Gαi/O-Coupled Htr2c in the Paraventricular Nucleus of the Hypothalamus Antagonizes the Anorectic Effect of Serotonin Agents

Authors

Eun-Seon Yoo
Li Li
Lin Jia
Caleb C Lord
Charlotte E Lee
Shari G Birnbaum
Claudia R Vianna
Eric D Berglund
Kathryn A Cunningham
Yong Xu
Jong-Woo Sohn
Chen Liu

Publication Date

11-16-2021

Journal

Cell Reports

DOI

10.1016/j.celrep.2021.109997

PMID

34788630

PMCID

PMC8636014

PubMedCentral® Posted Date

12-1-2021

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Animals, Anorexia, Appetite Depressants, Energy Metabolism, Feeding Behavior, GTP-Binding Protein alpha Subunits, Gi-Go, Hunger, Hypothalamus, Male, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Models, Animal, Neurons, Paraventricular Hypothalamic Nucleus, Potassium, Receptor, Serotonin, 5-HT2C, Serotonin, Serotonin Agents

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 Gαi/o-dependent activation of ATP-sensitive K+ conductance, a mechanism of action not identified previously in the mammalian nervous system.