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New clues to how major weight-loss drugs work

July 20, 2006

Some of the most important weight-loss drugs work by enhancing the effect of the brain chemical serotonin. These include sibutramine (trade name Meridia) and fenfluramine, which was recalled after the combination with dexfenfluramine, called fen-phen, was linked to potentially fatal heart valve abnormalities.

However, little has been known about the molecular mechanism by which serotonin suppresses appetite. Now, in an article in the July 20, 2006, Neuron, published by Cell Press, researchers have pinpointed key components in the mechanism of serotonin's action. The research was led by Michael Cowley of Oregon Health and Science University, Joel Elmquist of University of Texas Southwestern Medical Center at Dallas and formerly of Beth Israel Deaconess Medical Center and Harvard Medical School, and Lora K. Heisler of the University of Cambridge and formerly of Beth Israel Deaconess Medical Center and Harvard Medical School.

In their experiments with mice, they sought to discover whether serotonin acts on specific brain circuitry in the hypothalamus known to regulate the body's energy balance. Their tracer experiments showed that receptors for serotonin are, indeed, expressed on particular neurons in this circuitry that are potent modulators of food intake and body weight. What's more, the researchers found that both serotonin and drugs that affect serotonin's action acted on these neurons to reduce the release of a protein called AgRP that stimulates appetite and aid release of a protein called áMSH that curbs appetite.

To trace the effect of these two proteins downstream in the appetite-regulating pathway, the researchers analyzed the effects of various drugs that enhance or interfere with serotonin on feeding behavior in mice. They found that the drugs acted to disrupt function of receptors for a substance called melanocortin. It was known that AgRP and áMSH both act on these receptors to regulate appetite.

The researchers also identified a specific type of melanocortin receptor, called melanocortin receptor-4, as a critical target of the serotonin pathway. This pathway appears to be central to appetite regulation, wrote the researchers, since their experiments showed that blocking just this receptor type was sufficient to render ineffective the reduction of food intake caused by serotonin-enhancing drugs.

Cell Press