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.
Cliff Despres | EurekAlert!
Flavins keep a handy helper in their pocket
25.04.2018 | University of Freiburg
Complete skin regeneration system of fish unraveled
24.04.2018 | Tokyo Institute of Technology
At the Hannover Messe 2018, the Bundesanstalt für Materialforschung und-prüfung (BAM) will show how, in the future, astronauts could produce their own tools or spare parts in zero gravity using 3D printing. This will reduce, weight and transport costs for space missions. Visitors can experience the innovative additive manufacturing process live at the fair.
Powder-based additive manufacturing in zero gravity is the name of the project in which a component is produced by applying metallic powder layers and then...
Physicists at the Laboratory for Attosecond Physics, which is jointly run by Ludwig-Maximilians-Universität and the Max Planck Institute of Quantum Optics, have developed a high-power laser system that generates ultrashort pulses of light covering a large share of the mid-infrared spectrum. The researchers envisage a wide range of applications for the technology – in the early diagnosis of cancer, for instance.
Molecules are the building blocks of life. Like all other organisms, we are made of them. They control our biorhythm, and they can also reflect our state of...
University of Connecticut researchers have created a biodegradable composite made of silk fibers that can be used to repair broken load-bearing bones without the complications sometimes presented by other materials.
Repairing major load-bearing bones such as those in the leg can be a long and uncomfortable process.
Study published in the journal ACS Applied Materials & Interfaces is the outcome of an international effort that included teams from Dresden and Berlin in Germany, and the US.
Scientists at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) together with colleagues from the Helmholtz-Zentrum Berlin (HZB) and the University of Virginia...
Novel highly efficient and brilliant gamma-ray source: Based on model calculations, physicists of the Max PIanck Institute for Nuclear Physics in Heidelberg propose a novel method for an efficient high-brilliance gamma-ray source. A giant collimated gamma-ray pulse is generated from the interaction of a dense ultra-relativistic electron beam with a thin solid conductor. Energetic gamma-rays are copiously produced as the electron beam splits into filaments while propagating across the conductor. The resulting gamma-ray energy and flux enable novel experiments in nuclear and fundamental physics.
The typical wavelength of light interacting with an object of the microcosm scales with the size of this object. For atoms, this ranges from visible light to...
13.04.2018 | Event News
12.04.2018 | Event News
09.04.2018 | Event News
25.04.2018 | Physics and Astronomy
25.04.2018 | Physics and Astronomy
25.04.2018 | Information Technology