Synergistic effects of the serotonin 2c receptor and leptin on glucose homeostasis
To investigate how serotonin and leptin interact in the regulation of energy balance and glucose homeostasis, we created a genetic mouse model, the OB2C mouse, that lacks both functional leptin and functional serotonin 2C receptor (5HT2CR). These mice showed increased feeding and drinking behavior compared to mice with mutations of only leptin (OB) or the 5HT2CR (2C). They also had an enhanced diabetes phenotype, with elevated fasting glucose and impaired glucose tolerance. This enhanced diabetes develops at an age at which OB2C mice do not differ in body weight from OB mice, suggesting that the enhanced diabetes is not a consequence of increased adiposity. We further demonstrated that a serotonin agonist, fenfluramine, and a 5HT2CR antagonist, SB242084, had acute effects on glucose tolerance in wild-type mice which were blunted in 2C mutant mice, suggesting further body-weight independent effects of the 5HT2CR on glucose homeostasis. These findings may provide important insights into the obesogenic and diabetogenic side effects of serotonergic atypical antipsychotic drugs.