The role of metalloproteinases and their tissue inhibitors in adipose tissue remodelling and metabolic risk

French, Matthew (2017) The role of metalloproteinases and their tissue inhibitors in adipose tissue remodelling and metabolic risk. Doctoral thesis, University of East Anglia.

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Abstract

Metabolically unhealthy obesity (MUO) is associated with insulin resistance. In MUO, adipose tissue (AT) demonstrates features suggestive of dysfunctional remodelling, including adipocyte hypertrophy, ectopic lipid deposition and AT inflammation. Metalloproteinases (MPs) and their tissue inhibitors (TIMPs) have been implicated in AT remodelling, but their functions therein remain unclear. My investigations have identified an association between subcutaneous adipose tissue (SAT) Timp3 expression and adipocyte size. In order to address potential roles for TIMP-3 in MUO I have investigated its role in regulating shedding of the adipogenic regulator Dlk-1 and cytokine receptors in cultured human preadipocytes.

39 female subjects of a wide range of Body Mass Index (BMI) were recruited to a clinical study. SAT Timp3 expression correlated with SAT adipocyte area (r = 0.429, p = 0.041). In vitro, induction of preadipocyte differentiation significantly reduced Timp3 mRNA levels by 75%, while Tumour Necrosis Factor (TNF)-α reduced Timp3 mRNA levels by 66% (both n=3, p<0.0001). Increased shedding of both Dlk-1 and soluble TNF receptor (sTNFR) -1 by preadipocytes was observed in response to TNF-α treatment or by overexpression of adenovirally-delivered TIMP-3.

MPs and TIMPs regulate adipose tissue remodelling. TIMP-3 emerges as a novel node integrating inflammatory signals with networks controlling adipose remodelling. I hypothesise that dynamic modulation of TIMP-3 expression is essential for healthy adipose tissue expansion, but in MUO, excess TIMP-3 expression/activity may increase basal Dlk-1 shedding and reduce matrix turnover in adipogenesis, restricting preadipocyte differentiation and shifting AT growth towards adipocyte hypertrophy.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User:	Bruce Beckett
Date Deposited:	23 Jul 2018 09:27
Last Modified:	23 Jul 2018 09:27
URI:	https://ueaeprints.uea.ac.uk/id/eprint/67760
DOI:

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