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 1

Generation and validation of 2Cflox/Y mice.

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Generation and validation of 2Cflox/Y mice. (A) Strategy used to creat...
(A) Strategy used to create mice in which serotonin 2C receptors (Htr2c [2C]) could be conditionally ablated using cre-lox technology. 2Cflox/Y mice were validated by crossing with mice expressing cre in zona pellicuda (ZP3-cre) cells to produce whole-body Htr2c-null mice (2Cflox/Y × ZP3-cre). (B–D) Predicted decreases in survival as well as increases in body weight and 4- to 5-hour-fasted blood glucose levels in 2Cflox/Y × ZP3-cre mice versus littermate controls (n = 17–20 mice/genotype). Symbols in B are reduced in size to prevent overlap in the control groups. (E–I) Six- to 8-week-old male mice lacking Htr2c in POMC neurons that coexpress the fluorescent reporter tdTomato were functionally validated using treatment with the serotonin 2C receptor agonist mCPP (4 μM) during electrophysiological recordings. n = 5 POMC-cre (controls) and n = 17 2Cflox/Y × POMC-cre (2Cflox × POMC-cre) littermate mice in E–I. Results are shown as the mean ± SEM. *P < 0.05 versus other genotypes assessed using a Student’s t test.