Alhusaini, S. (Saif) (2011) The role of endoplasmic reticulum in human adipose tissue. PhD thesis, University of Warwick.

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Abstract

Adipose tissue plays a central role in the regulation of metabolic homeostasis. In obesity adipocytes are challenged by many insults: surplus energy, inflammation, insulin resistance and considerable endoplasmic reticulum (ER) stress. ER stress has been casually linked to increased inflammation and insulin resistance. Also, obesity linked type 2 diabetes is associated with hyperglycaemia, lipotoxicity and endotoxemia. Therefore, the aims of this thesis briefly were to 1) characterise human pre-adipocytes during differentiation, as a suitable primary cellular model to examine intracellular pathways, 2) investigate the role of glucose and fatty acids on ER stress pathway; as these primary insults are considered to have clear impact on inflammation, insulin resistance (IR) status and diabetes pathogenesis 3) to examine the role of lipopolysaccharide (LPS), a gut derived bacterial fragment, on ER stress; as LPS is now considered a systemic circulating factor raised in conditions of IR, 4) the role of salicylate, known to have anti-inflammatory properties which may negate or at least attenuate the effects of ER stress. Components of the ER stress pathways were studied in human abdominal subcutaneous (AbSc) adipose tissue (AT) from obese and lean subjects. Following characterisation, culture and differentiation of primary human pre-adipocytes, these adipocytes were treated with lipopolysaccharide (LPS), high glucose (HG), tunicamycin (Tun) and saturated fatty acids (SFA) either alone or in combination with sodium salicylate (Sal). Quantitative RT-PCR, western blotting, adipokine analysis were used to assess expression levels. Markers of ER stress were significantly increased in AbSc AT from subjects with obesity (P<0.001). Differentiated primary human adipocytes treated with LPS, Tun, HG and SFA showed significant activation of p-eIF2α and ATF6 and their downstream targets (P<0.05). This effect was alleviated in the presence of Sal. There was also significant activation of AktSer473 during ER stress (P<0.05). This thesis presents important evidence that firstly, there is increased ER stress in human adipose tissue of obese individuals, secondly, LPS, hyperglycaemia and saturated fatty acids induce significant ER stress in primary human adipocytes and finally that induction is alleviated by salicylate. Taken together these studies highlights that ER stress occurs in human differentiated pre-adipocytes is exacerbated in conditions of high glucose, high saturated fatty acids and LPS, as well as determining that such primary insults can be reduced by salicylates providing initial evidence that therapeutic agents have the potential capacity to alleviate ER stress in human adipose tissue.

Item Type:	Thesis or Dissertation (PhD)
Subjects:	Q Science > QP Physiology
Library of Congress Subject Headings (LCSH):	Endoplasmic reticulum -- Effect of stress on, Adipose tissues, Endotoxins -- Physiological effect, Salicylates -- Physiological effect
Date:	March 2011
Institution:	University of Warwick
Theses Department:	Warwick Medical School
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Tripathi, Gyanendra ; Kumar, Sudhesh
Extent:	xxx, 218 leaves : ill., charts
Language:	eng
URI:	http://wrap.warwick.ac.uk/id/eprint/36759

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