Identifier

etd-07012009-181133

Degree

Master of Science (MS)

Department

Human Ecology

Document Type

Thesis

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.

Date

2009

Document Availability at the Time of Submission

Release the entire work immediately for access worldwide.

Committee Chair

Jianping Ye

Included in

Human Ecology Commons

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