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most effective weight loss drugs, but was withdrawn from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@caregroup.harvard.edu
