Dorsolateral septum GLP-1R neurons regulate feeding via lateral hypothalamic projections

TY - JOUR

T1 - Dorsolateral septum GLP-1R neurons regulate feeding via lateral hypothalamic projections

AU - Lu, Yi

AU - Wang, Le

AU - Luo, Fang

AU - Savani, Rohan

AU - Rossi, Mark A.

AU - Pang, Zhiping P.

N1 - Publisher Copyright: © 2024 The Authors

PY - 2024/7

Y1 - 2024/7

N2 - Objective: Although glucagon-like peptide 1 (GLP-1) is known to regulate feeding, the central mechanisms contributing to this function remain enigmatic. Here, we aim to test the role of neurons expressing GLP-1 receptors (GLP-1R) in the dorsolateral septum (dLS; dLSGLP−1R) that project to the lateral hypothalamic area (LHA) on food intake and determine the relationship with feeding regulation. Methods: Using chemogenetic manipulations, we assessed how activation or inhibition of dLSGLP−1R neurons affected food intake in Glp1r-ires-Cre mice. Then, we used channelrhodopsin-assisted circuit mapping, chemogenetics, and electrophysiological recordings to identify and assess the role of the pathway from dLSGLP−1R →LHA projections in regulating food intake. Results: Chemogenetic inhibition of dLSGLP−1R neurons increases food intake. LHA is a major downstream target of dLSGLP−1R neurons. The dLSGLP−1R→LHA projections are GABAergic, and chemogenetic inhibition of this pathway also promotes food intake. While chemogenetic activation of dLSGLP−1R→LHA projections modestly decreases food intake, optogenetic stimulation of the dLSGLP−1R→LHA projection terminals in the LHA rapidly suppresses feeding behavior. Finally, we demonstrate that the GLP-1R agonist, Exendin 4 enhances dLSGLP−1R →LHA GABA release. Conclusions: Together, these results demonstrate that dLS-GLP-1R neurons and the inhibitory pathway to LHA can regulate feeding behavior, which might serve as a potential therapeutic target for the treatment of eating disorders or obesity.

AB - Objective: Although glucagon-like peptide 1 (GLP-1) is known to regulate feeding, the central mechanisms contributing to this function remain enigmatic. Here, we aim to test the role of neurons expressing GLP-1 receptors (GLP-1R) in the dorsolateral septum (dLS; dLSGLP−1R) that project to the lateral hypothalamic area (LHA) on food intake and determine the relationship with feeding regulation. Methods: Using chemogenetic manipulations, we assessed how activation or inhibition of dLSGLP−1R neurons affected food intake in Glp1r-ires-Cre mice. Then, we used channelrhodopsin-assisted circuit mapping, chemogenetics, and electrophysiological recordings to identify and assess the role of the pathway from dLSGLP−1R →LHA projections in regulating food intake. Results: Chemogenetic inhibition of dLSGLP−1R neurons increases food intake. LHA is a major downstream target of dLSGLP−1R neurons. The dLSGLP−1R→LHA projections are GABAergic, and chemogenetic inhibition of this pathway also promotes food intake. While chemogenetic activation of dLSGLP−1R→LHA projections modestly decreases food intake, optogenetic stimulation of the dLSGLP−1R→LHA projection terminals in the LHA rapidly suppresses feeding behavior. Finally, we demonstrate that the GLP-1R agonist, Exendin 4 enhances dLSGLP−1R →LHA GABA release. Conclusions: Together, these results demonstrate that dLS-GLP-1R neurons and the inhibitory pathway to LHA can regulate feeding behavior, which might serve as a potential therapeutic target for the treatment of eating disorders or obesity.

KW - Feeding

KW - GLP-1

KW - Hypothalamus

KW - Obesity

KW - Septum

UR - http://www.scopus.com/inward/record.url?scp=85193826522&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85193826522&partnerID=8YFLogxK

U2 - 10.1016/j.molmet.2024.101960

DO - 10.1016/j.molmet.2024.101960

M3 - Article

C2 - 38763494

SN - 2212-8778

VL - 85

JO - Molecular Metabolism

JF - Molecular Metabolism

M1 - 101960

ER -