Serotonin 2C receptors in pro-opiomelanocortin neurons regulate energy and glucose homeostasis.

Berglund ED, Liu C, Sohn JW, Liu T, Kim MH, Lee CE, Vianna CR, Williams KW, Xu Y, Elmquist JK
J Clin Invest. 2013 123 (12): 5061-70

PMID: 24177424 · PMCID: PMC3859401 · DOI:10.1172/JCI70338

Energy and glucose homeostasis are regulated by central serotonin 2C receptors. These receptors are attractive pharmacological targets for the treatment of obesity; however, the identity of the serotonin 2C receptor-expressing neurons that mediate the effects of serotonin and serotonin 2C receptor agonists on energy and glucose homeostasis are unknown. Here, we show that mice lacking serotonin 2C receptors (Htr2c) specifically in pro-opiomelanocortin (POMC) neurons had normal body weight but developed glucoregulatory defects including hyperinsulinemia, hyperglucagonemia, hyperglycemia, and insulin resistance. Moreover, these mice did not show anorectic responses to serotonergic agents that suppress appetite and developed hyperphagia and obesity when they were fed a high-fat/high-sugar diet. A requirement of serotonin 2C receptors in POMC neurons for the maintenance of normal energy and glucose homeostasis was further demonstrated when Htr2c loss was induced in POMC neurons in adult mice using a tamoxifen-inducible POMC-cre system. These data demonstrate that serotonin 2C receptor-expressing POMC neurons are required to control energy and glucose homeostasis and implicate POMC neurons as the target for the effect of serotonin 2C receptor agonists on weight-loss induction and improved glycemic control.

MeSH Terms (28)

Animals Appetite Depressants Body Weight Dietary Fats Dietary Sucrose Drug Resistance Energy Metabolism Feeding Behavior Female Glucagon Glucose Homeostasis Hyperglycemia Hyperinsulinism Hyperphagia Insulin Insulin Resistance Insulin Secretion Male Mice Mice, Knockout Neurons Obesity Pro-Opiomelanocortin Receptor, Serotonin, 5-HT2C Recombinant Fusion Proteins Serotonin Serotonin Receptor Agonists

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