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 (Lead / Corresponding author), Andrew A. Butler (Lead / Corresponding author), Lora K. Heisler (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    176 Citations (Scopus)


    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-HT2CRs 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
    Issue number5
    Publication statusPublished - 7 Nov 2007


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