Obesity has become one of the major health concerns of this century because of its prevalence and resistance to treatment. Specifically, one in four people in the UK are currently clinically obese. Significant progress has been made over the past decade in clarifying brain neurochemicals and regions regulating energy homeostasis. Among these is the key precursor polypeptide pro-opiomelanocortin (Pomc) within the homeostatic brain region the arcuate nucleus of the hypothalamus (ARC). The 5-hydroxytryptamine (5-HT, serotonin) 2C receptor (Htr2c; 5-HT2CR) agonist lorcaserin (Eisai Inc) is a new medication for obesity treatment that was recently launched in the USA. However, mechanism through which lorcaserin’s therapeutic effects are achieved remain to be elucidated. Here we clarify that the target of lorcaserin is 5-HT2CRs influencing the activity of ARC Pomc. Specifically, here we demonstrate that preventing Pomc production in the ARC (PomcNEO) is sufficient to abolish lorcaserin’s anorectic effects and that restoration of Pomc specifically within a subset of ARC neurons expressing 5-HT2CRs (PomcHtr2c) is sufficient to restore lorcaserin’s therapeutic effect. These findings illustrate that lorcaserin achieves it therapeutic benefit via activation of ARC Pomc peptides. To further clarify the brain circuit mediating lorcaserin’s appetite suppression, we next considered the receptors binding Pomc peptides. The melanocortin receptor most closely linked to appetite and body weight control is melanocortin4 receptor (Mc4r). Using a combination of viral and genetic technology, we reveal that lorcaserin suppresses appetite via action at PomcHtr2c signaling to Mc4rs. These findings reveal the mechanism underpinning the therapeutic benefit of the new obesity medication lorcaserin, via activation of a discrete melanocortin brain circuit.