Obesity and type-2 diabetes are major global health crises. The synthetic retinoid compound 4-hydroxy(phenyl)retinamide (Fenretinide, FEN), has been shown to inhibit adiposity and reverse insulin resistance in pre-clinical studies. Fenretinide acts via several different mechanisms, including induction of retinoid signalling and increased hepatic lipid oxidation to exert its metabolic effects. However, the signalling mechanisms behind these effects have yet to be fully elucidated. A number of approaches were taken in this thesis to investigate the signalling mechanisms of Fenretinide. To characterise the relationship between Fenretinide and leptin signalling, Fenretinide treatment was administered in two different leptin-deficient mouse models. Fenretinide effects on hepatic signalling mechanisms were further characterised by performing global transcriptomics analysis in liver from mice receiving HFD ± Fenretinide. In this analysis, the important metabolic hormone fibroblast growth factor (FGF) 21 was identified as a novel retinoid-dependent target of Fenretinide signalling, which was further characterised in multiple mouse models. Retinoic-acid receptor-specific ChIP-sequencing was performed in order to identify other liver genes that are regulated by Fenretinide via retinoid-dependent signalling mechanisms. This work has shown that the beneficial effects of Fenretinide on adiposity occur via a mechanism independent of that through which Fenretinide mediates effects on glucose homeostasis. Fenretinide effects on insulin sensitivity and glucose homeostasis are most likely mediated via the inhibition of ceramide synthesis in the liver and other metabolically active tissues. This work also shows that Fenretinide can normalise the effects of chronic HFD-feeding by targeting the expression of a set of PPARα-target genes in the liver via a retinoid-dependent signalling mechanism. Overall, the work described in this thesis both uncovers more detail about the signalling mechanisms of Fenretinide and identifies novel target genes that may be exploited for the development of new therapeutics to treat obesity and type 2 diabetes.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:715490 |
| Date | January 2017 |
| Creators | Morrice, Nicola |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=232274 |
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