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PMID: 17464333 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Tumour necrosis factor-alpha inhibits adipogenesis via a beta-catenin/TCF4(TCF7L2)-dependent pathway.

Cell death and differentiation ·Vol. 14 ·No. 7 ·2007-07-00 ·Pages 1361-73

Cawthorn WP, Heyd F, Hegyi K, Sethi JK

Abstract

Tumour necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine, is a potent negative regulator of adipocyte differentiation. However, the mechanism of TNF-alpha-mediated antiadipogenesis remains incompletely understood. In this study, we first confirm that TNF-alpha inhibits adipogenesis of 3T3-L1 preadipocytes by preventing the early induction of the adipogenic transcription factors peroxisome proliferator-activated receptor-gamma (PPARgamma) and CCAAT/enhancer binding protein-alpha (C/EBPalpha). This suppression coincides with enhanced expression of several reported mediators of antiadipogenesis that are also targets of the Wnt/beta-catenin/T-cell factor 4 (TCF4) pathway. Indeed, we found that TNF-alpha enhanced TCF4-dependent transcriptional activity during early antiadipogenesis, and promoted the stabilisation of beta-catenin throughout antiadipogenesis. We analysed the effect of TNF-alpha on adipogenesis in 3T3-L1 cells in which beta-catenin/TCF signalling was impaired, either via stable knockdown of beta-catenin, or by overexpression of dominant-negative TCF4 (dnTCF4). The knockdown of beta-catenin enhanced the adipogenic potential of 3T3-L1 preadipocytes and attenuated TNF-alpha-induced antiadipogenesis. However, beta-catenin knockdown also promoted TNF-alpha-induced apoptosis in these cells. In contrast, overexpression of dnTCF4 prevented TNF-alpha-induced antiadipogenesis but showed no apparent effect on cell survival. Finally, we show that TNF-alpha-induced antiadipogenesis and stabilisation of beta-catenin requires a functional death domain of TNF-alpha receptor 1 (TNFR1). Taken together these data suggest that TNFR1-mediated death domain signals can inhibit adipogenesis via a beta-catenin/TCF4-dependent pathway.

MeSH Terms
Adipocytes/drug effects,metabolism Adipogenesis/drug effects,physiology Adipose Tissue/metabolism Animals Apoptosis/drug effects,physiology CCAAT-Enhancer-Binding Proteins/metabolism Cell Survival/drug effects,physiology Down-Regulation/physiology Mice NIH 3T3 Cells PPAR gamma/metabolism Receptors, Tumor Necrosis Factor, Type I/drug effects,metabolism Signal Transduction/drug effects,physiology TCF Transcription Factors/metabolism Transcription Factor 7-Like 2 Protein Transcriptional Activation/drug effects,physiology Tumor Necrosis Factor-alpha/pharmacology,physiology beta Catenin/genetics,metabolism
Chemicals
CCAAT-Enhancer-Binding Proteins CEBPA protein, human PPAR gamma Receptors, Tumor Necrosis Factor, Type I TCF Transcription Factors TCF7L2 protein, human Tcf7l2 protein, mouse Transcription Factor 7-Like 2 Protein Tumor Necrosis Factor-alpha beta Catenin
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Cawthorn W P
Department of Clinical Biochemistry, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
Heyd F
Hegyi K
Sethi J K
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Article Info
Journal
Cell death and differentiation
Abbr.
Cell Death Differ
ISSN
1350-9047
DOI
10.1038/sj.cdd.4402127
Published
2007-07-00
Epub
2007-00-20
Pages
1361-73
Language
English
Region
England
NLM ID
9437445
PMCID
PMC4303765
Subset
IM
Grants
Biotechnology and Biological Sciences Research Council · JF16994 · United Kingdom
External Links
PubMed source DOI: 10.1038/sj.cdd.4402127 PMC Full Text View journal details
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