PDF(Pubmed)
Abstract：
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.
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.
摘要：
目的：尽管已知胰高血糖素样肽1（GLP-1）可以调节摄食，促成这一功能的核心机制仍然是神秘的。这里,我们旨在测试背外侧隔(dLS;dLSGLP-1R)中表达GLP-1受体(GLP-1R)的神经元对食物摄入的作用,并确定其与摄食调节的关系.
方法：使用化学遗传学操作，我们评估了Glp1r-ires-Cre小鼠中dLSGLP-1R神经元的激活或抑制如何影响食物摄入。然后，我们使用了通道视紫红质辅助电路映射，化学遗传学，和电生理记录，以确定和评估dLSGLP-1R→LHA预测途径在调节食物摄入中的作用。
结果：对dLSGLP-1R神经元的化学遗传抑制增加了食物摄入。LHA是dLSGLP-1R神经元的主要下游靶标。dLSGLP-1R→LHA投影是GABA能的，和该途径的化学遗传抑制也促进食物摄入。虽然dLSGLP-1R→LHA预测的化学遗传激活会适度降低食物摄入量，LHA中dLSGLP-1R→LHA投射末端的光遗传学刺激迅速抑制了摄食行为。最后,我们证明GLP-1R激动剂，Exendin4增强dLSGLP-1R→LHAGABA释放。
结论：一起，这些结果表明，dLS-GLP-1R神经元和对LHA的抑制途径可以调节摄食行为，这可能是治疗饮食失调或肥胖的潜在治疗靶点。
方法：使用化学遗传学操作，我们评估了Glp1r-ires-Cre小鼠中dLSGLP-1R神经元的激活或抑制如何影响食物摄入。然后，我们使用了通道视紫红质辅助电路映射，化学遗传学，和电生理记录，以确定和评估dLSGLP-1R→LHA预测途径在调节食物摄入中的作用。
结果：对dLSGLP-1R神经元的化学遗传抑制增加了食物摄入。LHA是dLSGLP-1R神经元的主要下游靶标。dLSGLP-1R→LHA投影是GABA能的，和该途径的化学遗传抑制也促进食物摄入。虽然dLSGLP-1R→LHA预测的化学遗传激活会适度降低食物摄入量，LHA中dLSGLP-1R→LHA投射末端的光遗传学刺激迅速抑制了摄食行为。最后,我们证明GLP-1R激动剂，Exendin4增强dLSGLP-1R→LHAGABA释放。
结论：一起，这些结果表明，dLS-GLP-1R神经元和对LHA的抑制途径可以调节摄食行为，这可能是治疗饮食失调或肥胖的潜在治疗靶点。
