New clues to how major weight-loss drugs work

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.

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The researchers include Lora K. Heisler of Addenbrooke's Hospital, University of Cambridge in Cambridge, United Kingdom and Beth Israel Deaconess Medical Center and Harvard Medical School in Boston, MA; Erin E. Jobst of Oregon National Primate Research Center at Oregon Health and Science University in Beaverton, OR and Pacific University in Forest Grove, OR; Gregory M. Sutton and Andrew A. Butler of Pennington Biomedical Research Center, Louisiana State University System in Baton Rouge, LA; Ligang Zhou of Addenbrooke's Hospital, University of Cambridge in Cambridge, United Kingdom; Erzsebet Borok and Tamas Horvath of Yale Medical School in New Haven, CT; Zoe Thornton-Jones and Peter G. Clifton of Sussex University in Brighton, United Kingdom; Hong Yan Liu and Jeffrey M. Friedman of Howard Hughes Medical Institute and The Rockefeller University in New York, NY; Jeffrey M. Zigman, Nina Balthasar, Charlotte E. Lee, Carl J. Aschkenasi, Chen-Yu Zhang, Jia Yu, Olivier Boss, and Bradford B. Lowell of Beth Israel Deaconess Medical Center and Harvard Medical School in Boston, MA; Toshiro Kishi of Shimane University School of Medicine in Izumo, Japan; Kathleen G. Mountjoy of University of Auckland in New Zealand; Joel K. Elmquist of Beth Israel Deaconess Medical Center and Harvard Medical School in Boston, MA and University of Texas Southwestern Medical Center in Dallas, TX; Michael A. Cowley of Oregon National Primate Research Center at Oregon Health and Science University in Beaverton, OR.

Data presented in this paper were supported by the following: L.K.H. (NIDDK DK065171, American Diabetes Association, and Boston Obesity Nutrition Research Center), N.B. (The Wellcome Trust, UK, ADA-EASD Transatlantic Fellowship, and Boston Obesity Nutrition Research Center), P.G.C. (BBSRC C505291), B.B.L. (NIDDK56116 and DK53301), A.A.B. (NIDDK DK068330 and American Diabetes Association), T.H. (NIDDK DK074386 and DK060711), J.K.E. (NIMH MH061583, NIDDK P01DK056116), and M.A.C. (NIH RR 00163, NIDDK, DK62202). M.A.C. and OHSU have a significant financial interest in Orexigen Therapeutics Inc., a company that may have a commercial interest in the results of this research and technology. This potential conflict of interest has been reviewed and managed by the OHSU Conflict of Interest in Research Committee and the Integrity Program Oversight Council.

Heisler et al.: "Serotonin Reciprocally Regulates Melanocortin Neurons to Modulate Food Intake." Publishing in Neuron 51, 239–249, July 20, 2006 DOI 10.1016/j.neuron.2006.06.004 www.neuron.org


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