Investigating the Potential of Novel Helminth-derived Peptides as Therapeutics for Obesity Related Pathologies

Rennie, Claire

Investigating the Potential of Novel Helminth-derived Peptides as Therapeutics for Obesity Related Pathologies

Rennie, Claire

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Publication Type:: Thesis
Issue Date:: 2022

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Field	Value	Language
dc.contributor.author	Rennie, Claire
dc.date.accessioned	2022-06-22T01:47:14Z
dc.date.available	2022-06-22T01:47:14Z
dc.date.issued	2022
dc.identifier.uri	http://hdl.handle.net/10453/158308
dc.description	University of Technology Sydney. Faculty of Science.	en_US.UTF-8
dc.description.abstract	Obesity and obesity-related diseases are increasing in prevalence to the point that it is considered endemic. An inflammatory state caused by overnutrition can lead to the development of insulin resistance, both of which contribute to the development of hepatic steatosis. There are currently no pharmacological treatments that resolve the chronic inflammation underlying the multiple pathologies arising as a result of obesity. However, parasitic worms (helminths) may hold the answer. Due to their ability to potently modulate the inflammatory response of their mammalian hosts, live infection with helminth parasites has been proposed as a potential therapeutic strategy to combat insulin resistance. To test this hypothesis a meta-analysis and systematic review was performed (Chapter 2). The result of this analysis indicated that infection in general improved metabolic outcomes. While the analysis of endemic infection presented here suggests that active infection with Schistosoma mansoni may provide the most beneficial effect, further investigation is required to definitively conclude whether specific helminths mediate a more potent protective effect against metabolic diseases than others. The pathological risks associated with live helminth infection preclude the clinical application of this approach. Rather, the use of the immune modulating molecules secreted by these parasites hold greater potential for therapeutic development. Accordingly, this project next evaluated the ability of two helminth-derived peptides for their potential to modulate inflammation associated with diet-induced obesity and non-alcoholic fatty liver disease. The results from these studies (Chapters 4 and 5) demonstrated that Fasciola hepatica FhHDM-1, and Schistosoma mansoni SmHDM-2, resolved hepatic inflammation. In addition, FhHDM-1 consistently reduced hepatic steatosis, while SmHDM-2 reduced hyperinsulinemia. These studies discovered a previously undescribed mechanism of action for helminth proteins. Treatment with both HDM peptides restored levels of NAD+ resulting in activation of the NAD+/SIRT pathway and an associated modulation of inflammation and lipogenesis. Based on this outcome, and with consideration for an identified role for NAD+ in the development of neurodegeneration, the impact of the helminth-derived peptides in a murine model of diet-induced neurodegeneration was examined (Chapter 6). Treatment of mice with both FhHDM-1 and SmHDM-2 improved the behaviour of obese mice, reducing depression- and anxiety-like behaviour; an outcome that has never previously been described for a parasite–derived molecule. This study has significantly advanced understanding of the mechanism of action, and the biological effect of the HDM peptides, and as a result has made meaningful progress towards the possible translation of helminth-derived therapies for obesity-induced pathologies.	en_US.UTF-8
dc.format	Thesis (PhD)
dc.language.iso	en_US	en_US.UTF-8
dc.relation	https://opus.lib.uts.edu.au/bitstream/10453/158308/2/02whole.pdf
dc.rights	info:eu-repo/semantics/openAccess
dc.rights	The author owns the copyright in this thesis including all reproduction and reuse rights for the work. The work may not be altered without the permission of the copyright owner. Attribution is essential when quoting or paraphrasing from this thesis.
dc.rights	au.edu.uts.lib/ppc
dc.rights	© 2022 Claire Rennie
dc.title	Investigating the Potential of Novel Helminth-derived Peptides as Therapeutics for Obesity Related Pathologies	en_US.UTF-8
dc.type	Thesis
utslib.copyright.status	open_access	*
utslib.copyright.embargo	2024-02-10T00:00:00+1000

Abstract:

Obesity and obesity-related diseases are increasing in prevalence to the point that it is considered endemic. An inflammatory state caused by overnutrition can lead to the development of insulin resistance, both of which contribute to the development of hepatic steatosis. There are currently no pharmacological treatments that resolve the chronic inflammation underlying the multiple pathologies arising as a result of obesity. However, parasitic worms (helminths) may hold the answer. Due to their ability to potently modulate the inflammatory response of their mammalian hosts, live infection with helminth parasites has been proposed as a potential therapeutic strategy to combat insulin resistance. To test this hypothesis a meta-analysis and systematic review was performed (Chapter 2). The result of this analysis indicated that infection in general improved metabolic outcomes. While the analysis of endemic infection presented here suggests that active infection with Schistosoma mansoni may provide the most beneficial effect, further investigation is required to definitively conclude whether specific helminths mediate a more potent protective effect against metabolic diseases than others. The pathological risks associated with live helminth infection preclude the clinical application of this approach. Rather, the use of the immune modulating molecules secreted by these parasites hold greater potential for therapeutic development. Accordingly, this project next evaluated the ability of two helminth-derived peptides for their potential to modulate inflammation associated with diet-induced obesity and non-alcoholic fatty liver disease. The results from these studies (Chapters 4 and 5) demonstrated that Fasciola hepatica FhHDM-1, and Schistosoma mansoni SmHDM-2, resolved hepatic inflammation. In addition, FhHDM-1 consistently reduced hepatic steatosis, while SmHDM-2 reduced hyperinsulinemia. These studies discovered a previously undescribed mechanism of action for helminth proteins. Treatment with both HDM peptides restored levels of NAD+ resulting in activation of the NAD+/SIRT pathway and an associated modulation of inflammation and lipogenesis. Based on this outcome, and with consideration for an identified role for NAD+ in the development of neurodegeneration, the impact of the helminth-derived peptides in a murine model of diet-induced neurodegeneration was examined (Chapter 6). Treatment of mice with both FhHDM-1 and SmHDM-2 improved the behaviour of obese mice, reducing depression- and anxiety-like behaviour; an outcome that has never previously been described for a parasite–derived molecule. This study has significantly advanced understanding of the mechanism of action, and the biological effect of the HDM peptides, and as a result has made meaningful progress towards the possible translation of helminth-derived therapies for obesity-induced pathologies.

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