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Title: Molecular mechanisms of anti-adipogenesis by tumour necrosis factor-alpha
Author: Cawthorn, W. P.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2008
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In this thesis, a candidate approach was taken to analyse the temporal characteristics of gene expression during TNF-α induced anti-adipogenesis. This suggested that TNF-α might activate Wnt/β-catenin signalling during anti-adipogenesis. Further investigations revealed stabilisation of β-catenin, enhanced TCF7L2 promoter activity and enhanced expression of Wnt/TCF7L2 target genes. The requirement of Wnt/β-catenin signalling for this process was investigated in preadipocytes with either stable knockdown of β-catenin or overexpression of a dominant-negative mutant of the transcription factor TCF7L2. Knockdown of β-catenin attenuated anti-adipogenesis and enhanced apoptosis by TNF-α, whereas overexpression of dnTCF7L2 prevented TNF-α-induced anti-adipogenesis without affecting cytotoxicity. The studies presented in this thesis also identify the serine kinase IKKi as a negative regulator of adipogenesis. IKKi expression was downregulated during adipogenesis but elevated during early TNF-α-induced anti-adipogenesis. Forced expression of IKKi attenuated adipogenesis, whereas stable knockdown of IKKi enhanced adipogenesis. TNF-α also regulated IKKi in mature adipocytes, and knockdown of IKKi in these cells blunted both the suppression of adipocyte genes and the induction of insulin resistance by TNF-α. Importantly, IKKi expression was found to be upregulated in the adipose tissue of obese and insulin-resistant mice and humans, conditions where TNF-α levels are known to be elevated and where adipogenesis may be impaired. In conclusion, the studies have identified two novel mechanisms by which TNF-α can inhibit adipogenesis: via a β-catenin/TCF7L2-dependent pathway and via induction of IKKi. These novel mechanisms of TNF-α action may impact on other aspects of cell fate determination, such as cell proliferation and survival.
Supervisor: Not available Sponsor: Biotechnology and Biological Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available