 By LEE BOWMAN Scripps Howard News Service July 19, 2006
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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