Although the "obesity
hormone" leptin can spur weight loss in laboratory animals, it's
not very helpful for overweight humans, who actually have lost their sensitivity
to the hormone and have extra-high levels in their blood.
Now a new study in mice suggests
that tinkering with a second substance, a signaling protein that appears
to be active in the "appetite center" in the brain, might increase
sensitivity to leptin.
The findings suggest that the
substance, known as protein tyrosine phosphatase (PTP1B), might be a target
for anti-obesity researchers.
With the increased incidence
of diabetes and obesity the study shows that one specific protein, PTP1B,
when inhibited, leads to increased leptin action.
Leptin is an important modulator
of energy metabolism and appetite and inhibiting PTP1B should promote
a decrease in weight gain even in severe cases of obesity.
Leptin is produced by fat cells
as a signal to the brain to curb eating when fat stores are adequate.
When it was first discovered in the 1990s, the finding was met with much
excitement and the hope was that weight would just "melt away"
if obese people were given leptin.
Unfortunately, it turned out
that the situation in overweight humans was much more complex than it
was in extra-large laboratory animals. Obese humans, it seems, had too
much leptin, and no longer responded to the hormone properly.
In the new study researchers
looked at the region of the brain affected by leptin, known as the hypothalamus.
They worked with two types
of mice. One type lacks the ability to produce leptin and is thus extremely
obese. The second type lacks PTP1B alone and is less likely than other
mice to become obese when fed a high-fat diet. By breeding the mice, they
were able to produce animals that lacked both leptin and PTP1B.
While mice that lacked only
leptin gained the most weight, the researchers found that, at 12 weeks
old, the mice that lacked both genes for leptin and PTP1B weighed 12%
less compared with mice that lacked only leptin. This was true even though
the mice consumed the same amounts of food.
Interestingly, the researchers
found that mice that lacked leptin but had one working gene for PTP1B
(normal mice inherit one gene from each parent) displayed an intermediate
weight gain between only-leptin-deficient mice and mice deficient in both
copies of leptin and PTP1B genes. This finding, according to the report,
suggests that "inhibiting half the levels of PTP1B may be sufficient
to invoke some weight loss."
The researchers also found
that a deficiency in PTP1B seemed to enhance sensitivity to leptin when
it was administered to animals.
Previously, how leptin signaling
is turned off in the body was not well known. This study demonstrates
that PTP1B is a direct regulator of leptin signaling in the hypothalamus.
This supports nicely the important value of PTP1B as a target in both
obesity and diabetes.
Developmental
Cell April 2002;2:497-503
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