Tumour necrosis factor-α inhibits adipogenesis via a β-catenin/TCF4(TCF7L2)-dependent pathway

Abstract

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

The Transcription Factor Paired-Related Homeobox 1 (Prrx1) Inhibits Adipogenesis by Activating Transforming Growth Factor-β (TGFβ) Signaling

“…Cell Culture-3T3-L1 cells were maintained in culture, differentiated into adipocytes and stained with Oil Red-O as described previously (18,19). Adipocytes were stained with BODIPY-conjugated dodecanoic acid (BODIPY FL C 12 ) or Hoechst 33258 (Invitrogen) according to the manufacturer's instructions.…”

Selective deletion of adipocytes, but not preadipocytes, by TNF-α through C/EBP- and PPARγ-mediated suppression of NF-κB

“…The results of our current study, together with previous reports, 2,5,6 show that TNF-a reduces adipose tissue mass through multiple mechanisms including inhibition of lipogenesis, facilitation of lipolysis, suppression of adipogenesis and selective induction of adipocyte apoptosis.…”

“…2 It is also known that TNF-a inhibits adipogenesis at picomolar concentrations. 5,6 Previous studies showed induction of apoptosis by TNF-a in human and rat adipocytes in primary cultures. 18,19 To examine the proapoptotic potential of TNF-a in 3T3-L1 adipocytes, we treated differentiated adipocytes (D4 adipocytes) with TNF-a for 48 h and subjected to phase-contrast microscopy and oil red O staining.…”

“…29,30 Some reports also suggested that TNF-a inhibits adipocyte differentiation through activation of TNF receptor 1 and consequent suppression of adipogenesis-committed genes including PPARg and C/EBPa. 5,6 These biological effects may contribute to reduction of adipose tissue mass by TNF-a. However, TNF-a-triggered loss of adipose mass may be caused not only by reduced store of lipids and inhibition of adipogenesis, but also by deletion of adipose tissue cells through apoptosis.…”

“…Indeed, previous reports showed that either secreted or transmembrane TNF-a has the potential to inhibit adipocyte differentiation through activation of TNF receptor 1. 5,6 In contrast, information is limited regarding whether and how TNF-a affects the fate of adipose tissue cells, especially preadipocytes. Recently, we found that preadipocytes were resistant to TNF-a-induced cell injury.…”