Location: Children's Nutrition Research CenterTitle: 5-HT2CRs expressed by pro-opiomelanocortin neurons regulate insulin sensitivity in liver) Author
Submitted to: Nature Neuroscience
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/15/2010
Publication Date: 10/31/2010
Citation: Xu, Y., Berglund, E.D., Sohn, J., Holland, W.L., Chuang, J., Fukuda, M., Rossi, J., Williams, K.W., Jones, J.E., Zigman, J.M., Lowell, B.B., Scherer, P.E., Elmquist, J.K. 2010. 5-HT2CRs expressed by pro-opiomelanocortin neurons regulate insulin sensitivity in liver. Nature Neuroscience. 13(12):1457-1459. Interpretive Summary: Type II diabetes is a serious global health problem due to its increasing prevalence and comorbiditis. Interventions that increase bioavailability of serotonin (5-HT) have been shown to improve insulin sensitivity and could be used to treat type II diabetes. However, the mechanisms underlying these beneficial effects remain unknown. We generated two mouse models. In one, a 5-HT receptor, called 5-HT2CR, was globally deleted; in another, 5-HT2CRs were re-expressed only in a subset of neurons in the brain, called pro-opiomelanocortin (POMC) neurons. Metabolic characterization of these two mouse models revealed that global deletion of 5-HT2CRs eliminated the anti-diabetic effects of 5-HT compounds, while re-expression of 5-HT2CRs only in POMC neurons is sufficient to restore these benefits. These findings highlighted 5-HT2CRs expressed by POMC neurons as the key regulator of insulin sensitivity. This 5-HT2CR population could be a potential target for development of novel anti-diabetic therapies.
Technical Abstract: Mice lacking 5-HT 2C receptors displayed hepatic insulin resistance, a phenotype normalized by re-expression of 5-HT2CRs only in pro-opiomelanocortin (POMC) neurons. 5-HT2CR deficiency also abolished the anti-diabetic effects of meta-chlorophenylpiperazine (a 5-HT2CR agonist); these effects were restored when 5-HT2CRs were re-expressed in POMC neurons. Our findings indicate that 5-HT2CRs expressed by POMC neurons are physiologically relevant regulators of insulin sensitivity and glucose homeostasis in the liver.