Serotonin 5-HT2C receptor agonist promotes hypophagia via downstream activation of melanocortin 4 receptors.
The neurotransmitter serotonin (5-hydroxytryptamine) is a well-established modulator of energy balance. Both pharmacological and genetic evidence implicate the serotonin 2C receptor (5-HT(2C)R) as a critical receptor mediator of serotonin's effects on ingestive behavior. Here we characterized the effect of the novel and selective 5-HT(2C)R agonist BVT.X on energy balance in obese and lean mice and report that BVT.X significantly reduces acute food intake without altering locomotor activity or oxygen consumption. In an effort to elucidate the mechanism of this effect, we examined the chemical phenotype of 5-HT(2C)R-expressing neurons in a critical brain region affecting feeding behavior, the arcuate nucleus of the hypothalamus. We show that 5-HT(2C)Rs are coexpressed with neurons containing proopiomelanocortin, known to potently affect appetite, in the arcuate nucleus of the hypothalamus of the mouse. We then demonstrate that prolonged infusion with BVT.X in obese mice significantly increases Pomc mRNA and reduces body weight, percent body fat, and initial food intake. To evaluate the functional importance of melanocortin circuitry in the effect of BVT.X on ingestive behavior, we assessed mice with disrupted melanocortin pathways. We report that mice lacking the melanocortin 4 receptor are not responsive to BVT.X-induced hypophagia, demonstrating that melanocortins acting on melanocortin 4 receptor are a requisite downstream pathway for 5-HT(2C)R agonists to exert effects on food intake. The data presented here not only indicate that the novel 5-HT(2C)R agonist BVT.X warrants further investigation as a treatment for obesity but also elucidate specific neuronal pathways potently affecting energy balance through which 5-HT(2C)R agonists regulate ingestive behavior.
Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, United Kingdom.
Daniel D
DD
Lam
Magdalena J
MJ
Przydzial
Simon H
SH
Ridley
Giles S H
GS
Yeo
Justin J
JJ
Rochford
Stephen
S
O'Rahilly
Lora K
LK
Heisler
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001067:Appetite Depressants / Q000494:pharmacology*; D001069:Appetite Regulation / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004435:Eating / Q000187:drug effects / Q000502:physiology*; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D001068:Feeding and Eating Disorders / Q000209:etiology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics / Q000378:metabolism*; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D058826:Serotonin 5-HT2 Receptor Agonists
D001067:Appetite Depressants; D012333:RNA, Messenger; D044105:Receptor, Melanocortin, Type 4; D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists; D012701:Serotonin; D011333:Pro-Opiomelanocortin