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Science 26 July 2002:
Vol. 297. no. 5581, pp. 609 - 611
DOI: 10.1126/science.1072327
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Reports

Activation of Central Melanocortin Pathways by Fenfluramine

Lora K. Heisler,1 Michael A. Cowley,23 Laurence H. Tecott,4 Wei Fan,3 Malcolm J. Low,3 James L. Smart,3 Marcelo Rubinstein,5 Jeffrey B. Tatro,6 Jacob N. Marcus,1 Henne Holstege,1 Charlotte E. Lee,1 Roger D. Cone,3 Joel K. Elmquist1*

D-fenfluramine (d-FEN) was once widely prescribed and was among the most effective weight loss drugs, but was withdrawn from clinical use because of reports of cardiac complications in a subset of patients. Discerning the neurobiology underlying the anorexic action of d-FEN may facilitate the development of new drugs to prevent and treat obesity. Through a combination of functional neuroanatomy, feeding, and electrophysiology studies in rodents, we show that d-FEN-induced anorexia requires activation of central nervous system melanocortin pathways. These results provide a mechanistic explanation of d-FEN's anorexic actions and indicate that drugs targeting these downstream melanocortin pathways may prove to be effective and more selective anti-obesity treatments.

1 Division of Endocrinology, Diabetes and Metabolism, Departments of Medicine and Neurology, Beth Israel Deaconess Medical Center, and Program in Neuroscience, Harvard Medical School, Boston, MA 02215, USA.
2 Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA.
3 Vollum Institute, Oregon Health and Science University, Portland, OR 97201, USA.
4 Department of Psychiatry and Center for Neurobiology and Psychiatry, University of California, San Francisco, CA 94117, USA.
5 Instituto de Investigaciones en Ingeniería Genética y Biología Molecular (CONICET) and Department of Biological Sciences, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina.
6 Division of Endocrinology, Diabetes, Metabolism and Molecular Medicine, Tufts-New England Medical Center, and Department of Neuroscience and Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USA.
*   To whom correspondence should be addressed. E-mail: jelmquis{at}caregroup.harvard.edu

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