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

Research output: Contribution to journalArticle

151 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 languageEnglish
Pages (from-to)398-405
Number of pages8
JournalCell Metabolism
Volume6
Issue number5
DOIs
Publication statusPublished - 7 Nov 2007

Keywords

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

Cite this

Serotonin 2C receptor agonists improve type 2 diabetes via melanocortin-4 receptor signaling pathways. / Zhou, Ligang; Sutton, Gregory M.; Rochford, Justin J.; Semple, Robert K.; Lam, Daniel D.; Oksanen, Laura J.; Thornton-Jones, Zoe D.; Clifton, Peter G.; Yueh, Chen-Yu; Evans, Mark L.; McCrimmon, Rory J.; Elmquist, Joel K.; Butler, Andrew A.; Heisler, Lora K.

In: Cell Metabolism, Vol. 6, No. 5, 07.11.2007, p. 398-405.

Research output: Contribution to journalArticle

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
Zhou, Ligang ; Sutton, Gregory M. ; Rochford, Justin J. ; Semple, Robert K. ; Lam, Daniel D. ; Oksanen, Laura J. ; Thornton-Jones, Zoe D. ; Clifton, Peter G. ; Yueh, Chen-Yu ; Evans, Mark L. ; McCrimmon, Rory J. ; Elmquist, Joel K. ; Butler, Andrew A. ; Heisler, Lora K. / Serotonin 2C receptor agonists improve type 2 diabetes via melanocortin-4 receptor signaling pathways. In: Cell Metabolism. 2007 ; Vol. 6, No. 5. pp. 398-405.
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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.",
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