The central serotonin (5-hydroxytryptamine, 5-HT) system is an established modulator of energy balance. Therefore, it is unsurprising that recent (e.g. sibutramine) and drug discovery (e.g. lorcaserin) obesity treatments target serotonin pathways to affect food intake, body weight, and glucose homeostasis. Pharmacological and genetic research implicates the Gq-coupled serotonin 2C receptor (5-HT2CR) specifically in these effects. We sought to clarify how serotonin in general, and the 5-HT2CRs in particular, modulates these effects. We found that 5-HT2CR agonists require melanocortin pathways to exert effects on appetite and glucose homeostasis. Specifically, we observed that 5-HT2- CRs are co-expressed with neurons containing the endogenous anorectic melanocortin agonist pro-opiomelanocortin (POMC)/ α-melanocyte stimulating hormone (α-MSH) in the arcuate nucleus of the hypothalamus. We found that anorectic concentrations of 5-HT2CR agonists activated POMC/α-MSH neurons. Furthermore, we observed that 5-HT2CR agonists improved glucose and insulin tolerance at concentrations insufficient to influence appetite. These improvements were associated with enhanced insulin signalling in liver and muscle and reduced hepatic gluconeogensis. In the brain, α-MSH acts at the melanocortin 3 (MC3) and melanocortin 4 (MC4) receptors. To further clarify the pathway through which serotonin influences appetite and glucose homeostasis, we examined whether pharmacological blockade or genetic inactivation of the MC3Rs or MC4Rs abolishes 5-HT2CR agonist hypophagia and improvements in glucose homeostasis. We observed that activation of the MC4Rs, but not the MC3Rs, is required for 5-HT2CR agonists to influence feeding and insulin action. A model is presented in which activation of the melanocortin system is downstream of serotonin and is necessary to produce the complete effect of 5-HT2CR agonists on energy balance.
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