Lateral Septum as a Melanocortin Downstream Site in Obesity Development

Authors

Yuanzhong Xu
Zhiying Jiang
Hongli Li
Jing Cai
Yanyan Jiang
Joshua Otiz-Guzman
Yong Xu
Benjamin R Arenkiel
Qingchun Tong

Publication Date

5-30-2023

Journal

Cell Reports

DOI

10.1016/j.celrep.2023.112502

PMID

37171957

PMCID

PMC10317244

PubMedCentral® Posted Date

7-3-2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Humans, Paraventricular Hypothalamic Nucleus, Melanocortins, Obesity, Body Weight, Glutamic Acid

Abstract

The melanocortin pathway is well established to be critical for body-weight regulation in both rodents and humans. Despite extensive studies focusing on this pathway, the downstream brain sites that mediate its action are not clear. Here, we found that, among the known paraventricular hypothalamic (PVH) neuron groups, those expressing melanocortin receptors 4 (PVHMc4R) preferably project to the ventral part of the lateral septum (LSv), a brain region known to be involved in emotional behaviors. Photostimulation of PVHMc4R neuron terminals in the LSv reduces feeding and causes aversion, whereas deletion of Mc4Rs or disruption of glutamate release from LSv-projecting PVH neurons causes obesity. In addition, disruption of AMPA receptor function in PVH-projected LSv neurons causes obesity. Importantly, chronic inhibition of PVH- or PVHMc4R-projected LSv neurons causes obesity associated with reduced energy expenditure. Thus, the LSv functions as an important node in mediating melanocortin action on body-weight regulation.