RNA editing that converts adenosine to inosine replaces the gene-encoded Ile, Asn, and Ile (INI) of serotonin [5-hydroxytryptamine (5-HT)] receptor 2C (5-HT2CR) with Val, Gly, and Val (VGV). Up to 24 different 5-HT2CR isoforms are detected in different brain regions (Burns et al., 1997; Fitzgerald et al., 1999; Wang et al., 2000). To elucidate the physiological significance of5-HT2CRmRNA editing, we derived mutant mouse lines harboring a knock-inINIorVGVallele, resulting in sole expression of one of two extremely different editing isoforms 5-HT2CR-INI (editing blocked) or -VGV (fully edited). AlthoughINImice grew normally,VGVmice had a severely reduced fat mass, despite compensatory hyperphagia, as a result of constitutive activation of the sympathetic nervous system and increased energy expenditure. Furthermore, serotonergic neurotransmission was oversensitized inVGVmice, most likely because of the increased cell surface expression of VGV receptors. Melanocortin 4 receptor (MC4R) regulates energy homeostasis (Balthasar et al., 2005; Heisler et al., 2006; Lam et al., 2008), andMc4r−/−mice are obese because of hyperphagia and reduced energy expenditure (Huszar et al., 1997). However, the elevated energy expenditure ofVGVmice could not be rescued in theMc4r−/−background, indicating the presence of a distinct signaling pathway mediated via 5-HT2CR-VGV that dominates the MC4R-dependent pathway in control of energy expenditure. Our results highlight the importance of regulated5-HT2CRmRNA editing, because dysregulation could result in the pathological consequences such as growth retardation seen inVGVmice.