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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #416092
Research Project: Molecular, Cellular, and Regulatory Aspects of Obesity Development

Location: Children's Nutrition Research Center

Title: Lateral septum as a melanocortin downstream site in obesity development

Author
item XU, YUANZHONG - University Of Texas Health Science Center
item JIANG, ZHIYING - University Of Texas Health Science Center
item LI, HONGLI - University Of Texas Health Science Center
item CAI, JING - University Of Texas Health Science Center
item JIANG, YANYAN - University Of Texas Health Science Center
item ORTIZ-GUZMAN, JOSHUS - Baylor College Of Medicine
item XU, YONG - Children'S Nutrition Research Center (CNRC)
item ARENKIEL, BENJAMIN - Children'S Nutrition Research Center (CNRC)
item TONG, QINGCHUN - University Of Texas Health Science Center

Submitted to: Cell Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/26/2023
Publication Date: 5/11/2023
Citation: Xu, Y., Jiang, Z., Li, H., Cai, J., Jiang, Y., Ortiz-Guzman, J., Xu, Y., Arenkiel, B.R., Tong, Q. 2023. Lateral septum as a melanocortin downstream site in obesity development. Cell Reports. 42(5):Article 112502. https://doi.org/10.1016/j.celrep.2023.112502.
DOI: https://doi.org/10.1016/j.celrep.2023.112502

Interpretive Summary: The melanocortin pathway, known for its pivotal role in body-weight regulation, lacks clarity regarding the downstream brain sites responsible for mediating its effects. Through meticulous investigation, this study identified a specific group of paraventricular hypothalamic (PVH) neurons expressing melanocortin receptors 4 (PVHMc4R), which predominantly project to the ventral part of the lateral septum (LSv)—a brain region associated with emotional behaviors. Photostimulation of these PVHMc4R neurons' terminals in the LSv resulted in reduced feeding and aversion, while the absence of Mc4Rs or disruption of glutamate release from LSv-projecting PVH neurons led to obesity. Additionally, interfering with AMPA receptor function in PVH-projected LSv neurons also induced obesity. Notably, chronic inhibition of PVH or PVHMc4R projections to LSv neurons resulted in obesity, accompanied by diminished energy expenditure. This study highlights the significant role of the LSv as a key mediator in transmitting the effects of the melanocortin pathway on body-weight regulation.

Technical 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.