de Barra, Conor (2024) Defining the Impact of Obesity and Obesity-Targeted Therapies on Natural Killer Cell Metabolism and Function. PhD thesis, National University of Ireland Maynooth.

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Abstract

Obesity is a chronic progressive disease, which is strongly linked to numerous co-morbid conditions, and thus is a major global healthcare concern. A major mechanism via which obesity drives the development and/or progression of co-morbid disease is via immune dysregulation. These dysregulations can both weaken the immune system, exposing people with obesity (PWO) to increased rates of viral infections and various cancers but can also drive chronic inflammation, a major contributor to chronic pathologies. Natural Killer (NK) cells are an important subset of immune cells, with a critical role in protection from viral infection and cancer. NK cells are significantly impacted by obesity, with reduced numbers, defective metabolism, and reduced function reported in PWO. In this thesis, by describing the function and metabolism of NK cells from people without obesity I outline some of the deficiencies of NK cells from PWO, in particular focusing on the importance of iron for optimal NK cell function and investigate strategies for restoring NK cell immunity in PWO. Paper I of this thesis reviews our current understating of NK cell function and metabolism and collates the available information on how obesity affects NK cells. Our group and others report that obesity is linked to lower numbers of peripheral NK cells that have a defective metabolism which leads to a reduced ability to carry out their core function as cytokine producing cells and cytotoxic cells. There are some indications that various weight loss therapies and aids such as diet advice, exercise and bariatric surgery can help remedy some of the effects of obesity on NK cells and this is explored and discussed in Paper I. Following from this review, in Paper II we examine the importance of iron for human NK cell biology. We find that iron is crucial for mitochondrial health in human NK cells, which in turn means iron is critical for NK cell cytokine production and de novo protein synthesis. As iron deficiency is a common comorbidity with obesity, we examined the effect that low circulating iron has on NK cells. We demonstrate that PWO who have low serum iron have more dysfunctional NK cells, in comparison to both healthy controls and PWO who had normal serum iron levels. This paper not only highlights the key role iron plays for NK cell biology but highlights that obesity-related iron deficiency may, in part, underpin the reported defects in NK cells in the setting of obesity. Finally, Paper III continues to describe the effect of obesity on NK cell metabolism and function. In addition to functioning mitochondria, NK cells require amino acids to stabilise mTOR which is a key driver of increased metabolic activity for activated NK cells, in particular an increased dependence on glycolysis. We show that NK cells from PWO have lower levels of a key amino acid transporter and metabolic enzymes that are required for optimal NK cell metabolism and function. This translates to a reduced capacity to produce cytokines such as IFN-γ and kill target cells in comparison to healthy controls. However, we show for the first time that after six months of GLP-1 analogue therapy, an approved for weight loss therapeutic, NK cell metabolism and function is significantly improved in PWO, independent of weight loss. Collectively, this thesis aims to expand on our current understanding of human NK cell biology, how obesity impact NK cells and explores approaches to restore NK cell immunity in PWO.

Item Type:	Thesis (PhD)
Keywords:	Impact; Obesity; Obesity-Targeted Therapies; Natural Killer Cell Metabolism; Function;
Academic Unit:	Faculty of Science and Engineering > Biology
Item ID:	18883
Depositing User:	IR eTheses
Date Deposited:	13 Sep 2024 14:11
URI:
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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