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.
| Identifer | oai:union.ndltd.org:LSU/oai:etd.lsu.edu:etd-07012009-181133 |
| Date | 06 July 2009 |
| Creators | Wang, Yanning |
| Contributors | Jianping Ye, Michael Keenan, Richard Tulley |
| Publisher | LSU |
| Source Sets | Louisiana State University |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.lsu.edu/docs/available/etd-07012009-181133/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached herein a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to LSU or its agents the non-exclusive license to archive and make accessible, under the conditions specified below and in appropriate University policies, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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