A study led by a UT Southwestern Medical Center researcher sheds light
on how the brain chemical serotonin, when spurred by diet drugs such
as Fen-phen, works to curb appetite.

That knowledge could aid in the design of safer anti-obesity drugs
nearly a decade after Fen-phen was banned for causing harmful side
effects.

The study, which tested the effect of several drugs that alter
serotonin levels in the brain, found that serotonin activates some
neurons and melanocortin-4 receptors, or MC4Rs, to curb appetite and
at the same time blocks other neurons that normally act to increase
appetite.

The dual effect helps explain how such drugs, including Fen-phen, spur
weight loss.

The finding, available online and in the July 20 issue of Neuron, also
reinforces the role of serotonin - a regulator of emotions, mood and
sleep - in affecting the brain's melanocortin system, a key molecular
pathway that controls body weight.

"The more we understand about the pathways and the way serotonergic
drugs regulate body weight, the more it one day might lead to
harnessing beneficial properties of anti-obesity treatments like
Fen-phen and minimizing the harmful side effects," said Dr. Joel
Elmquist, professor of internal medicine at UT Southwestern and
co-senior author of the study.

In the United States, about 66 percent of adults are obese or
overweight, as are 16 percent of young people aged 6 to 19, according
to the Centers for Disease Control and Prevention. The trend is
significant because being overweight or obese increases the risk of
harmful health consequences, such as heart disease, stroke, diabetes,
non-alcoholic liver disease and death.

Drugs that enhance the brain's release of serotonin have helped people
lose weight. Fen-phen, which paired fenfluramine with phentermine, had
such success. The drug combination, however, also led some patients to
develop cardiac complications, Dr. Elmquist said. The drug was removed
from the market in 1997.

But the mechanisms of how it caused weight loss were never fully
determined, he said.

So a few years ago, Dr. Elmquist and his research team set out to
detail how fenfluramine affected the brain's molecular pathways to
reduce appetite. In 2002, they examined the region of the brain's
hypothalamus containing the arcuate nucleus, or ARC. In the ARC,
drug-induced serotonin activates brain cells called
pro-opiomelanocortin neurons, or POMC, which in turn release a hormone
that acts on the MC4R to reduce appetite.

The team's new study shows how serotonin also simultaneously blocks
other neurons, known as NPY/AgRP, from being able to inhibit activity
of MC4Rs. By blocking this inhibitory activity, serotonin prevents an
increase in appetite.

Researchers studied the effect of Fen-phen and other
serotonin-inciting drugs on both normal and genetically engineered
lean and obese mice. They found that serotonin's dual regulation of
POMC and AgRP neurons is necessary to promote weight loss.

"The finding increases the understanding of the molecular circuitry
that controls body weight in response to changing levels of
serotonin," Dr. Elmquist said. "An overarching goal of this
understanding, for humans, is to design specific, safe drugs to fight
obesity."

Dr. Elmquist, who recently left Harvard Medical School, directs the
newly formed Center for Hypothalamic Research at UT Southwestern. The
center, along with the Taskforce for Obesity Research, a National
Institutes of Health Interdisciplinary Research Center, is part of the
institution's effort to investigate the causes of obesity, metabolic
syndrome and diabetes.

Labels: No Prescription, Online Pharmacy, Prescription Drugs

# posted by Network @ 5:41 AM