A Novel Mechanism for Regulating Hepatic Glycogen Synthesis Involving Serotonin and Cyclin-Dependent Kinase-5
- Susan J. Tudhope1,
- Chung-Chi Wang1,
- John L. Petrie1,
- Lloyd Potts1,
- Fiona Malcomson1,
- Julius Kieswich2,
- Muhammad M. Yaqoob2,
- Catherine Arden1,
- Laura J. Hampson1 and
- Loranne Agius1⇓
- 1Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne, U.K.
- 2Centre for Translational Medicine and Therapeutics, William Harvey Research Institute, Queen Mary University of London, London, U.K.
- Corresponding author: Loranne Agius, .
S.J.T. and C.-C.W. contributed equally to this study.
Hepatic autonomic nerves regulate postprandial hepatic glucose uptake, but the signaling pathways remain unknown. We tested the hypothesis that serotonin (5-hydroxytryptamine [5-HT]) exerts stimulatory and inhibitory effects on hepatic glucose disposal. Ligands of diverse 5-HT receptors were used to identify signaling pathway(s) regulating glucose metabolism in hepatocytes. 5-HT had stimulatory and inhibitory effects on glycogen synthesis in hepatocytes mediated by 5-HT1/2A and 5-HT2B receptors, respectively. Agonists of 5-HT1/2A receptors lowered blood glucose and increased hepatic glycogen after oral glucose loading and also stimulated glycogen synthesis in freshly isolated hepatocytes with greater efficacy than 5-HT. This effect was blocked by olanzapine, an antagonist of 5-HT1/2A receptors. It was mediated by activation of phosphorylase phosphatase, inactivation of glycogen phosphorylase, and activation of glycogen synthase. Unlike insulin action, it was not associated with stimulation of glycolysis and was counteracted by cyclin-dependent kinase (cdk) inhibitors. A role for cdk5 was supported by adaptive changes in the coactivator protein p35 and by elevated glycogen synthesis during overexpression of p35/cdk5. These results support a novel mechanism for serotonin stimulation of hepatic glycogenesis involving cdk5. The opposing effects of serotonin, mediated by distinct 5-HT receptors, could explain why drugs targeting serotonin function can cause either diabetes or hypoglycemia in humans.
- Received June 22, 2011.
- Accepted September 30, 2011.
- © 2012 by the American Diabetes Association.
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