Ghrelin system signalling in appetite and reward: in vitro and in vivo perspectives

Howick, Kenneth P.

Ghrelin system signalling in appetite and reward: in vitro and in vivo perspectives

dc.check.embargoformat	Apply the embargo to both hard bound copy and e-thesis (If you have submitted an e-thesis and a hard bound thesis and want to embargo both)	en
dc.check.opt-out	Not applicable	en
dc.check.reason	This thesis is due for publication or the author is actively seeking to publish this material	en
dc.contributor.advisor	Griffin, Brendan T.	en
dc.contributor.advisor	Schellekens, Harriët	en
dc.contributor.author	Howick, Kenneth P.
dc.contributor.funder	FHI 360	en
dc.date.accessioned	2019-06-05T11:52:15Z
dc.date.issued	2018
dc.date.submitted	2018
dc.description.abstract	The regulation of food intake is one of the most intricate internal balances in mammalian behaviour. Dysregulation of the central mechanisms underlying appetite control and metabolism result in both disorders of under- and over-eating. Disorders of appetite result in significant morbidity and mortality, and represent a major unmet clinical need. The endogenous hormone ghrelin and its receptor, the growth hormone secretagogue receptor (GHSR-1a), have long been known as pharmacological targets for appetite-related and metabolic disorders. Nutraceutical and bioactive peptides offer the opportunity to prevent onset and escalation of lifestyle-associated diseases of appetite and metabolism. However, there is a dearth of clinical evidence to justify the development of many bioactives as nutraceuticals. The potential applicability of dairy-derived bioactives in appetite-related disorders is now becoming increasingly apparent. We investigate whether a dairy-derived hydrolysate can increase GHSR-1a signalling in vitro, and whether this can be translated to evidence of effect in vivo in a pre-clinical model (Chapter 2). Subsequently, by leveraging advanced pharmaceutical technology, we develop a gastro-protective and sustained delivery system with a high payload capacity (Chapter 3). Furthermore, ligand-dependent biased signalling, and ligand biodistribution may have important roles to play in increasing efficacy of ghrelin ligands in vivo. Therefore, we investigate whether two synthetic ghrelin ligands, anamorelin and HM01, exert differential effects on the GHSR-1a in vitro (Chapter 4). The divergent effects of these two ligands on appetite and reward-motivated behaviours, as well as effects on central neuronal activation and reward system dopamine (DA) levels will also be investigated with a view to informing strategies to optimize future ghrelin therapies (Chapter 4 and 5). Chapter 2 and 3 provide an effective platform for gastro-protected delivery of bioactive peptides to enable further proof-of-concept studies across the appetite modulation field. Evidence of an orexigenic effect of the bioactive is seen in vivo in a rodent model. The oral delivery system developed served as a clinical formulation platform for proof-of-concept studies in humans to be conducted within the wider Food for Health Ireland research consortium. Chapters 4 and 5 show the importance of biased signalling and biodistribution of ghrelin ligands. Greater maximal food intake is reported by the brain penetrant HM01 vs. the peripherally limited anamorelin. Divergent neuronal activation of the two ligands is also shown in reward processing areas using c-fos immunostaining. Targeting specific downstream signalling pathways will enable the provision of more efficacious appetite modulation therapies, while centrally penetrant ligands will provide further therapeutic avenues through greater reward system activation.	en
dc.description.status	Not peer reviewed	en
dc.description.version	Accepted Version
dc.format.mimetype	application/pdf	en
dc.identifier.citation	Howick, K. P. 2018. Ghrelin system signalling in appetite and reward: in vitro and in vivo perspectives. PhD Thesis, University College Cork.	en
dc.identifier.endpage	314	en
dc.identifier.uri	https://hdl.handle.net/10468/8017
dc.language.iso	en	en
dc.publisher	University College Cork	en
dc.rights	© 2018, Kenneth P. Howick.	en
dc.rights.uri	http://creativecommons.org/licenses/by-nc-nd/3.0/	en
dc.subject	Ghrelin	en
dc.subject	Food intake	en
dc.subject	Reward	en
dc.subject	Bioactive	en
dc.subject	Dairy	en
dc.thesis.opt-out	false
dc.title	Ghrelin system signalling in appetite and reward: in vitro and in vivo perspectives	en
dc.type	Doctoral thesis	en
dc.type.qualificationlevel	Doctoral	en
dc.type.qualificationname	PhD	en
ucc.workflow.supervisor	brendan.griffin@ucc.ie