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Understanding the mechanisms regulating SCFA mediated release of anorectic gut hormones

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Title: Understanding the mechanisms regulating SCFA mediated release of anorectic gut hormones
Authors: Caengprasath, Natarin
Item Type: Thesis or dissertation
Abstract: Obesity is a fast-growing epidemic that poses a major challenge to the public health. There is a current lack of safe and effective anti-obesity treatment options, therefore an improved treatment option is critical. Short chain fatty acids (SCFAs), produced in the colon via fermentation of non-digestible carbohydrates by gut microbiota, activates FFA2 and FFA3, G-protein coupled receptors (GPCRs) that stimulate the release of anorectic gut hormones GLP-1 and PYY. However, the underlying molecular mechanisms stimulating their release are poorly understood. A fundamental mechanism controlling the signalling capacity of GPCRs is via receptor trafficking to diverse cellular compartments such as early endosomes (EE), or very early endosomes (VEE). A subpopulation of VEEs contains the adaptor protein APPL1, essential for driving receptor recycling from the VEE and regulating endosomal G protein signalling. I therefore characterised the signalling pathways exerted by SCFAs in intestinal enteroendocrine cells and colonic organoids and elucidated the trafficking properties of FFA2 that regulate anorectic gut hormone release. In enteroendocrine cells, SCFAs are unable to elicit Gαq/11-signalling but robustly activates Gαi/o signalling which is important for propionate induced GLP-1 secretion. FFA2 undergoes both constitutive and ligand induced internalisation. Following ligand-induced internalisation, FFA2 traffics to the VEE to activate Gαi endosomal signalling that is regulated by APPL1. In addition, by employing high resolution single vesicle imaging, I unveiled propionate-induced FFA2 recycling is APPL1 dependent. I also examined the dependence of receptor internalisation and found that receptor internalisation is critical only for propionate induced- Gαi/o signalling, p38 activation and GLP-1 release, while Gαq/11 signalling occurs from the plasma membrane. Together these findings suggest an important spatial requirement for propionate-mediated activity and uncovers novel mechanisms regulating the release of anorectic gut hormone, GLP-1.
Content Version: Open Access
Issue Date: Jan-2019
Date Awarded: Jun-2019
URI: http://hdl.handle.net/10044/1/75550
DOI: https://doi.org/10.25560/75550
Copyright Statement: Creative Commons Attribution NonCommercial NoDerivatives Licence
Supervisor: Frost, Gary
Hanyaloglu, Aylin
Tate, Edward
Department: Department of Medicine
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Medicine PhD theses