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Depot-specific mechanisms determining human fat distribution

Body fat distribution is a strong determinant of human metabolic health but the mechanisms underpinning regional deposition of white adipose tissue (WAT) remain poorly understood. WAT also exhibits striking depot-specific functional properties. The aim of this project was to investigate the potential role of specific candidate genes implicated in regulating WAT development and/or function in a depot-specific manner. Cartilage oligomeric matrix protein (COMP) is an extracellular matrix protein that is highly differentially expressed between subcutaneous abdominal and gluteal WAT but has primarily been studied in the context of bone biology. WAT COMP expression was found to be significantly up-regulated in obesity; COMP expression in preadipocytes was increased by glucocorticoids; and COMP promoted adipogenesis in (immortalised) subcutaneous abdominal and gluteal preadipocytes. Building on a finding during the COMP study, bone morphogenetic protein (BMP)-2 was identified as another candidate. BMP2 exerts positive adipogenic effects in murine models and a recent genome-wide association study meta-analysis identified a significant association between BMP2 and body fat distribution. BMP2 was found to exert a pro-adipogenic effect specifically in subcutaneous abdominal preadipocytes, with this effect requiring activation of SMAD1/5/8 signalling via type 1 BMP receptors. These data identify BMP2 as a novel depot-specific regulator of human adipogenesis. Particularly lipid-laden cells were formed when conventional adipogenic medium was supplemented with fatty acids; these cells were captured, de-differentiated (DFAT) and expanded to generate immortalised abdominal and gluteal DFAT cells. These DFAT cells exhibit a greatly enhanced adipogenic potential compared to the mixed stromovascular (SVF) population from which they derive and retained an intrinsic memory of their anatomical origin. The use of DFAT cells is likely to represent a valid and enhanced model system to study various depot-specific aspects of WAT biology such as adipogenesis. Overall, the data from this thesis emphasise the striking depot-specific biology exhibited by WAT and provide novel insights into the mechanisms governing the regional distribution of WAT in humans.
Date January 2017
CreatorsDenton, Nathan
ContributorsKarpe, Fredrik ; Pinnick, Katherine
PublisherUniversity of Oxford
Source SetsEthos UK
Detected LanguageEnglish
TypeElectronic Thesis or Dissertation

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