Abstract
Tumour necrosis factor-α (TNF-α), a proinflammatory cytokine, is a potent negative regulator of adipocyte differentiation. However, the mechanism of TNF-α-mediated antiadipogenesis remains incompletely understood. In this study, we first confirm that TNF-α inhibits adipogenesis of 3T3-L1 preadipocytes by preventing the early induction of the adipogenic transcription factors peroxisome proliferator-activated receptor-γ (PPARγ) and CCAAT/enhancer binding protein-α (C/EBPα). This suppression coincides with enhanced expression of several reported mediators of antiadipogenesis that are also targets of the Wnt/β-catenin/T-cell factor 4 (TCF4) pathway. Indeed, we found that TNF-α enhanced TCF4-dependent transcriptional activity during early antiadipogenesis, and promoted the stabilisation of β-catenin throughout antiadipogenesis. We analysed the effect of TNF-α on adipogenesis in 3T3-L1 cells in which β-catenin/TCF signalling was impaired, either via stable knockdown of β-catenin, or by overexpression of dominant-negative TCF4 (dnTCF4). The knockdown of β-catenin enhanced the adipogenic potential of 3T3-L1 preadipocytes and attenuated TNF-α-induced antiadipogenesis. However, β-catenin knockdown also promoted TNF-α-induced apoptosis in these cells. In contrast, overexpression of dnTCF4 prevented TNF-α-induced antiadipogenesis but showed no apparent effect on cell survival. Finally, we show that TNF-α-induced antiadipogenesis and stabilisation of β-catenin requires a functional death domain of TNF-α receptor 1 (TNFR1). Taken together these data suggest that TNFR1-mediated death domain signals can inhibit adipogenesis via a β-catenin/TCF4-dependent pathway.
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Abbreviations
- TNF-α:
-
tumour necrosis factor-alpha
- TNFR1:
-
TNF-α receptor-1
- PPAR:
-
peroxisome proliferators-activated receptor
- C/EBP:
-
CCAAT/enhancer-binding protein
- TCF4:
-
T-cell factor 4 (also known as TCF7L2)
- NF-κB:
-
nuclear factor kappa B
References
Farmer SR . Transcriptional control of adipocyte formation. Cell Metab 2006; 4: 263–273.
MacDougald OA, Mandrup S . Adipogenesis: forces that tip the scales. Trends Endocrinol Metab 2002; 13: 5–11.
Ross SE, Hemati N, Longo KA, Bennett CN, Lucas PC, Erickson RL et al. Inhibition of adipogenesis by Wnt signaling. Science 2000; 289: 950–953.
Xu H, Sethi JK, Hotamisligil GS . Transmembrane tumor necrosis factor (TNF)-alpha inhibits adipocyte differentiation by selectively activating TNF receptor 1. J Biol Chem 1999; 274: 26287–26295.
Huelsken J, Behrens J . The Wnt signalling pathway. J Cell Sci 2002; 115: 3977–3978.
Moldes M, Zuo Y, Morrison RF, Silva D, Park BH, Liu J et al. Peroxisome-proliferator-activated receptor gamma suppresses Wnt/beta-catenin signalling during adipogenesis. Biochem J 2003; 376: 607–613.
Yang X, Jansson PA, Nagaev I, Jack MM, Carvalho E, Sunnerhagen KS et al. Evidence of impaired adipogenesis in insulin resistance. Biochem Biophys Res Commun 2004; 317: 1045–1051.
Sethi JK, Vidal-Puig AJ . Thematic Review Series on Adipocyte Biology: Adipose tissue function and plasticity orchestrate nutritional adaptation. J Lipid Res 2007 (in press).
Xu H, Hotamisligil GS . Signaling pathways utilized by tumor necrosis factor receptor 1 in adipocytes to suppress differentiation. FEBS Lett 2001; 506: 97–102.
Chae GN, Kwak SJ . NF-kappaB is involved in the TNF-alpha induced inhibition of the differentiation of 3T3-L1 cells by reducing PPARgamma expression. Exp Mol Med 2003; 35: 431–437.
Suzawa M, Takada I, Yanagisawa J, Ohtake F, Ogawa S, Yamauchi T et al. Cytokines suppress adipogenesis and PPAR-gamma function through the TAK1/TAB1/NIK cascade. Nat Cell Biol 2003; 5: 224–230.
