Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 123, Issue 12, Pages 5061-5070Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI70338
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Funding
- NIH [NIDDK F32 DK092083, NIDDK R01 DK093587, R00 DK085330, R01 DK088423, R37 DK053301, DK 059637]
- Hilda and Preston Davis Foundation
- American Diabetes Association [7-11-MN-16, 1-11-BS-180]
- Klarman Family Foundation
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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 tamoydfen-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.
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