位于后脑的后区域(AP)和孤束核(NTS)是感知和整合外周营养信号并因此调节进食行为的关键核。虽然单细胞转录组学已在小鼠中用于揭示下丘脑关键群体的基因表达谱和异质性,尚未在后脑进行类似的深入研究.
使用单核RNA测序,我们提供了在进食和禁食状态下小鼠的AP和NTS内的16,034个细胞的详细调查。
其中,8,910个神经元分为30个簇,其中4,289来自随意喂食的小鼠,4,621来自禁食过夜的小鼠。总共有7124个细胞核来自非神经元细胞,包括少突胶质细胞,星形胶质细胞,和小胶质细胞.有趣的是,我们发现少突胶质细胞群体对禁食过夜在转录上特别敏感.受体GLP1R,GIPR,GFRAL,和CALCR,它绑定GLP1,GIP,GDF15和胰淀素,分别,都在后脑中表达,并且是抗肥胖疗法的主要靶标。我们对这四个种群的转录组进行了表征,并表明它们的基因表达谱不会因过夜禁食而发生显着改变。值得注意的是,我们发现大约一半表达GIPR的细胞是少突胶质细胞.此外,我们描述了后脑中表达POMC的神经元,并证明84%的POMC神经元表达PCSK1,PSCK2或两者,这意味着黑皮质素肽可能是由这些神经元产生的。
我们提供了关键抗肥胖药物的AP和NTS细胞表达受体的详细单细胞水平表征,这些药物已被批准用于人体或临床试验。该资源将有助于描绘这些化合物有效性的潜在机制,并且还证明可用于继续寻找其他新的治疗靶标。
The area postrema (AP) and nucleus tractus solitarius (NTS) located in the hindbrain are key nuclei that sense and integrate peripheral nutritional signals and consequently regulate feeding behaviour. While single-cell transcriptomics have been used in mice to reveal the gene expression profile and heterogeneity of key hypothalamic populations, similar in-depth studies have not yet been performed in the hindbrain.
Using single-nucleus RNA sequencing, we provide a detailed survey of 16,034 cells within the AP and NTS of mice in the fed and fasted states.
Of these, 8,910 were neurons that group into 30 clusters, with 4,289 from mice fed ad libitum and 4,621 from overnight fasted mice. A total of 7,124 nuclei were from non-neuronal cells, including oligodendrocytes, astrocytes, and microglia. Interestingly, we identified that the oligodendrocyte population was particularly transcriptionally sensitive to an overnight fast. The receptors GLP1R, GIPR, GFRAL, and CALCR, which bind GLP1, GIP, GDF15, and amylin, respectively, are all expressed in the hindbrain and are major targets for anti-obesity therapeutics. We characterise the transcriptomes of these four populations and show that their gene expression profiles are not dramatically altered by an overnight fast. Notably, we find that roughly half of cells that express GIPR are oligodendrocytes. Additionally, we profile POMC-expressing neurons within the hindbrain and demonstrate that 84% of POMC neurons express either PCSK1, PSCK2, or both, implying that melanocortin peptides are likely produced by these neurons.
We provide a detailed single-cell level characterisation of AP and NTS cells expressing receptors for key anti-obesity drugs that are either already approved for human use or in clinical trials. This resource will help delineate the mechanisms underlying the effectiveness of these compounds and also prove useful in the continued search for other novel therapeutic targets.