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Brown fat cell switch may help fight obesity
Brown fats cells, as opposed to white fat cells, make heat for the body, and are thought to have evolved to help mammals cope with the cold. But, their role in generating warmth might also be applied to coping with obesity and diabetes.
The lab of Patrick Seale, PhD, at the Perelman School of Medicine, University of Pennsylvania, studies what proteins guide the development, differentiation, and function of fat cells. Seale and postdoctoral fellow Sona Rajakumari, PhD, along with Jun Wu from the Dana-Farber Cancer Institute, found that a protein switch called early B cell factor-2 (Ebf2) determines which developmental path fat precursor cells take – the brown vs. white cell trajectory.
"Brown fat cells are the professional heat-producing cells of the body," says Seale. Because of this they are protective against obesity as well as diabetes. Seale is an assistant professor of Cell and Developmental Biology and a member of the Institute for Diabetes, Obesity and Metabolism. The investigators published their findings this week in Cell Metabolism.
The team showed that early B cell factor-2 (Ebf2)
regulates the binding activity of PPAR-gamma,
a protein that regulates differentiation of developing
cell types and is the target of anti-diabetic drugs.
Ebf2 affects PPAR-gamma's ability to determine if precursor
cells go down the white or brown fat cell path. The team
surmises that Ebf2 may alter epigenetic proteins in
brown fat genes to expose PPAR-gamma binding sites.
Brown fat cells are thought to counteract obesity by burning off excess energy stored in lipids. White fat cells store energy. However, brown fat cells contain many smaller droplets of lipids as well as the most mitochondria (containing pigmented cytochromes that bind iron) of any cell type, which make them brown.
Rajakumari conducted a genome-wide study of PPAR-gamma binding regions in white versus brown fat cells. She found that brown cell-specific binding sites also contained a DNA-recognition site for Ebf2 transcription factors. Also, that Ebf2 was strongly expressed in brown fat cells only.
When Rajakumari overexpressed Ebf2 in precursor white
fat cells, those cells matured into brown fat cells.
The brown fat cell status of the reprogrammed white fat
cells was confirmed as they (1) consumed greater amounts
of oxygen—a surrogate measure of heat production, (2) had
increased mitochondria, and (3) had an increased
expression of genes involved in heat production,
all characteristics of normal brown fat cells.
Rajakumari also looked at whether Ebf2 was required for brown fat cell development, by observing Ebf2 knockout mice. Brown fat cells are typically located along the upper half of the spine, toward the shoulders. In contrast, white fat cells are in the abdominal region.
Rajakumari found that in late-stage embryos of these knockout mice, white fat cells existed where brown fat cell reserves were in normal mice, indicating that stem cells differentiate into white fat in the absence of Ebf2.
Over the past few years, PET scan studies on
glucose uptake by different tissues, suggests that
the amount of brown fat cells in people is inversely
correlated with body mass index and age.
This suggests that brown fat cells might play
an unappreciated role in human metabolism.
What's more, researchers have begun to suggest
that "turning on" brown fat could be a new way
to fight obesity and burn the extra stored
lipids in white fat cells.
Ebf2 is the earliest known protein in the timeline of the development and differentiation of brown fat cells.
"Many times, the earlier in the developmental stage that a guiding protein is active, the more powerful it is in driving a certain process of differentiation," notes Seale. "Ebf2 is not really a readily druggable target, but perhaps a protein related to it is."
Because Ebf2 is a transcription factor, it doesn't have a clear binding pocket, but the researchers propose that it might be possible to pharmacologically block or stimulate the interaction of Ebf2 with a partner protein.
Penn co-authors are Hee-Woong Lim and K.J. Won from the Department of Genetics.
The research was funded by the Functional Genomics Core of the Penn Diabetes and Endocrinology Research center (DK 19525), the NIDDK (1K01DK094824, R00DK081605), and a Searle Scholars Award.
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 Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise.
The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 16 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $398 million awarded in the 2012 fiscal year.
The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; and Pennsylvania Hospital - the nation's first hospital, founded in 1751. Penn Medicine also includes additional patient care facilities and services throughout the Philadelphia region.
Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2012, Penn Medicine provided $827 million to benefit our community.
Original article: http://www.uphs.upenn.edu/news/News_Releases/2013/03/seale/
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