1. Synergistic impairment of glucose homeostasis in ob/ob mice lacking functional serotonin 2C receptors.
- Author
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Wade JM, Juneja P, MacKay AW, Graham J, Havel PJ, Tecott LH, and Goulding EH
- Subjects
- Animals, Diabetes Mellitus metabolism, Diabetes Mellitus pathology, Diabetes Mellitus physiopathology, Disease Models, Animal, Drinking physiology, Eating physiology, Female, Fenfluramine pharmacology, Islets of Langerhans pathology, Islets of Langerhans physiopathology, Leptin genetics, Male, Mice, Mice, Obese, Obesity pathology, Obesity physiopathology, Receptor, Serotonin, 5-HT2C genetics, Serotonin metabolism, Serotonin Agents pharmacology, Glucose metabolism, Homeostasis physiology, Leptin metabolism, Obesity metabolism, Receptor, Serotonin, 5-HT2C metabolism
- Abstract
To investigate how serotonin and leptin interact in the regulation of energy balance and glucose homeostasis, we generated a genetic mouse model, the OB2C mouse, which lacks functional serotonin 2C receptors and the adipocyte hormone leptin. The OB2C mice exhibited a dramatic diabetes phenotype, evidenced by a synergistic increase in serum glucose levels and water intake. The severity of the animals' diabetes phenotype would not have been predicted from the phenotypic characterization of mice bearing mutations of either the leptin (OB mutant mice) or the serotonin 2C receptor gene (2C mutant mice). The synergistic impairment in glucose homeostasis developed at an age when OB2C mice did not differ in body weight from OB mice, suggesting that this impairment was not an indirect consequence of increased adiposity. We also demonstrated that the improvement in glucose tolerance in wild-type mice treated with the serotonin releaser and reuptake inhibitor fenfluramine was blunted in 2C mutant mice. These pharmacological and genetic findings provide evidence that the serotonin 2C receptor has direct effects on glucose homeostasis.
- Published
- 2008
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