Serotonin 2C receptors in pro-opiomelanocortin neurons regulate energy and glucose homeostasis
Eric D. Berglund, … , Yong Xu, Joel K. Elmquist
Eric D. Berglund, … , Yong Xu, Joel K. Elmquist
Published November 1, 2013
Citation Information: J Clin Invest. 2013;123(12):5061-5070. https://doi.org/10.1172/JCI70338.
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Research Article Metabolism

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

Abstract

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.

Authors

Eric D. Berglund, Chen Liu, Jong-Woo Sohn, Tiemin Liu, Mi Hwa Kim, Charlotte E. Lee, Claudia R. Vianna, Kevin W. Williams, Yong Xu, Joel K. Elmquist

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Figure 3

Mice lacking Htr2c in POMC neurons and chronically fed an HFHS diet exhibit obesity and altered energy balance.

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Mice lacking Htr2c in POMC neurons and chronically fed an HFHS diet exhi...
(A–E) Body weight, food intake, VO2, VCO2, and physical activity over a 1-week period in metabolic cages of 20-week-old male mice fed an HFHS diet for 12 weeks (n = 6–9 mice per genotype). Control genotypes (WT, POMC-cre, and 2Cflox/Y littermates) are combined to improve clarity in C (no differences exist between these groups). Results are shown as the mean ± SEM. *P < 0.05 assessed using Student’s t-tests or ANOVA.