Serotonin 2C receptor agonists improve type 2 diabetes via melanocortin-4 receptor signaling pathways

Ligang Zhou; Gregory M. Sutton; Justin J. Rochford; Robert K. Semple; Daniel D. Lam; Laura J. Oksanen; Zoe D. Thornton-Jones; Peter G. Clifton; Chen-Yu Yueh; Mark L. Evans; Rory J. McCrimmon; Joel K. Elmquist; Andrew A. Butler; Lora K. Heisler

doi:10.1016/j.cmet.2007.10.008

Serotonin 2C receptor agonists improve type 2 diabetes via melanocortin-4 receptor signaling pathways

Ligang Zhou, Gregory M. Sutton, Justin J. Rochford, Robert K. Semple, Daniel D. Lam, Laura J. Oksanen, Zoe D. Thornton-Jones, Peter G. Clifton, Chen-Yu Yueh, Mark L. Evans, Rory J. McCrimmon, Joel K. Elmquist, Andrew A. Butler, Lora K. Heisler^*

^*Corresponding author for this work

The Rowett Institute of Nutrition and Health

Research output: Contribution to journal › Article › peer-review

193 Citations (Scopus)

Abstract

The burden of type 2 diabetes and its associated premature morbidity and mortality is rapidly growing, and the need for novel efficacious treatments is pressing. We report here that serotonin 2C receptor (5-HT2CR) agonists, typically investigated for their anorectic properties, significantly improve glucose tolerance and reduce plasma insulin in murine models of obesity and type 2 diabetes. Importantly, 5-HT2CR agonist-induced improvements in glucose homeostasis occurred at concentrations of agonist that had no effect on ingestive behavior, energy expenditure, locomotor activity, body weight, or fat mass. We determined that this primary effect on glucose homeostasis requires downstream activation of melanocortin-4 receptors (MC4Rs), but not MC3Rs. These findings suggest that pharmacological targeting of 5-HT(2C)Rs may enhance glucose tolerance independently of alterations in body weight and that this may prove an effective and mechanistically novel strategy in the treatment of type 2 diabetes.

Original language	English
Pages (from-to)	398-405
Number of pages	8
Journal	Cell Metabolism
Volume	6
Issue number	5
DOIs	https://doi.org/10.1016/j.cmet.2007.10.008
Publication status	Published - 7 Nov 2007

Keywords

central-nervous-system
mice
obesity
organization
expression
neurons
mouse
rat
humdisease
molneuro

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cmet.2007.10.008

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Zhou, L., Sutton, G. M., Rochford, J. J., Semple, R. K., Lam, D. D., Oksanen, L. J., Thornton-Jones, Z. D., Clifton, P. G., Yueh, C.-Y., Evans, M. L., McCrimmon, R. J., Elmquist, J. K., Butler, A. A., & Heisler, L. K. (2007). Serotonin 2C receptor agonists improve type 2 diabetes via melanocortin-4 receptor signaling pathways. Cell Metabolism, 6(5), 398-405. https://doi.org/10.1016/j.cmet.2007.10.008

Zhou, L, Sutton, GM, Rochford, JJ, Semple, RK, Lam, DD, Oksanen, LJ, Thornton-Jones, ZD, Clifton, PG, Yueh, C-Y, Evans, ML, McCrimmon, RJ, Elmquist, JK, Butler, AA & Heisler, LK 2007, 'Serotonin 2C receptor agonists improve type 2 diabetes via melanocortin-4 receptor signaling pathways', Cell Metabolism, vol. 6, no. 5, pp. 398-405. https://doi.org/10.1016/j.cmet.2007.10.008

