Activation of central melanocortin pathways by fenfluramine.
D-fenfluramine (d-FEN) was once widely prescribed and was among the most effective weight loss drugs, but was withdrawn from clinical use because of reports of cardiac complications in a subset of patients.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.
Heisler
Lora K
LK
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Cowley
Michael A
MA
Tecott
Laurence H
LH
Fan
Wei
W
Low
Malcolm J
MJ
Smart
James L
JL
Rubinstein
Marcelo
M
Tatro
Jeffrey B
JB
Marcus
Jacob N
JN
Holstege
Henne
H
Lee
Charlotte E
CE
Cone
Roger D
RD
Elmquist
Joel K
JK
D000818:Animals; D001067:Appetite Depressants / Q000494:pharmacology*; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D005247:Feeding Behavior / Q000187:drug effects*; D005277:Fenfluramine / Q000494:pharmacology*; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology; D051379:Mice; D008820:Mice, Obese; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D044405:Receptor, Serotonin, 5-HT2C; D018043:Receptors, Corticotropin / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D018490:Serotonin Agents / Q000494:pharmacology; D000521:alpha-MSH / Q000378:metabolism*
D001067:Appetite Depressants; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D044405:Receptor, Serotonin, 5-HT2C; D018043:Receptors, Corticotropin; D011985:Receptors, Serotonin; D018490:Serotonin Agents; C103272:SHU 9119; D005277:Fenfluramine; D012701:Serotonin; D000521:alpha-MSH; D011333:Pro-Opiomelanocortin; D009074:Melanocyte-Stimulating Hormones