A group of scientists at the University of Michigan
carried out a study to understand why the fat-storing cells get fatter and
takes a long time to metabolize fat in obese individuals.
Obesity is a fast becoming
a world -wide phenomenon and the morbidity and mortality burden due to obesity
is increasing globally at an alarming rate.
Ormond MacDougald and his
colleagues tried to study the signals sent by fat-storing cells to each other
in their effort to understand why fat cells get fatter and how people become
In an array of experiments
carried out on mice, the researchers revealed the presence of a molecule called Sfrp5. They showed that
this molecule influences a signaling
pathway known as WNT, stimulates the adipocytes (fat cells) to grow bigger and
larger and suppress the rate at which fat is metabolized in the mitochondria of
By preventing the adipose cells
from producing Sfrp5, the researchers were able to prevent the mice from
becoming fat quite so quickly. Despite being fed on high-fat diet, the
adipocytes in these mice didn't grow large.
The research was carried
out with NIH funding in the U-M Medical School laboratory of Ormond MacDougald,
Ph.D., in the Department of Molecular & Integrative Physiology.
The team had realized the importance of WNT signaling in fat cell
development through their previous work.
"WNT signaling plays
a crucial role in regulating, and inhibiting, white fat cell growth and the
recruitment of new cells to store fat," MacDougald explains. "But it
appears that in obesity, Sfrp5 can interfere with that signaling, and may
create a feedback loop that keeps stimulating production of more of
MacDougald and his team
began to zero in on the molecule Sfrp5 after several years of observing WNT
signaling between adipocytes. It was observed by several groups of researchers that
the amounts of Sfrp5 generated in fat tissues of obese animals were much
Initially, when they bred mice
that could not produce the Sfrp5, they expected to see non-obese mice that
resisted obesity due to their inability to convert more cells into adipocytes and
thereby store fat. But what they found was that the mice without the molecule
had as many fat cells as those with the molecule, but they came with a
difference - the adipocytes in the former did not grow bigger and accumulate
fat.These mice did not become fat no matter how calorie- laden their diet was.
Another feature of these
Sfrp5-deficient mice was that the mitochondrial genes inside the adipose cells
registered a surge of activity, as a result of which fat was easily burned down
for the cell's activities. It was as if the 'mitochondrial furnaces' began to
work over time in the absence of these molecules.
"From our results, we
believe that Sfrp5 is an important moderator of mitochondrial activity-- the
first time this has been seen for the WNT signaling pathway in
adipocytes," says Mori the lead author of the study "This underscores
the complexity of WNT signaling," mori adds.
A look into the underlying mechanism reveals that Sfrp5 works as a
decoy receptor to which WNT signals bind. This prevents them from binding to
the cell surface receptors that they would otherwise bind to. When the WNT
signaling is reduced, the adipose cells grow larger and don't burn fat that
easily. The cells grow larger to store the accumulated fat. Then, a feedback
loop is created and the cells produce more Sfrp5, creating the tendency for
adipocytes to accumulate more lipid.
It may be possible for
anti-obesity drugs to target the signalling pathway but, MacDougald warns that
more experiments need to be carried out in mice and humans before going down
the drug trail. With the world in the grip of obesity, and its related health
conditions, this field of research demands immediate attention.
Mori et al; Journal of Clinical Investigation (online) 2012; July issue