@article{17278f2ef02544d9a600c09ffac8306c,

title = "Serotonin 2C receptor agonists improve type 2 diabetes via melanocortin-4 receptor signaling pathways",

abstract = "The burden of type 2 diabetes and its associated premature morbidity and mortality is rapidly growing, and the need for novel efficacious treatments is pressing. We report here that serotonin 2C receptor (5-HT2CR) agonists, typically investigated for their anorectic properties, significantly improve glucose tolerance and reduce plasma insulin in murine models of obesity and type 2 diabetes. Importantly, 5-HT2CR agonist-induced improvements in glucose homeostasis occurred at concentrations of agonist that had no effect on ingestive behavior, energy expenditure, locomotor activity, body weight, or fat mass. We determined that this primary effect on glucose homeostasis requires downstream activation of melanocortin-4 receptors (MC4Rs), but not MC3Rs. These findings suggest that pharmacological targeting of 5-HT(2C)Rs may enhance glucose tolerance independently of alterations in body weight and that this may prove an effective and mechanistically novel strategy in the treatment of type 2 diabetes.",

keywords = "central-nervous-system, mice, obesity, organization, expression, neurons, mouse, rat, humdisease, molneuro",

author = "Ligang Zhou and Sutton, {Gregory M.} and Rochford, {Justin J.} and Semple, {Robert K.} and Lam, {Daniel D.} and Oksanen, {Laura J.} and Thornton-Jones, {Zoe D.} and Clifton, {Peter G.} and Chen-Yu Yueh and Evans, {Mark L.} and McCrimmon, {Rory J.} and Elmquist, {Joel K.} and Butler, {Andrew A.} and Heisler, {Lora K.}",

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doi = "10.1016/j.cmet.2007.10.008",

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AU - Zhou, Ligang

AU - Sutton, Gregory M.

AU - Rochford, Justin J.

AU - Semple, Robert K.

AU - Lam, Daniel D.

AU - Oksanen, Laura J.

AU - Thornton-Jones, Zoe D.

AU - Clifton, Peter G.

AU - Yueh, Chen-Yu

AU - Evans, Mark L.

AU - McCrimmon, Rory J.

AU - Elmquist, Joel K.

AU - Butler, Andrew A.

AU - Heisler, Lora K.

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N2 - The burden of type 2 diabetes and its associated premature morbidity and mortality is rapidly growing, and the need for novel efficacious treatments is pressing. We report here that serotonin 2C receptor (5-HT2CR) agonists, typically investigated for their anorectic properties, significantly improve glucose tolerance and reduce plasma insulin in murine models of obesity and type 2 diabetes. Importantly, 5-HT2CR agonist-induced improvements in glucose homeostasis occurred at concentrations of agonist that had no effect on ingestive behavior, energy expenditure, locomotor activity, body weight, or fat mass. We determined that this primary effect on glucose homeostasis requires downstream activation of melanocortin-4 receptors (MC4Rs), but not MC3Rs. These findings suggest that pharmacological targeting of 5-HT(2C)Rs may enhance glucose tolerance independently of alterations in body weight and that this may prove an effective and mechanistically novel strategy in the treatment of type 2 diabetes.

AB - The burden of type 2 diabetes and its associated premature morbidity and mortality is rapidly growing, and the need for novel efficacious treatments is pressing. We report here that serotonin 2C receptor (5-HT2CR) agonists, typically investigated for their anorectic properties, significantly improve glucose tolerance and reduce plasma insulin in murine models of obesity and type 2 diabetes. Importantly, 5-HT2CR agonist-induced improvements in glucose homeostasis occurred at concentrations of agonist that had no effect on ingestive behavior, energy expenditure, locomotor activity, body weight, or fat mass. We determined that this primary effect on glucose homeostasis requires downstream activation of melanocortin-4 receptors (MC4Rs), but not MC3Rs. These findings suggest that pharmacological targeting of 5-HT(2C)Rs may enhance glucose tolerance independently of alterations in body weight and that this may prove an effective and mechanistically novel strategy in the treatment of type 2 diabetes.

KW - central-nervous-system

KW - mice

KW - obesity

KW - organization

KW - expression

KW - neurons

KW - mouse

KW - rat

KW - humdisease

KW - molneuro

U2 - 10.1016/j.cmet.2007.10.008

DO - 10.1016/j.cmet.2007.10.008

M3 - Article

SN - 1550-4131

VL - 6

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EP - 405

JO - Cell Metabolism

JF - Cell Metabolism

IS - 5

ER -

Serotonin 2C receptor agonists improve type 2 diabetes via melanocortin-4 receptor signaling pathways

Abstract

Keywords

UN SDGs

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