Characterization of human neurons expressing the glucagon-like peptide 1-receptor (GLP1-R)

Lead Research Organisation: University of Cambridge
Department Name: Institute of Metabolic Science

Abstract

Rotation 1 - October - December 2019
Characterization of human neurons expressing the glucagon-like peptide 1-receptor (GLP1-R)

Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M011194/1 01/10/2015 31/03/2024
2292908 Studentship BB/M011194/1 01/10/2019 30/09/2023 Georgina Dowsett
 
Description We identified key cell populations in the mouse hindbrain and their potential roles in food intake control. We made this resource available which will help delineate the mechanisms underlying the effectiveness of current therapeutics for the treatment of obesity.
Exploitation Route We made this resource available which will help delineate the mechanisms underlying the effectiveness of current therapeutics for the treatment of obesity and be useful in identifying new therapeutic targets.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology
 
Title A survey of the mouse hindbrain in the fed and fasted states using single-nucleus RNA sequencing. 
Description OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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. 
Type Of Material Database/Collection of data 
Year Produced 2021 
Provided To Others? Yes  
Impact We report single-nucleus RNA sequencing of 30 neuronal and 11 non-neuronal populations residing within the AP/NTS. We provide extensive profiling of differential gene expression that occurs in response to an overnight fast and identify that oligodendrocytes in fact exhibit the greatest changes in transcriptional expression. We provide detailed profiling of GLP1R, CALCR, GIPR, and GFRAL cells based on their expression of receptors, ion channels, and transporters as well as their neuronal/glial properties, informing future studies that will examine these particular targets. We identify and characterise POMC cells residing within the AP/NTS on the single-cell level. This resource will help delineate the mechanisms underlying these compounds' effectiveness and also prove useful in the continued search for other novel therapeutic targets for obesity. 
URL https://www.repository.cam.ac.uk/handle/1810/321600
 
Description Study on GHSR expression in pancreatic islet cells 
Organisation University of Texas Southwestern Medical Center
Country United States 
Sector Academic/University 
PI Contribution Data analysis for publication
Collaborator Contribution Wrote a publication together (PMID: 34289060)
Impact Publication PMID 34289060
Start Year 2020