IRF4 transcription factor plays a key role in brown fat thermogenic process -
The body contains two types of fat cells, easily distinguished by color: white and brown. While white fat is used to store excess calories until they are needed by the body, brown fat cells actually burn fat by converting it into heat. Since it was discovered that adult humans are home to substantial amounts of brown fat, the investigators worked to better understand its burning properties thermogenic fat with the ultimate goal of developing new therapies to fight against obesity and diabetes.
Now, research conducted by researchers at Beth Israel Medical Center Deaconess (BIDMC) adds another piece to the puzzle, which shows that the IRF4 transcription factor (factor regulating interferon 4) plays a key role in brown fat thermogenic process, regulation of energy expenditure and cold tolerance. The findings appear in the July 3 issue of the journal cell .
"The discovery several years ago that brown fat is active in metabolism suggested that if we could handle the number or activity of these fat cells, we could force our body to burn extra calories, "says lead author Evan Rosen study, MD, PhD, an investigator in the Division of endocrinology, diabetes and metabolism at BIDMC and Associate Professor of medicine at Harvard medical School." Now that we have identified an important factor driving this process, we can consider new approaches to exploit this for therapeutic benefit. "
Excited by cold temperatures and certain hormones and drugs, including epinephrine, brown fat generates heat through the actions of a group of genes collectively, the gene expression program thermogenic, best known coding for uncoupling protein 1 (UCP1). UCP1 dissipates, or waste, energy in the mitochondria of brown fat cells, which causes the generation of heat as a byproduct.
"It has been a keen interest in how the UCP1 gene is regulated, with most attention focused on a molecule called PGC1-alpha," says Rosen. " PGC1-alpha was discovered 15 years ago in the laboratory of co-author Bruce Spiegelman, and is a transcriptional co-factor, which means it indirectly leads to gene transcription as UCP1 because he does has not the ability to bind to DNA itself. This suggests that there must be a bona fide transcription factor, or protein binding to DNA, which has been mediating the effects of PGC-1alpha, but despite years of work and several candidates promising no clear partner to PGC-1alpha was found to increase thermogenesis. It happens that IRF4 is that partner. "
interferon regulatory factor (IRF) play an important role in regulating the immune system. The Rosen Group had already identified IRF4 as a key element in the development of adipocytes and handling of lipids, having discovered that the expression of IRF4 is induced by fasting in fat and that animals lacking IRF4 in adipose tissue are obese, insulin resistant and intolerant cold.
in this new work, led by first author Xingxing Kong, PhD, a postdoctoral fellow in the Rosen lab, scientists have speculated that, in addition to serving as a key regulator of lipolysis, IRF4 could also play thermogenic direct role in brown fat.
experiments on mouse models confirmed their hypothesis, demonstrating that IRF4 is induced by cold and cAMP in adipocytes and is sufficient to promote increasing thermogenic gene expression, energy expenditure and cold tolerance. Conversely, loss of IRF4 in brown fat resulted in reduced expression thermogenic gene and energy expenditure, obesity and intolerance to cold. Finally, the researchers showed that IRF4 physically interacts with PGC-1 alpha to promote the expression of UCP1 and thermogenesis.
"We know a lot about how these genes are activated by cold or when stimulated by catelcholamine drugs such as adrenaline," says Rosen. "But we KnowWhat turned this gene program at the molecular level. This new discovery of the role of key transcription IRF4, perhaps we can identify new drug targets that directly affect this path, what could be more specific than just give epinephrine -as drugs, which lead to heart rate and blood pressure. "
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