The protein Dab2
has long been linked to cancer. The molecule is associated with a chain
of signaling proteins called the Ras-MAPK pathway. In many cancers,
elements of Ras-MAPK mutate and start telling cells to grow
Sylvester Comprehensive Cancer Center researcher Xiang-Xi Michael
Xu, who is also a professor of cell biology at the University of
Miami Miller School of Medicine, discovered Dab2 more than 20 years ago
and has been studying its relationship to cancer ever since.
‘Dab2 controls a population of fat stem cells that slowly
disappears. It was observed that young mice without Dab2 protein do not gain weight when given excessive food.’
he's found that Dab2 has been living a secret life all along - one that
could have public health implications for fighting obesity. In a paper
published in the journal Scientific Reports
, the Xu lab has shown that young mice without Dab2 don't gain weight when given excessive food.
"These mice look and act normal," says Xu. "Everything seems fine,
except when we give them a high-fat diet. They just don't get fat."
The underlying mechanism may revolve around fat stem cells: immature
cells that can either divide into more stem cells or differentiate into
mature fat cells. In normal mice, Dab2 suppresses Ras-MAPK, which in
turn elevates a protein called PPAR, which helps fat stem cells make the
jump to mature fat cells. Eliminating Dab2 short-circuits that process.
While normal mice eating a calorie-dense diet pack on weight, the
Dab2 knockouts stay lean - but only for a while. As the mice mature, the
metabolic effect dissipates. By six months, the loss of Dab2 has
virtually no effect. Xu believes this happens because mice (and humans)
lose their fat stem cells as they reach maturity. This early impact
could help explain why early weight problems could persist into
adulthood and many adults have such a hard time losing weight.
"Dab2 controls a population of fat stem cells that slowly
disappears," said Xu. "It seems that children are especially affected by
diet. They can both increase fat cell number and fat cell size when
they are young. Later in life, they can still make fat, but that's
existing fat cells getting bigger. Habits of childhood could be
affecting adults, making them more susceptible to obesity."
From a public health standpoint, these findings may reinforce the
importance of steering children away from high-fat diets. Identifying
this role for Dab2 could also lead to new pharmaceutical strategies to
combat childhood obesity, as the protein could make an attractive target
for drug development.
"It would be very hard for a small laboratory like ours to develop a
new drug that targets Dab2," said Xu. "But perhaps a pharmaceutical
company will pick it up and develop it."