Jackisch, Laura (2019) Molecular mechanisms of adipose tissue mitochondrial (mal)adaptation in obesit. PhD thesis, University of Warwick.

Preview

PDF WRAP_Theses_Jackisch_2019.pdf - Submitted Version - Requires a PDF viewer. Download (248Mb) | Preview

Request Changes to record.

Abstract

Obesity is one of the most serious public health challenges of the 21st century, associated with a wide range of debilitating and life-threatening conditions. The continuing increase in its prevalence underscores the urgent need for novel therapeutic targets, leads and strategies in the treatment of obesity. A metabolic imbalance of nutrient signal input results in adipose tissue dysfunction, and at the centre of this challenging environment lie mitochondria. While there have been studies into the functional changes of mitochondria in obesity, the underlying cellular and molecular mechanisms underlying this phenomenon are mostly unknown, especially in human adipose tissue. As such, this thesis set out to elucidate the impact of obesity on mitochondrial form and function in human adipocytes and adipose tissue. Firstly, gene expression analysis of a number of mitochondrial proteins was carried out in a large cohort of women with di↵ering levels of adiposity (lean, overweight and obese). These findings identified that the onset of obesity is accompanied by alterations of mitochondrial gene expression, worsening with weight gain, contributing to a more indepth understanding of adipose tissue mitochondria. This was revealed by alterations in genes encoding key markers of mitochondrial functions, including oxidative phosphorylation (1.2-fold # COX4I1 ), mitochondria dynamics (1.23-fold " FIS1 and 1.21-fold # MFN2)), and oxidative stress (1.29-fold " SOD2), in response to weight gain. Give the outcomes of these investigations, the molecular basis of mitochondrial maladaptation was explored by investigating the impact of endoplasmic reticulum (ER) stress on mitochondrial function. Based upon these studies, ER stress was identified as a possible attributer to mitochondrial dysfunction in obesity, as demonstrated by altered respiratory function which corresponded with diminished mitochondrial efficiency (1.43-fold #), impaired mitochondrial membrane potential (1.32-fold #) and a fragmented mitochondrial network. Subsequently, GPR120 agonism was probed as a promising therapeutic avenue to relieve the stress of mitochondria during prolonged overfeeding, though these studies did not conclusively determine this receptor to be a potential future target for treating mitochondrial function in white adipocytes. Finally, SGBS spheroids were identified as an exciting new 3D model for future studies into metabolic disease in human adipocytes. Collectively the findings presented in this thesis highlight the close relationship between obesity and mitochondrial dysfunction, which is in part precipitated by ER stress.

Item Type:	Thesis (PhD)
Subjects:	Q Science > QH Natural history > QH426 Genetics Q Science > QP Physiology R Medicine > RC Internal medicine
Library of Congress Subject Headings (LCSH):	Obesity -- Physiological aspects, Adipose tissues, Fat cells, Mitochondrial pathology, Gene expression
Official Date:	August 2019
Dates:	Date Event August 2019 UNSPECIFIED
Institution:	University of Warwick
Theses Department:	Warwick Medical School
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Christian, Mark, (Associate professor)
Sponsors:	Warwick Medical School ; Randeva, Harpal S.
Format of File:	pdf
Extent:	xvi, 245 leaves : illustrations
Language:	eng

Request changes or add full text files to a record

Repository staff actions (login required)

View Item

Downloads