Voyias, Philip D. (2015) Regulation of endoplasmic reticulum stress in adipose tissue metabolism. PhD thesis, University of Warwick.

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Abstract

Obesity is the most significant risk factor for developing type II diabetes mellitus (T2DM). Obesity induces adipocyte endoplasmic reticulum (ER) stress, prior to onset of insulin resistance. A pathological inability of white adipose tissue (WAT) to expand to accommodate excess energy is predominantly due to impaired adipogenesis. The research hypothesis was that ER stress in human WAT is important in inducing WAT dysfunction and subsequent insulin resistance and T2DM. The aims of this study were to elucidate interactions of ER stress in human WAT and to characterise the role of ER stress in human adipogenesis. Abdominal SAT biopsies and anthropometry were collected from T2DM subjects before and after bariatric surgery and non-diabetic subjects. Preadipocytes were extracted from human WAT and differentiated into adipocytes. Lipogenesis, lipolysis, glucose uptake, insulin sensitivity, and ER stress and adipogenesis gene and protein expression were assessed in control cells and with ER stress inducers, inhibitors or siRNA. The results of this study found both restrictive and malabsorptive bariatric interventions are effective weight loss interventions for obese T2DM patients and result in significantly improved glucose and insulin levels six months after surgery. WAT health is better following restrictive procedures as shown by lower and better regulation of ER stress markers. Adipogenesis in primary human preadipocytes is influenced by adiposity and WAT depot and the IRE1-XBP1s UPR is essential in human adipogenesis. XBP1s plays a vital role upstream of CEBP and PPAR in human adipogenesis and it is necessary for mediating the action of insulin. Wnt10b plays an inhibitory role in human adipogenesis and acts independently of XBP1s. Collectively these findings suggest that WAT function is key for metabolic health and can be impaired by ER stress; however regulated adipogenesis may serve to improve WAT function and therefore improve metabolic health.

Item Type:	Thesis (PhD)
Subjects:	R Medicine > RC Internal medicine
Library of Congress Subject Headings (LCSH):	Endoplasmic reticulum, Insulin resistance, Adipose tissues
Official Date:	June 2015
Dates:	Date Event June 2015 Submitted
Institution:	University of Warwick
Theses Department:	Warwick Medical School
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Tripathi, Gyanendra
Extent:	264 leaves : charts
Language:	eng

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