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 have shown that serotonin 2C receptor agonists, typically investigated for their anorectic properties, significantly improve glucose and insulin tolerance in murine models of obesity and type 2 diabetes. Importantly, these improvements in glucose homeostasis occurred at concentrations of agonist which had no effect on ingestive behavior, VO2, locomotor activity, body weight, or fat mass. We determined that this primary effect on glucose homeostasis requires downstream activation of central melanocortin-4 receptors (MC4Rs), but not MC3Rs, and is associated with MC4R-mediated stimulation of sympathetic preganglionic neurons in the spinal cord, increased insulin signaling in liver and skeletal muscle, and inhibition of heptatic gluconeogenesis at the transciptional level. 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.
University of Oxford (2008) Proc Physiol Soc 12, C8 and PC18
Oral Communications: Serotonin 2C receptor agonists improve type 2 diabetes via central MC4R signaling pathways
L. Zhou2, G. M. Sutton3, J. J. Rochford4, R. K. Semple4, D. Lam1,4, L. J. Oksanen5, Z. D. Thornton-Jones6, P. G. Clifton6, C. Yueh4, M. L. Evans4, R. J. McCrimmon2, J. K. Elmquist7, A. A. Butler3, L. K. Heisler1,4
1. Pharmacology, University of Cambridge, Cambridge, United Kingdom. 2. Internal Medicine, Yale Univeristy, New Haven, Connecticut, USA. 3. Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana, USA. 4. Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom. 5. Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. 6. Psychology, University of Sussex, Brighton, United Kingdom. 7. Internal Medicine, University of Texas Southwestern Medical Centre, Dallas, Texas, USA.
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Where applicable, experiments conform with Society ethical requirements.