Understanding how a weight loss drug works: serotonin linked to MC4R

Some years ago, the dietary pill Fen-Phen was a fairly widely used, effective drug for weight loss, and was even reported to be helpful in PWS in a small clinical trial: Selikowitz M, et al. Unfortunately, its adverse effects on the heart and lungs led the FDA to withdraw it from the market in 1997.

Despite its problems, Fen-Phen actually seemed to help curb hunger, so researchers are interested in understanding why - with the hope of producing a drug that retains the hunger curbing effects but not the cardiotoxic effects. This drug was known to act as a ‘nonselective serotonin receptor agnonist’ – meaning it activates serotonin receptors, enhancing the effect of serotonin. Fenfluramine (the fen of fen-phen) was known to act on the serotonin 5HT2C receptor, but also activates other receptors in the brain (hence, the term nonselective).

It has long been appreciated that the serotonin (a.k.a. 5-HT) system in the brain is linked to hunger and appetite control (increased serotonin leads to decreased food intake), but exactly how serotonin causes a decrease in appetite is not completely understood. This paper addressed that question and looked at the link between the serotonin system and another brain circuit known to be important in food intake and energy balance, the melanocortin system. The investigators first showed that a particular serotonin receptor (5HT1B receptor) is found on the neurons in the hypothalamus that regulate food intake and body weight. Further, they showed (in mice) that serotonin and drugs stimulating the 5HT1B receptors affected the neurons by reducing release of the peptide AgRP (a naturally made appetite stimulant) and increasing the release of alpha-MSH (alpha-melanocyte stimulating hormone, an appetite suppressing peptide). They then showed that release of alpha-MSH activates the melanocortin-4 receptors (MC4Rs) on neurons. The melanocortins and their receptors are known to influence weight regulation, and MC4R has been implicated in hunger and weight control. The authors conclude that drugs that affect the serotonin system and decrease appetite do so through activation of MC4Rs.

Heiser et al. Serotonin reciprocally regulates melanocortin neurons to modulate food intake. Neuron 51, 239-249, 2006.


This study is important to PWS because it provides a more clear understanding of how drugs affecting the serotonin system work to reduce appetite. A better understanding of how the serotonin and melanocortin circuits intersect and influence each other should help guide drug development efforts. Further, although this study focused specifically on the serotonin receptor 5HT1BR, previous studies have linked the serotonin receptor 5HT2CR to the melanocortin system as well. Alterations in the serotonin system, specifically the 5HT2C receptors, may be present in PWS (recall the recent study by Stamm and colleagues), and may prove important when considering the potential of different anti-obesity drugs in the PWS population. Finally, this study suggests that targeting the MC4R for anti-obesity drug development (as in this paper, for example).


A press release regarding the article is available here.

Topics: Research

Theresa Strong


Theresa V. Strong, Ph.D., received a B.S. from Rutgers University and a Ph.D. in Medical Genetics from the University of Alabama at Birmingham (UAB). After postdoctoral studies with Dr. Francis Collins at the University of Michigan, she joined the UAB faculty, leading a research lab focused on gene therapy for cancer and directing UAB’s Vector Production Facility. Theresa is one of the founding members of FPWR and has directed FPWR’s grant program since its inception. In 2016, she transitioned to a full-time position as Director of Research Programs at FPWR. She remains an Adjunct Professor in the Department of Genetics at UAB. She and her husband Jim have four children, including a son with PWS.

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