Suggests novel strategy for treating obesity in people
Bruce Spiegelman, PhD
Researchers at Dana-Farber Cancer Institute have shown that they can
engineer mouse and human cells to produce brown fat, a natural
energy-burning type of fat that counteracts obesity. If such a strategy
can be developed for use in people, the scientists say, it could open a
novel approach to treating obesity and diabetes.
A team led by Bruce Spiegelman, PhD, has identified both parts of a
molecular switch that normally causes some immature muscle cells in the
embryo to become brown fat cells. With this switch in hand, the
scientists showed they could manipulate it to force other types of cells
in the laboratory to produce brown fat, known as Brown Adipose Tissue
(BAT). Their findings are being reported in the journal Nature as an advanced online publication on July 29.
The scientists then transplanted these synthetic brown fat
precursors, known as eBAT (engineered BAT), into adult mice to augment
their innate stores of brown fat. Tests showed that the brown fat
transplants were burning caloric energy at a high rate — energy that
otherwise would have been stored as fat in white adipose tissue.
Microscope image of brown fat (e-BAT, or engineered Brown Adipose
Tissue) created by adding a key control switch to skin cells of mice.
Presence of green-stained objects (droplets of oil stored in the cell)
confirms the skin cells have been converted to brown fat-producing
cells. Blue objects are cell nuclei. (courtesy of Shingo Kajimura,
Dana-Farber Cancer Institute)
"Since brown fat cells have very high capacity to dissipate excess
energy and counteract obesity, eBAT has a very high potential for
treating obesity," said Shingo Kajimura, PhD, lead author of the paper.
"We are currently working on this."
Excess caloric energy in the diet is stored in white fat calls that
pile up in the body, particularly in the thighs and abdomen. The
accumulated fat content in overweight people puts stress on these cells,
which give out signals that cause inflammation in body organs and the
circulatory system, creating risks of heart disease and diabetes.
Brown fat, by contrast, works in an opposite fashion; it evolved to
protect animals from cold conditions and prevent obesity. Brown fat
cells are equipped with a large supply of mitochondria - tiny organelles
that use oxygen to burn sugar from the diet to generate heat, rather
than store the energy as fat.
Scientists have long thought that brown fat was present in young
animals and human newborns but virtually absent in human adults.
Recently, however, researchers have used modern PET (positron emission
tomography) scanners — which detect tissue that is actively absorbing
sugar — to search for deposits of brown fat in adults. Such experiments
have revealed unexpectedly large amounts of brown fat scattered through
the neck and chest areas.
In 2007, Spiegelman's team, led by Patrick Seale, PhD, who is the second author of the new Nature
paper, discovered a protein, PRDM16, that serves as a switch that
determines whether immature muscle cells will develop into mature muscle
cells or become brown fat cells.
But this was not the whole story. The scientists suspected that
PRDM16 worked with another unknown protein to initiate brown fat
development. This proved to be the case. In the new experiments, the
Spiegelman group found that PRMD16 works in tandem with the protein
C/EBP-beta, and only as a two-part unit are they sufficient to
jump-start brown fat development in several types of cells.
To find out if the PRDM16-C/EBP-beta switch could change the identity
of other types of cells, forcing them to become brown fat cells, the
researchers used viruses to transfer the switch into embryonic mouse
connective tissue cells called fibroblasts. They also installed the
switch into adult mouse skin cells, and into human skin cells isolated
from foreskins removed from newborns during circumcision.
In all three cases, the fibroblasts produced mature brown fat cells.
The scientists then transplanted the cells into mice, where they
produced brown fat tissue. PET scans confirmed that the new brown fat
tissue was burning excess energy in the animals, as they should. The
experiments did not test whether the extra brown fat actually protected
the mice from becoming obese.
Spiegelman said the results "give a lot more credence" to efforts to
manipulate the brown fat switch as a potential means of treating people
with obesity and diabetes. One strategy would be to remove some tissue
from the patient, add the PRDM16-C/EBP switch, and return it to the
patient where it would manufacture additional brown fat.
A more conventional possibility would be to administer a drug to the
patient that would ramp up the production of brown fat without the need
for a transplant, said Spiegelman, who is also a professor of cell
biology at Harvard Medical School. "If we can find a hormone that does
that, it's reasonable to think that it might provide a direct
Other authors on the paper are Kazuishi Kubota, PhD, and Steven P.
Gygi, PhD, of Harvard Medical School, and Elaine Lunsford and John V.
Frangioni, MD, PhD, of Beth Israel Deaconess Medical Center.
The research was supported by grants from the National Institutes of Health and the Picower Foundation.