¹Department of Clinical Biochemistry, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK

Correspondence: JK Sethi, Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Box 232, Hills Road, Cambridge CB2 2QR, UK. Tel: +44 1223 762633; Fax: +44 1223 330598; E-mail: jks30@cam.ac.uk

Received 16 January 2007; Revised 23 February 2007; Accepted 23 February 2007; Published online 20 April 2007.

Abstract

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