Mice lacking 5-HT 2C receptors (5-HT_2CRs) displayed hepatic insulin resistance, a phenotype normalized by re-expression of 5-HT_2CRs only in pro-opiomelanocortin (POMC) neurons. 5-HT_2CR deficiency also abolished the anti-diabetic effects of meta-chlorophenylpiperazine (a 5-HT_2CR agonist); these effects were restored when 5-HT_2CRs were re-expressed in POMC neurons. Our findings indicate that 5-HT_2CRs expressed by POMC neurons are physiologically relevant regulators of insulin sensitivity and glucose homeostasis in the liver.