Altered regulation of adipogenesis with respect to disease processes

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dc.contributor.advisor McCarthy, Tommie V. en Davies, Stephanie Jane 2017-04-12T12:09:00Z 2017 2017
dc.identifier.citation Davies, S. J. 2017. Altered regulation of adipogenesis with respect to disease processes. PhD Thesis, University College Cork. en
dc.identifier.endpage 188 en
dc.description.abstract Dysregulation of adipose tissue metabolism is associated with multiple metabolic disorders. One such disease, known as Dunnigan-type familial partial lipodystrophy (FPLD2) is characterised by defective fat metabolism and storage. FPLD2 is caused by a specific subset of mutations in the LMNA gene. The mechanisms by which LMNA mutations lead to the adipose specific FPLD2 phenotype have yet to be determined. Previous work employed RNA-Seq analysis to assess the effects of wild-type (WT) and mutant (R482W) LMNA on the expression profile of differentiating 3T3-L1 mouse preadipocytes and identified over 200 transcripts whose expression was altered. Four of these genes namely ITM2A, IGFBP5, PTPRQ and WNT6 were selected for detailed investigation using the 3T3-L1 in-vitro adipogenesis model. Preliminary investigations carried out identified a complex endogenous IGFBP5 expression profile in 3T3-L1 differentiation, with IGFBP5 over-expression and knockdown leading to inhibited and enhanced differentiation, respectively. Investigation into the effects of LMNA over-expression on IGFBP5 yielded conflicting results and further analysis is required to elucidate the mechanisms regulating IGFBP5 expression in adipogenesis. In this thesis ITM2A is identified as a novel modulator of adipogenesis and results show that endogenous ITM2A expression is transiently down-regulated during induction of 3T3-L1 differentiation. ITM2A over-expression was seen to moderately inhibit differentiation of 3T3-L1 preadipocytes while shRNA mediated knockdown of ITM2A significantly enhanced 3T3-L1 differentiation. Investigation of PPARγ levels indicate that this enhanced adipogenesis is mediated through the stabilization of the PPARγ protein at specific time points during differentiation. The results demonstrate that ITM2A knockdown is sufficient to rescue the inhibitory effects of LMNA WT and R482W mutant over-expression on 3T3-L1 differentiation and indicate a novel therapeutic approach for FPLD2. en
dc.description.sponsorship Higher Education Authority (PRTLI Molecular Cell Biology PhD program) en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2017, Stephanie Jane Davies. en
dc.rights.uri en
dc.subject Adipogenesis en
dc.subject Lipodystrophy en
dc.subject FPLD2 en
dc.title Altered regulation of adipogenesis with respect to disease processes en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral Degree (Structured) en
dc.type.qualificationname PhD (Science) en
dc.internal.availability Full text not available en
dc.description.version Accepted Version
dc.contributor.funder Higher Education Authority en
dc.description.status Not peer reviewed en Biochemistry en
dc.check.reason This thesis is due for publication or the author is actively seeking to publish this material en
dc.check.opt-out No en
dc.thesis.opt-out false
dc.check.entireThesis Entire Thesis Restricted
dc.check.embargoformat Both hard copy thesis and e-thesis en
dc.internal.conferring Summer 2017 en

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© 2017, Stephanie Jane Davies. Except where otherwise noted, this item's license is described as © 2017, Stephanie Jane Davies.
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