Molecular switch found in mice could lead to future obesity treatments, scientists say
Bruce Spiegelman, PhD
A surprise discovery – that calorie-burning brown fat can be produced
experimentally from muscle precursor cells in mice – raises the
prospect of new ways to fight obesity and overweight, say scientists
from Dana-Farber Cancer Institute.
Reporting in the Aug. 21 issue of the journal Nature, the researchers
demonstrated that brown fat, which is known as the "good" form of fat –
so called because it burns calories and releases energy, unlike "bad"
white fat that simply stores extra calories – can be generated from
unspecialized precursors that routinely spawn skeletal muscle.
The team led by Dana-Farber's Bruce Spiegelman, PhD,
showed that a previously known molecular switch, PRDM16, regulates the
creation of brown fat from immature muscle cells. They also determined
that the process is a two-way street: Knocking out PRDM16 in brown fat
cells can convert them into muscle cells. However, Spiegelman called the
latter an "experimental lab trick" for which he currently envisions no
The "huge surprise" of the study results, he said, was that muscle
precursor cells known as "satellite cells" are able to give birth to
brown fat cells under the control of PRDM16.
Spiegelman said the finding confirms that PRDM16 is the "master
regulator" of brown fat development. The confirmation will spur ongoing
research in his laboratory, he said, to see if drugs that rev up PRDM16
in mice – and potentially, in people – could convert white fat into
brown fat and thereby treat obesity. Another strategy, he said, might be
to transplant brown fat cells into an overweight person to turn on the
"I think we now have very convincing evidence that PRDM16 can turn
cells into brown fat cells, with the possibility of combating obesity,"
said Spiegelman, the senior author of the paper. The lead author is Patrick Seale, PhD, a postdoctoral fellow in the Spiegelman lab.
Another paper in the same issue of Nature described a different
trigger of brown fat production, a molecule called BMP7. A commentary in
the journal by Barbara Cannon, an internationally recognized researcher
in the biology of fat cells at the University of Stockholm, said that
the two reports "take us a step closer to the ultimate goal of promoting
the brown fat lineage as a potential way of counteracting obesity."
The Spiegelman group has long studied fat cells both as a model for
normal and abnormal cell development, which relates to cancer, and also
because fat cells play such a key role in the growing epidemics of
obesity and diabetes.
Mouse brown fat cells in culture in which the molecular switch PRDM16 has been knocked down, leading to the formation of muscle cells (elongated fibers).
There is much interest in brown fat's role in regulating metabolism.
Rodents and human infants have abundant brown fat that dissipates food
energy as heat to protect against the cold. Though human adults have
little brown fat, it apparently does have a metabolic function,
including the potential to be amplified in some way to combat obesity.
In 2007, Spiegelman and colleagues reported they had inserted PRDM16
genes into white fat precursors, which they implanted under the skin of
mice. The PRDM16 switch coaxed the white fat precursors to produce brown
fat cells instead of white. To Spiegelman, this suggested the
possibility of transplanting PRDM16-equipped white fat precursors into
people who are at high risk of becoming obese, to shift their metabolism
slightly into a calorie-burning mode.
The new research adds another potential source of brown fat – the
muscle cell progenitors, or myoblasts, that exist in the body to replace
mature muscle cells as needed. The progenitors, which can be thought of
as "adult stem cells," are committed to becoming specialized muscle
cells when activated by appropriate signals, or, as the study revealed,
brown fat cells when PDRM16 is turned on. The PRDM16 trigger "is very
powerful at what it does," said Spiegelman, who is also a professor of
cell biology at Harvard Medical School.
Other authors of the paper include Bryan Bjork, PhD, and David R. Beier, PhD, MD, of Brigham and Women's Hospital; Michael Rudnicki, PhD, of the Ottawa Health Research Institute; and Hediye Erdjument-Bromage, PhD, and Paul Tempst, PhD, of Memorial Sloan-Kettering Cancer Center.
The research was supported by grants from the National Institutes of Health and the Picower Foundation.
Dana-Farber Cancer Institute (www.dana-farber.org) is a principal
teaching affiliate of the Harvard Medical School and is among the
leading cancer research and care centers in the United States. It is a
founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC),
designated a comprehensive cancer center by the National Cancer