Berg AH, Lin Y, Lisanti MP, Scherer PE . Adipocyte differentiation induces dynamic changes in NF-kappaB expression and activity. Am J Physiol Endocrinol Metab 2004; 287: E1178–1188.
Castro-Munozledo F, Beltran-Langarica A, Kuri-Harcuch W . Commitment of 3T3-F442A cells to adipocyte differentiation takes place during the first 24–36 h after adipogenic stimulation: TNF-alpha inhibits commitment. Exp Cell Res 2003; 284: 163–172.
Morrison RF, Farmer SR . Role of PPARgamma in regulating a cascade expression of cyclin-dependent kinase inhibitors, p18(INK4c) and p21(Waf1/Cip1), during adipogenesis. J Biol Chem 1999; 274: 17088–17097.
Burton GR, Nagarajan R, Peterson CA, McGehee Jr RE . Microarray analysis of differentiation-specific gene expression during 3T3-L1 adipogenesis. Gene 2004; 329: 167–185.
Tong Q, Dalgin G, Xu H, Ting CN, Leiden JM, Hotamisligil GS . Function of GATA transcription factors in preadipocyte–adipocyte transition. Science 2000; 290: 134–138.
Ninomiya-Tsuji J, Torti FM, Ringold GM . Tumor necrosis factor-induced c-myc expression in the absence of mitogenesis is associated with inhibition of adipocyte differentiation. Proc Natl Acad Sci USA 1993; 90: 9611–9615.
Freytag S, Geddes TJ . Reciprocal regulation of adipogenesis by Myc and C/EBPalpha. Science 1992; 256: 379–382.
Fu M, Rao M, Bouras T, Wang C, Wu K, Zhang X et al. Cyclin D1 inhibits peroxisome proliferator-activated receptor gamma-mediated adipogenesis through histone deacetylase recruitment. J Biol Chem 2005; 280: 16934–16941.
Shi Y, Hon M, Evans RM . The peroxisome proliferator-activated receptor delta, an integrator of transcriptional repression and nuclear receptor signaling. PNAS 2002; 99: 2613–2618.
He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT et al. Identification of c-MYC as a target of the APC pathway. Science 1998; 281: 1509–1512.
Shtutman M, Zhurinsky J, Simcha I, Albanese C, D'Amico M, Pestell R et al. The cyclin D1 gene is a target of the beta -catenin/LEF-1 pathway. PNAS 1999; 96: 5522–5527.
He TC, Chan TA, Vogelstein B, Kinzler KW . PPARdelta is an APC-regulated target of nonsteroidal anti-inflammatory drugs. Cell 1999; 99: 335–345.
Hagen T, Sethi JK, Foxwell N, Vidal-Puig A . Signalling activity of beta-catenin targeted to different subcellular compartments. Biochem J 2004; 379: 471–477.
Kolligs FT, Hu G, Dang CV, Fearon ER . Neoplastic transformation of RK3E by mutant beta-catenin requires deregulation of Tcf/Lef transcription but not activation of c-myc expression. Mol Cell Biol 1999; 19: 5696–5706.
Bennett CN, Ross SE, Longo KA, Bajnok L, Hemati N, Johnson KW et al. Regulation of Wnt signaling during adipogenesis. J Biol Chem 2002; 277: 30998–31004.
Gustafson B, Smith U . Cytokines promote WNT signaling and inflammation and impair the normal differentiation and lipid accumulation in 3T3-L1 preadipocytes. J Biol Chem 2006; 281: 9507–9516.
Christodoulides C, Laudes M, Cawthorn WP, Schinner S, Soos M, O'Rahilly S et al. The Wnt antagonist Dickkopf-1 and its receptors are coordinately regulated during early human adipogenesis. J Cell Sci 2006; 119: 2613–2620.
Wu Z, Rosen ED, Brun R, Hauser S, Adelmant G, Troy AE et al. Cross-regulation of C/EBP alpha and PPAR gamma controls the transcriptional pathway of adipogenesis and insulin sensitivity. Mol Cell 1999; 3: 151–158.
Chen S, Guttridge DC, You Z, Zhang Z, Fribley A, Mayo MW et al. Wnt-1 signaling inhibits apoptosis by activating beta-catenin/T cell factor-mediated transcription. J Cell Biol 2001; 152: 87–96.
