Scientists Find Molecular Switch that Inhibits Fat Cell Development
U-M Medical School scientists have discovered a molecular switch
that controls the formation of fat cells in mice. If the switch
is on, fat cells will not develop. Switch it off, and even would-be
muscle cells turn to fat.
 
Tissue samples from experimental
control mice in the U-M study show how expression of Wnt
blocks formation of adipocytes. (Left) Fat cells develop
in tissue grown from pre-adipocyte cells. (Right) Cells
remain unchanged in tissue grown from the same preadipocyte
cells when Wnt is espressed. Photo:
Ormond MacDougald |
This powerful molecular switch is one of several related proteins
called Wnts (pronounced "wints"), which exist in all
types of animals. Wnts regulate the complex genetic and biochemical
changes that take place during embryological development.
Development begins with a ball of generic stem cells capable
of becoming any type of cell. Stem cells become precursor cells,
which can change into a limited number of cell types. By the
end of the developmental stage, cells are committed to just
one cellular future.
Scientists knew that Wnt proteins were involved in early cell
development, but the U-M study is the first to identify the
importance of Wnts in fat cell formation. "We found that
Wnt signaling represses adipogenesis or fat cell development,"
says Sarah E. Ross, a U-M graduate student and first author
of the study published in Science on August 11, 2000.
"This is just the first piece of the puzzle, but it is
an important one," says Ormond A. MacDougald, Ph.D., who
directed the study. MacDougald is an assistant professor of
physiology in the Medical School and a member of the U-M Center
for Organogenesis. "Understanding this developmental pathway
could help scientists learn how and why obesity develops."
Ormond MacDougald, assistant
professor of physiology, and Sarah Ross, graduate student,
examine assay results to determine which Wnt proteins are
expressed during fat cell development. Ross and MacDougald’s
discoveryof how Wnts control the formation of fat cells
in mice was featured in the Aug. 11
issue of Science.
Photo: Bill Wood,
UM Photo Services |
MacDougald and his research team worked with two types of mouse
cells — precursor muscle cells called myoblasts and precursor
fat cells called preadipocytes. "In the absence of Wnt,
both cell types consistently differentiated into fat cells,"
Ross says.
When Wnt protein binds to a cell membrane receptor, it sets
off a chain of biochemical signals, according to Ross. Signals
are passed from one messenger molecule to another until they
reach the cell nucleus where they either turn on or turn off
genes that regulate development.
Ross demonstrated Wnt’s power to control cell differentiation
by blocking proteins in this signaling pathway to interrupt
the Wnt signal. After just a few days, myoblasts already on
their way to differentiating into muscle cells spontaneously
switched gears and became fat cells instead. "This suggests
that active Wnt signaling is required for continued commitment
to the myocyte lineage," says MacDougald.
Other significant results documented in the Science article
include:
- Of 18 known proteins in the Wnt family, Wnt 10b is the one
most likely responsible for regulating adipogenesis.
- Wnt appears to repress fat cell development by inhibiting
production of two transcription factor proteins, C/EBPalpha
and PPARgamma.
- Preadipocytes were injected beneath the skin of laboratory
mice and allowed to grow for seven weeks into a small pad
of tissue. Tissue grown from Wnt-free cells contained adipocytes,
while tissue from cells expressing Wnt remained undifferentiated.
In future research, MacDougald will study whether Wnt 10b has
the same fat cell-inhibiting effect in living mice as it does
in mouse cell cultures. "We plan to use genetic engineering
to direct expression of Wnt 10b to the developing adipocyte,"
says MacDougald. "Our goal is to create a fat-free mouse."
Other U-M collaborators in the study included Nahid Hemati,
research associate; Kenneth A. Longo, Ph.D., postdoctoral fellow;
Christina Bennett and Robin Erickson, graduate students; and
Peter C. Lucas, M.D., Ph.D., resident in pathology. The study
was funded by the National Institutes of Health, the Natural
Sciences and Engineering Research Council of Canada, and the
U-M.
MacDougald can be reached at macdouga@umich.edu;
Ross can be reached at saraross@umich.edu.
— Sally Pobojewski
 
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