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  • Metabolic Messengers
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Metabolic Messengers: tumour necrosis factor

Nature Metabolism volume 3, pages 1302–1312 (2021)Cite this article

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Abstract

Tumour necrosis factor (TNF) is a classical, pleiotropic pro-inflammatory cytokine. It is also the first ‘adipokine’ described to be produced from adipose tissue, regulated in obesity and proposed to contribute to obesity-associated metabolic disease. In this review, we provide an overview of TNF in the context of metabolic inflammation or metaflammation, its discovery as a metabolic messenger, its sites and mechanisms of action and some critical considerations for future research. Although we focus on TNF and the studies that elucidated its immunometabolic actions, we highlight a conceptual framework, generated by these studies, that is equally applicable to the complex network of pro-inflammatory signals, their biological activity and their integration with metabolic regulation, and to the field of immunometabolism more broadly.

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Fig. 1: Discovery of TNF as an immunometabolic messenger.
Fig. 2: Target tissues and metabolic activities of TNF.
Fig. 3: TNF-induced signalling and metabolic reprogramming.

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References

  1. Mathis, D. & Shoelson, S. E. Immunometabolism: an emerging frontier. Nat. Rev. Immunol. 11, 81–83 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Padmanabha, D. & Baker, K. D. Drosophila gains traction as a repurposed tool to investigate metabolism. Trends Endocrinol. Metab. 25, 518–527 (2014).

    Article  CAS  PubMed  Google Scholar 

  3. Mattila, J. & Hietakangas, V. Regulation of carbohydrate energy metabolism in Drosophila melanogaster. Genetics 207, 1231–1253 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Hotamisligil, G. S. Foundations of immunometabolism and implications for metabolic health and disease. Immunity 47, 406–420 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Agrawal, N. et al. The Drosophila TNF Eiger is an adipokine that acts on insulin-producing cells to mediate nutrient response. Cell Metab. 23, 675–684 (2016).

    Article  CAS  PubMed  Google Scholar 

  6. Fève, B. & Bastard, J. P. The role of interleukins in insulin resistance and type 2 diabetes mellitus. Nat. Rev. Endocrinol. 5, 305–311 (2009).

    Article  PubMed  CAS  Google Scholar 

  7. Tack, C. J., Stienstra, R., Joosten, L. A. & Netea, M. G. Inflammation links excess fat to insulin resistance: the role of the interleukin-1 family. Immunol. Rev. 249, 239–252 (2012).

    Article  CAS  PubMed  Google Scholar 

  8. Donath, M. Y. Targeting inflammation in the treatment of type 2 diabetes: time to start. Nat. Rev. Drug Discov. 13, 465–476 (2014).

    Article  CAS  PubMed  Google Scholar 

  9. Hotamisligil, G. S. Inflammation, metaflammation and immunometabolic disorders. Nature 542, 177–185 (2017).

    Article  CAS  PubMed  Google Scholar 

  10. Libert, C. Cytokine anniversary: TNF trailblazers five centuries apart. Nature 523, 158 (2015).

    Article  CAS  PubMed  Google Scholar 

  11. Tracey, K. J. & Cerami, A. Metabolic responses to cachectin/TNF. A brief review. Ann. N.Y. Acad. Sci. 587, 325–331 (1990).

    Article  CAS  PubMed  Google Scholar 

  12. Pennica, D. et al. Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin. Nature 312, 724–729 (1984).

    Article  CAS  PubMed  Google Scholar 

  13. Beutler, B. et al. Identity of tumour necrosis factor and the macrophage-secreted factor cachectin. Nature 316, 552–554 (1985).

    Article  CAS  PubMed  Google Scholar 

  14. Ruddle, N. H. Lymphotoxin and TNF: how it all began—a tribute to the travelers. Cytokine Growth Factor Rev. 25, 83–89 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hellman, B. Studies in obese-hyperglycemic mice. Ann. N. Y. Acad. Sci. 131, 541–558 (1965).

    Article  CAS  PubMed  Google Scholar 

  16. Hausberger, F. X. Pathological changes in adipose tissue of obese mice. Anat. Rec. 154, 651–660 (1966).

    Article  CAS  PubMed  Google Scholar 

  17. Pekala, P., Kawakami, M., Vine, W., Lane, M. D. & Cerami, A. Studies of insulin resistance in adipocytes induced by macrophage mediator. J. Exp. Med. 157, 1360–1365 (1983).

