Gαi/o-coupled Htr2c in the paraventricular nucleus of the hypothalamus antagonizes the anorectic effect of serotonin agents
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
Affiliations
Eun-Seon Yoo
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea
Li Li
Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA
Lin Jia
Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX 75080, USA
Caleb C. Lord
Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA
Charlotte E. Lee
Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA
Shari G. Birnbaum
Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX 75390, USA; Peter O’Donnell Jr. Brain Institute, UT Southwestern Medical Center, Dallas, TX 75390, USA
Claudia R. Vianna
Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA
Eric D. Berglund
Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA
Kathryn A. Cunningham
Center for Addiction Research and Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA
Yong Xu
Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
Jong-Woo Sohn
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea; Corresponding author
Chen Liu
Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390, USA; Peter O’Donnell Jr. Brain Institute, UT Southwestern Medical Center, Dallas, TX 75390, USA; Corresponding author
Summary: 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.
