Title page for ETD etd-07012009-181133


Type of Document Master's Thesis
Author Wang, Yanning
Author's Email Address ywang34@tigers.lsu.edu
URN etd-07012009-181133
Title TNF-alpha Inhibition of Adiponectin Expression by Targeting PPAR-gamma and C/EBP in Adipocytes
Degree Master of Science (M.S.)
Department Human Ecology
Advisory Committee
Advisor Name Title
Jianping Ye Committee Chair
Michael Keenan Committee Member
Richard Tulley Committee Member
Keywords
  • C/EBP
  • PPAR-gamma
  • TNF-alpha
  • Adiponectin
Date of Defense 2009-06-15
Availability unrestricted
Abstract
Chronic inflammation is involved in the adipose tissue dysfunction through regulation of endocrine and storage function of adipocytes. As a representative proinflammatory cytokine, TNF-α was reported to inhibit expression of adiponectin. However, the mechanism of inhibition remains to be identified. Here, we provide experimental evidence that TNF-α inhibits adiponectin at both transcriptional and posttranscriptional levels. In three animal models (aP2-P65, ob/ob and high fat diets-fed mice), an increase in TNF-α expression was associated with a decrease in adiponectin expression. In 3T3-L1 adipocytes, TNF-α inhibition of adiponectin was observed at mRNA and protein levels. Luciferase reporter assay and mRNA stability tests suggest that the mRNA reduction is a consequence of inhibition of gene transcription and mRNA stability. TNF-α inhibited expression and function of PPAR-γ, an activator of adiponectin gene promoter. The inhibitory activity of TNF-α was blocked by chemical inhibitors of NF-κB or recombinant IκBα (ssIκBα), suggesting that the IκBα/NF-κB pathway mediates the TNF-α signal. The inhibition was attenuated by troglitazone, C/EBPs were required for PPAR-γ expression and their activities were reduced by HDAC3, a nuclear receptor corepressor. The study suggests a signaling pathway of TNF/NF-κB/HDAC3/CEBPs/PPAR-γ/-Adiponectin for inhibition of adiponectin transcription by TNF-α.
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