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5-HT2CRs expressed by pro-opiomelanocortin neurons regulate insulin sensitivity in liver

Abstract

Mice lacking 5-HT 2C receptors (5-HT2CRs) 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.

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Figure 1: mCPP-induced depolarization of POMC neurons is abolished in 2C null mice and restored in 2C/POMC mice.
Figure 2: Re-expression of 5-HT2CRs in POMC neurons rescues insulin resistance.

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Acknowledgements

We thank the University of Texas Southwestern Mouse Metabolic Phenotyping Core (supported by PL1 DK081182 and UL1RR024923). This work was supported by grants to Y.X. (Canadian Institute of Health Research and K99DK085330), E.D.B. (TL1DK081181), J.-W.S. (American Diabetes Association), W.L.H. (F32 DK083866-01), M.F. (American Heart Association), J.R. (Sigrid Jusélius Foundation), K.W.W. (K01 DK087780), J.M.Z. (K08DK068069), P.E.S. (PO1 DK088761, RC1-DK086629 and R01-DK55758), B.B.L. (PO1 DK56116) and J.K.E. (R01DK088423, R01DK53301, R01MH61583 and RL1DK081185).

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Authors and Affiliations

Authors

Contributions

Y.X. conducted the glucose/insulin experiments and wrote the manuscript. E.D.B. performed clamp studies. J.-W.S. and K.W.W. conducted electrophysiological recordings. J.-C.C., M.F. and J.R. contributed to the islet studies. J.E.J., J.M.Z. and B.B.L. generated mice. W.L.H., P.E.S. and B.B.L. assisted in data interpretation. J.K.E. supervised the project.

Corresponding author

Correspondence to Joel K Elmquist.

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The authors declare no competing financial interests.

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Supplementary Figure 1, Supplementary Table 1 and Supplementary Methods (PDF 262 kb)

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Xu, Y., Berglund, E., Sohn, JW. et al. 5-HT2CRs expressed by pro-opiomelanocortin neurons regulate insulin sensitivity in liver. Nat Neurosci 13, 1457–1459 (2010). https://doi.org/10.1038/nn.2664

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