angeles
An international team of physicists has monitored the scattering behaviour of electrons in a non-conducting material in real-time. Their insights could be beneficial for radiotherapy.
We can refer to electrons in non-conducting materials as ‘sluggish’. Typically, they remain fixed in a location, deep inside an atomic composite. It is hence...
Two-dimensional magnetic structures are regarded as a promising material for new types of data storage, since the magnetic properties of individual molecular building blocks can be investigated and modified. For the first time, researchers have now produced a wafer-thin ferrimagnet, in which molecules with different magnetic centers arrange themselves on a gold surface to form a checkerboard pattern. Scientists at the Swiss Nanoscience Institute at the University of Basel and the Paul Scherrer Institute published their findings in the journal Nature Communications.
Ferrimagnets are composed of two centers which are magnetized at different strengths and point in opposing directions. Two-dimensional, quasi-flat ferrimagnets...
An Australian-Chinese research team has created the world's thinnest hologram, paving the way towards the integration of 3D holography into everyday...
In the race to produce a quantum computer, a number of projects are seeking a way to create quantum bits -- or qubits -- that are stable, meaning they are not much affected by changes in their environment. This normally needs highly nonlinear non-dissipative elements capable of functioning at very low temperatures.
In pursuit of this goal, researchers at EPFL's Laboratory of Photonics and Quantum Measurements LPQM (STI/SB), have investigated a nonlinear graphene-based...
Dental plaque and the viscous brown slime in drainpipes are two familiar examples of bacterial biofilms. Removing such bacterial depositions from surfaces is...
23.05.2017 | Event News
22.05.2017 | Event News
17.05.2017 | Event News
23.05.2017 | Physics and Astronomy
23.05.2017 | Life Sciences
23.05.2017 | Medical Engineering