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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #395809
Research Project: Molecular, Cellular, and Regulatory Aspects of Obesity Development

Location: Children's Nutrition Research Center

Title: Galphai/o coupled Htr2c in the paraventricular nucleus of the hypothalamus antagonizes the anorectic effect of serotonin agents

Author
item YOO, EUN-SEON - Korea Institute Of Science And Technology
item LI, LI - University Of Texas Southwestern Medical Center
item JIA, LIN - University Of Texas Southwestern Medical Center
item LORD, CALEB - University Of Texas Southwestern Medical Center
item LEE, CHARLOTTE - University Of Texas Southwestern Medical Center
item BIRNBAUM, SHARI - University Of Texas Southwestern Medical Center
item VIANNA, CLAUDIA - University Of Texas Southwestern Medical Center
item BERGLUND, ERIC - University Of Texas Southwestern Medical Center
item CUNNINGHAM, KATHRYN - University Of Texas Medical Branch
item XU, YONG - Children'S Nutrition Research Center (CNRC)
item SOHN, JONG-WOO - Korea Institute Of Science And Technology
item LIU, CHEN - University Of Texas Southwestern Medical Center

Submitted to: Cell Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/21/2021
Publication Date: 11/16/2021
Citation: Yoo, E., Li, L., Jia, L., Lord, C., Lee, C., Birnbaum, S., Vianna, C., Berglund, E., Cunningham, K., Xu, Y., Sohn, J., Liu, C. 2021. Galphai/o coupled Htr2c in the paraventricular nucleus of the hypothalamus antagonizes the anorectic effect of serotonin agents. Cell Reports. 37:109997. https://doi.org/10.1016/j.celrep.2021.109997.
DOI: https://doi.org/10.1016/j.celrep.2021.109997

Interpretive Summary: The brain serotonin system is a target for weight loss therapies. Previously, we expected the activation of serotonin 2c receptors (Htr2cs) to be the driving force behind the therapeutic effects. We studied this by creating mouse genetic models in which this receptor can be deleted. Unexpectedly, our findings showed that Htr2c can both inhibit and promote food intake depending on where the receptor is located in the brain. These findings may help explain why drugs targeting the Htr2c have only modest effects on obesity.

Technical Abstract: The anorexigenic effect of serotonergic compounds has largely been attributed to activation of serotonin 2C receptors (Htr2cs). Using mouse genetic models in which Htr2c can be selectively deleted or restored (in Htr2c-null mice), we investigate the role of Htr2c in forebrain Sim1 neurons. Unexpectedly, we find that Htr2c acts in these neurons to promote food intake and counteract the anorectic effect of serotonergic appetite suppressants. Furthermore, Htr2c marks a subset of Sim1 neurons in the paraventricular nucleus of the hypothalamus (PVH). Chemogenetic activation of these neurons in adult mice suppresses hunger, whereas their silencing promotes feeding. In support of an orexigenic role of PVH Htr2c, whole-cell patch-clamp experiments demonstrate that activation of Htr2c inhibits PVH neurons. Intriguingly, this inhibition is due to Galphai/0-dependent activation of ATP-sensitive K+ conductance, a mechanism of action not identified previously in the mammalian nervous system.