Serotonin 2C receptors in pro-opiomelanocortin neurons regulate energy and glucose homeostasis
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
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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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 5

Impaired glucoregulation in mice lacking serotonin 2C receptors (Htr2c) specifically in POMC neurons.

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Impaired glucoregulation in mice lacking serotonin 2C receptors (Htr2c) ...
(A–C) Blood glucose, plasma insulin, and plasma glucagon in chow- and HFHS-fed conditions respectively; n = 9–12 mice per genotype per diet. Ad libitum (Ad lib) blood glucose values in A represent measurements taken at 0700 h. Postabsorptive values represent a 4- to 5-hour morning fast, and 12- and 24-hour fasts denote removal of food at 2100 h or 1800 h, respectively, the night before in A–C. HFHS values in A–C are from 4- to 5-hour-fasted mice. (D and E) Basal and clamp plasma insulin and glucagon levels in 4- to 5-hour morning-fasted (0800–0900 h to 1300 h; n = 7–8 mice per genotype), chronically catheterized, conscious mice during a 120-minute hyperinsulinemic-euglycemic (4 mU/kg/minute, 150 mg/dl, respectively) clamp. (F) Exogenous GIR needed to clamp blood glucose. (G and H) Endogenous rates of endo Ra and Rd were determined using a constant infusion of [3-3H]glucose and steady-state calculations. (I–M) Similar clamp parameters for 12-hour overnight-fasted (2100 h–0900 h; n = 7–8 mice per genotype). Blood was taken from the cut tail, and results are shown as the mean ± SEM. *P < 0.05 versus other genotypes, #P < 0.05 versus ad libitum and/or 5-hour-fasted chow-fed conditions within a genotype, and †P < 0.05 versus basal values during hyperinsulinemic-euglycemic clamp using Student’s t tests.