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Research Project: MOLECULAR, CELLULAR, AND REGULATORY ASPECTS OF OBESITY DEVELOPMENT IN CHILDREN

Location: Children's Nutrition Research Center

Title: Serotonin 2c receptors in pro-opiomelanocortin neurons regulate energy and glucose homeostasis

Author
item Berglund, Eric - University Of Texas Southwestern Medical Center
item Liu, Chen - University Of Texas Southwestern Medical Center
item Sohn, Jong-woo - University Of Texas Southwestern Medical Center
item Liu, Tiemin - University Of Texas Southwestern Medical Center
item Kim, Mi Hwa - University Of Texas Southwestern Medical Center
item Lee, Charlotte - University Of Texas Southwestern Medical Center
item Vianna, Claudia - University Of Texas Southwestern Medical Center
item Williams, Kevin - University Of Texas Southwestern Medical Center
item Xu, Yong - Children's Nutrition Research Center (CNRC)
item Elmquist, Joel - University Of Texas Southwestern Medical Center

Submitted to: Journal of Clinical Investigation
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/22/2013
Publication Date: 11/1/2013
Citation: Berglund, E.D., Liu, C., Sohn, J., Liu, T., Kim, M., Lee, C.E., Vianna, C.R., Williams, K.W., Xu, Y., Elmquist, J.K. 2013. Serotonin 2c receptors in pro-opiomelanocortin neurons regulate energy and glucose homeostasis. Journal of Clinical Investigation. 123(12):5061-5070.

Interpretive Summary: Obesity and type 2 diabetes are serious global health problems. Interventions that increase the bioavailability of serotonin (5-ht) have been shown to decrease body weight and improve insulin sensitivity, and therefore could be used to treat obesity and type 2 diabetes. However, the mechanisms underlying these beneficial effects remain unknown. We generated a mouse model in which a receptor, called 5-ht2cr, was deleted in a subset of neurons in the brain, called pro-opiomelanocortin (pomc) neurons. We revealed that 5-ht2crs is required to mediate anti-obesity and anti-diabetic effects. These findings highlighted 5-ht2crs as the key regulator of body weight and insulin sensitivity. This 5-ht2cr population could be a potential target for development of novel therapies for obesity and/or diabetes.

Technical 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.