Serotonin 2C receptors (5-HT 2CRs) expressed by pro-opiomelanocortin (POMC) neurons of hypothalamic arcuate nucleus regulate food intake, energy homeostasis and glucose metabolism. However, the cellular mechanisms underlying the effects of 5-HT to regulate POMC neuronal activity via 5-HT 2CRs have not yet been identified. In the present study, we found the putative transient receptor potential C (TRPC) channels mediate the activation of a subpopulation of POMC neurons by mCPP (a 5-HT 2CR agonist). Interestingly, mCPP-activated POMC neurons were found to be a distinct population from those activated by leptin. Together, our data suggest that 5-HT 2CR and leptin receptors are expressed by distinct subpopulations of arcuate POMC neurons and that both 5-HT and leptin exert their actions in POMC neurons via TRPC channels. Display omitted ► 5-HT2CRs excite arcuate POMC neurons independent of altering GIRK channel activity ► Arcuate POMC 5-HT2CRs activate a Na +/Ca 2+ permeable mixed-cation conductance ► 5-HT2CR-induced excitation of arcuate POMC neurons requires a putative TRPC channel ► 5-HT2CR- and LepR-activated arcuate POMC neurons are anatomically segregated