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

Academic Article
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Overview

authors

  • 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, Andrew
  • Heisler, L. K.

publication date

  • November 2007

journal

  • Cell Metabolism  Journal

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-HT(2C)R) 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-HT(2C)R 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.

subject areas

  • Absorptiometry, Photon
  • Animals
  • Blotting, Western
  • Diabetes Mellitus, Type 2
  • Gene Expression
  • Glucose
  • Glucose Intolerance
  • Glucose Tolerance Test
  • Homeostasis
  • Immunohistochemistry
  • Insulin
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Obese
  • Neurons
  • Piperazines
  • Polymerase Chain Reaction
  • Pro-Opiomelanocortin
  • Receptor, Melanocortin, Type 4
  • Serotonin 5-HT2 Receptor Agonists
  • Serotonin Receptor Agonists
  • Signal Transduction
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Identity

PubMed Central ID

  • PMC2075535

International Standard Serial Number (ISSN)

  • 1550-4131

Digital Object Identifier (DOI)

  • 10.1016/j.cmet.2007.10.008

PubMed ID

  • 17983585
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Additional Document Info

start page

  • 398

end page

  • 405

volume

  • 6

issue

  • 5

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