Orford K, Orford CC, Byers SW . Exogenous expression of beta-catenin regulates contact inhibition, anchorage-independent growth, anoikis, and radiation-induced cell cycle arrest. J Cell Biol 1999; 146: 855–868.
Korinek V, Barker N, Moerer P, van Donselaar E, Huls G, Peters PJ et al. Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat Genet 1998; 19: 379–383.
Cauchi S, Meyre D, Dina C, Choquet H, Samson C, Gallina S et al. Transcription factor TCF7L2 genetic study in the French population: expression in human beta-cells and adipose tissue and strong association with type 2 diabetes. Diabetes 2006; 55: 2903–2908.
Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet 2006; 38: 320–323.
Saxena R, Gianniny L, Burtt NP, Lyssenko V, Giuducci C, Sjogren M et al. Common single nucleotide polymorphisms in TCF7L2 are reproducibly associated with type 2 diabetes and reduce the insulin response to glucose in nondiabetic individuals. Diabetes 2006; 55: 2890–2895.
Sharma C, Pradeep A, Wong L, Rana A, Rana B . Peroxisome proliferator-activated receptor-gamma activation can regulate beta-catenin levels via a proteasome-mediated and Adenomatous Polyposis Coli-independent pathway. J Biol Chem 2004; 279: 35583–35594.
Liu J, Farmer SR . Regulating the balance between peroxisome proliferator-activated receptor gamma and beta-catenin signaling during adipogenesis. A glycogen synthase kinase 3beta phosphorylation-defective mutant of beta-catenin inhibits expression of a subset of adipogenic genes. J Biol Chem 2004; 279: 45020–45027.
Lamberti C, Lin KM, Yamamoto Y, Verma U, Verma IM, Byers S et al. Regulation of beta-catenin function by the IkappaB kinases. J Biol Chem 2001; 276: 42276–42286.
Carayol N, Wang CY . IKKalpha stabilizes cytosolic beta-catenin by inhibiting both canonical and non-canonical degradation pathways. Cell Signal 2006; 18: 1941–1946.
Ding Q, Xia W, Liu JC, Yang JY, Lee DF, Xia J et al. Erk Associates with and Primes GSK-3beta for Its Inactivation Resulting in Upregulation of beta-Catenin. Mol Cell 2005; 19: 159–170.
Tran SE, Holmstrom TH, Ahonen M, Kahari VM, Eriksson JE . MAPK/ERK overrides the apoptotic signaling from Fas, TNF, and TRAIL receptors. J Biol Chem 2001; 276: 16484–16490.
Tartaglia LA, Ayres TM, Wong GH, Goeddel DV . A novel domain within the 55 kd TNF receptor signals cell death. Cell 1993; 74: 845–853.
Boone E, Vanden Berghe T, Van Loo G, De Wilde G, De Wael N, Vercammen D et al. Structure/Function analysis of p55 tumor necrosis factor receptor and fas-associated death domain. Effect on necrosis in L929sA cells. J Biol Chem 2000; 275: 37596–37603.
Jiang Y, Woronicz JD, Liu W, Goeddel DV . Prevention of constitutive TNF receptor 1 signaling by silencer of death domains. Science 1999; 283: 543–546.
Nawaratne R, Gray A, Jorgensen CH, Downes CP, Siddle K, Sethi JK . Regulation of insulin receptor substrate 1 pleckstrin homology domain by protein kinase C: role of serine 24 phosphorylation. Mol Endocrinol 2006; 20: 1838–1852.
Acknowledgements
We are grateful to Toni Vidal-Puig, members of his laboratory, Gökhan Hotamisligil, Thilo Hagen and Dirk Hadaschik, for helpful discussions and/or reagents. This research was supported by a MRC studentship (WPC), a Studienstiftung des deutschen Volkes diploma studentship (FH), a Corpus Christi College-Brooke Scholarship (KH) and a Biotechnology and Biological Sciences Research Council David Phillips Fellowship (JKS).
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Cawthorn, W., Heyd, F., Hegyi, K. et al. Tumour necrosis factor-α inhibits adipogenesis via a β-catenin/TCF4(TCF7L2)-dependent pathway. Cell Death Differ 14, 1361–1373 (2007). https://doi.org/10.1038/sj.cdd.4402127
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DOI: https://doi.org/10.1038/sj.cdd.4402127
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