    Article  CAS  PubMed  Google Scholar 

  18. Mahoney, J. R. Jr et al. Lipopolysaccharide-treated RAW 264.7 cells produce a mediator that inhibits lipoprotein lipase in 3T3-L1 cells. J. Immunol. 134, 1673–1675 (1985).

    Article  CAS  PubMed  Google Scholar 

  19. Hotamisligil, G. S., Shargill, N. S. & Spiegelman, B. M. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259, 87–91 (1993).

    Article  CAS  PubMed  Google Scholar 

  20. Bordon, Y. TNF short-circuits the insulin receptor. Nature Milestones: Diabetes, 12. https://www.nature.com/articles/d42859-021-00015-0 (2021).

  21. Kern, P. A. et al. The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. J. Clin. Invest. 95, 2111–2119 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Saghizadeh, M., Ong, J. M., Garvey, W. T., Henry, R. R. & Kern, P. A. The expression of TNF alpha by human muscle. Relationship to insulin resistance. J. Clin. Invest. 97, 1111–1116 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hube, F. & Hauner, H. The role of TNF-alpha in human adipose tissue: prevention of weight gain at the expense of insulin resistance? Horm. Metab. Res. 31, 626–631 (1999).

    Article  CAS  PubMed  Google Scholar 

  24. Mohamed-Ali, V. et al. Production of soluble tumor necrosis factor receptors by human subcutaneous adipose tissue in vivo. Am. J. Physiol. 277, E971–E975 (1999).

    CAS  PubMed  Google Scholar 

  25. Lasselin, J. et al. Adipose inflammation in obesity: relationship with circulating levels of inflammatory markers and association with surgery-induced weight loss. J. Clin. Endocrinol. Metab. 99, E53–E61 (2014).

    Article  PubMed  Google Scholar 

  26. Liu, C. et al. Adiponectin, TNF-α and inflammatory cytokines and risk of type 2 diabetes: a systematic review and meta-analysis. Cytokine 86, 100–109 (2016).

    Article  CAS  PubMed  Google Scholar 

  27. Sookoian, S. C., González, C. & Pirola, C. J. Meta-analysis on the G-308A tumor necrosis factor alpha gene variant and phenotypes associated with the metabolic syndrome. Obes. Res. 13, 2122–2131 (2005).

    Article  PubMed  Google Scholar 

  28. Van der Poll, T. et al. Tumor necrosis factor mimics the metabolic response to acute infection in healthy humans. Am. J. Physiol. 261, E457–E465 (1991).

    PubMed  Google Scholar 

  29. Plomgaard, P. et al. Tumor necrosis factor-alpha induces skeletal muscle insulin resistance in healthy human subjects via inhibition of Akt substrate 160 phosphorylation. Diabetes 54, 2939–2945 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Plomgaard, P., Fischer, C. P., Ibfelt, T., Pedersen, B. K. & van Hall, G. Tumor necrosis factor-alpha modulates human in vivo lipolysis. J. Clin. Endocrinol. Metab. 93, 543–549 (2008).

    Article  CAS  PubMed  Google Scholar 

  31. Feingold, K. R. et al. Effect of tumor necrosis factor (TNF) on lipid metabolism in the diabetic rat. Evidence that inhibition of adipose tissue lipoprotein lipase activity is not required for TNF-induced hyperlipidemia. J. Clin. Invest. 83, 1116–1121 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ling, P. R., Bistrian, B. R., Mendez, B. & Istfan, N. W. Effects of systemic infusions of endotoxin, tumor necrosis factor, and interleukin-1 on glucose metabolism in the rat: relationship to endogenous glucose production and peripheral tissue glucose uptake. Metabolism 43, 279–284 (1994).

    Article  CAS  PubMed  Google Scholar 

  33. Miles, P. D. et al. TNF-alpha-induced insulin resistance in vivo and its prevention by troglitazone. Diabetes 46, 1678–1683 (1997).

    Article  CAS  PubMed  Google Scholar 

  34. Uysal, K. T., Wiesbrock, S. M., Marino, M. W. & Hotamisligil, G. S. Protection from obesity-induced insulin resistance in mice lacking TNF-α function. Nature 389, 610–614 (1997).

    Article  CAS  PubMed  Google Scholar 

  35. Ventre, J. et al. Targeted disruption of the tumor necrosis factor-alpha gene: metabolic consequences in obese and nonobese mice. Diabetes 46, 1526–1531 (1997).

