The brain chemical serotonin activates some cells that curb appetite
and blocks others that normally increase hunger at the same time,
according to a new study into the effects of several weight-loss
drugs.
Working with mice, researchers from several institutions sought to
learn whether serotonin acts on specific brain circuits in the
hypothalamus region that are known to regulate the body's energy
balance.
Their tracer experiments showed that receptors for serotonin dot
specific nerve cells within these circuits. And they found that both
serotonin and drugs like fenfluramine and sibutramine (Meridia) that
change levels of serotonin acted on those brain cells to reduce the
release of one protein that stimulates appetite and aids the release
of another protein that helps curb the desire to eat.
The findings, published Thursday in the journal Neuron, reinforce the
role of serotonin in affecting a key molecular pathway that controls
weight, in addition to its better-known function as a regulator of
sleep, mood and emotions.
Fenfluramine with phentermine, or Fen-phen, helped tens of thousands
of people lose weight. But the combination also caused heart problems,
including defects in the valves of the heart or a form of
hypertension, in many patients and it was removed from the market in
1997.
But the mechanisms of how the drugs caused weight loss were never
fully determined.
Researchers led by Dr. Joel Elmquist, then at Harvard Medical School
and now at the University of Texas Southwestern Medical Center in
Dallas began studying those molecular pathways that reduce appetite,
working with both normal mice and those genetically engineered to be
lean or fat.
In 2002, they found that drug-induced serotonin releases activate
brain cells to, in turn, release a hormone that reduces appetite.
The team's new study shows how serotonin also simultaneously blocks
other neurons from being able to inhibit the activity of the
hunger-suppressing system, and concluded that both mechanisms are
required to promote weight loss.
"The more we understand about the pathways and the way serotonergic
drugs regulate body weight, the more it one day might lead to
harnessing the beneficial properties of anti-obesity treatments like
Fen-phen and minimizing the harmful side effects,'' said Elmquist, a
professor of internal medicine at UT Southwestern.
The search for more effective and safe drugs to combat obesity is
viewed as a public health priority in the United States.
According to the federal Centers for Disease Control and Prevention,
about two thirds of American adults are overweight, as are 16 percent
of youths aged 6 to 19. Being overweight or obese increases the risk
of many harmful health conditions, including heart disease, stroke,
diabetes and liver disease.
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