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Serotonin 5-HT_2C Receptor Agonist Promotes Hypophagia via Downstream Activation of Melanocortin 4 Receptors

Department of Pharmacology (D.D.L., M.J.P., L.K.H.), University of Cambridge, Cambridge CB2 1PD, United Kingdom; and Department of Clinical Biochemistry (D.D.L., M.J.P., S.H.R., G.S.H.Y., J.J.R., S.O’R., L.K.H.), Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke’s Hospital, University of Cambridge, Cambridge CB2 2QQ, United Kingdom

Address all correspondence and requests for reprints to: Lora K. Heisler, Ph.D., Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, United Kingdom. E-mail: lkh30{at}cam.ac.uk.

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_2CR) as a critical receptor mediator of serotonin’s effects on ingestive behavior. Here we characterized the effect of the novel and selective 5-HT_2CR 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_2CR-expressing neurons in a critical brain region affecting feeding behavior, the arcuate nucleus of the hypothalamus. We show that 5-HT_2CRs 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_2CR agonists to exert effects on food intake. The data presented here not only indicate that the novel 5-HT_2CR 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_2CR agonists regulate ingestive behavior.

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