    Article  CAS  PubMed  Google Scholar 

  36. Uysal, K. T., Wiesbrock, S. M. & Hotamisligil, G. S. Functional analysis of tumor necrosis factor (TNF) receptors in TNF-alpha-mediated insulin resistance in genetic obesity. Endocrinology 139, 4832–4838 (1998).

    Article  CAS  PubMed  Google Scholar 

  37. da Costa, R. M. et al. TNF-α induces vascular insulin resistance via positive modulation of PTEN and decreased Akt/eNOS/NO signaling in high fat diet-fed mice. Cardiovasc. Diabetol. 15, 119 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Borst, S. E. & Bagby, G. J. Neutralization of tumor necrosis factor reverses age-induced impairment of insulin responsiveness in skeletal muscle of Sprague-Dawley rats. Metabolism 51, 1061–1064 (2002).

    Article  CAS  PubMed  Google Scholar 

  39. Liang, H. et al. Blockade of tumor necrosis factor (TNF) receptor type 1-mediated TNF-alpha signaling protected Wistar rats from diet-induced obesity and insulin resistance. Endocrinology 149, 2943–2951 (2008).

    Article  CAS  PubMed  Google Scholar 

  40. McKellar, G. E., McCarey, D. W., Sattar, N. & McInnes, I. B. Role for TNF in atherosclerosis? Lessons from autoimmune disease. Nat. Rev. Cardiol. 6, 410–417 (2009).

    Article  CAS  PubMed  Google Scholar 

  41. Salomon, B. L. Insights into the biology and therapeutic implications of TNF and regulatory T cells. Nat. Rev. Rheumatol. 17, 487–504 (2021).

    Article  PubMed  Google Scholar 

  42. Crespo, J. et al. Gene expression of tumor necrosis factor alpha and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology 34, 1158–1163 (2001).

    Article  CAS  PubMed  Google Scholar 

  43. Kugelmas, M., Hill, D. B., Vivian, B., Marsano, L. & McClain, C. J. Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E. Hepatology 38, 413–419 (2003).

    Article  CAS  PubMed  Google Scholar 

  44. Henao-Mejia, J. et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482, 179–185 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Divella, R. et al. Synergism of adipocytokine profile and ADIPOQ/TNF-α polymorphisms in NAFLD-associated MetS predict colorectal liver metastases outgrowth. Cancer Genomics Proteomics 16, 519–530 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Park, E. J. et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 140, 197–208 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Nakagawa, H. et al. ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development. Cancer Cell 26, 331–343 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Tomita, K. et al. Tumour necrosis factor alpha signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice. Gut 55, 415–424 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Bluemel, S., Wang, Y., Lee, S. & Schnabl, B. Tumor necrosis factor alpha receptor 1 deficiency in hepatocytes does not protect from non-alcoholic steatohepatitis, but attenuates insulin resistance in mice. World J. Gastroenterol. 26, 4933–4944 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Wandrer, F. et al. TNF-Receptor-1 inhibition reduces liver steatosis, hepatocellular injury and fibrosis in NAFLD mice. Cell Death Dis. 11, 212 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Verhoeven, F. et al. Safety of TNF inhibitors in rheumatic disease in case of NAFLD and cirrhosis. Semin. Arthritis Rheum. 50, 544–548 (2020).

    Article  CAS  PubMed  Google Scholar 

  52. Tang, K. T., Dufour, J. F., Chen, P. H., Hernaez, R. & Hutfless, S. Antitumour necrosis factor-α agents and development of new-onset cirrhosis or non-alcoholic fatty liver disease: a retrospective cohort. BMJ Open Gastroenterol. 7, e000349 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Ohta, H. et al. Disruption of tumor necrosis factor-alpha gene diminishes the development of atherosclerosis in ApoE-deficient mice. Atherosclerosis 180, 11–17 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Avgerinou, G. et al. Anti-tumor necrosis factor α treatment with adalimumab improves significantly endothelial function and decreases inflammatory process in patients with chronic psoriasis. Int. J. Cardiol. 151, 382–383 (2011).

    Article  PubMed  Google Scholar 

  55. Tam, L. S., Kitas, G. D. & González-Gay, M. A. Can suppression of inflammation by anti-TNF prevent progression of subclinical atherosclerosis in inflammatory arthritis? Rheumatology (Oxford) 53, 1108–1119 (2014).

    Article  CAS  Google Scholar 

  56. Spinelli, F. R. et al. Decrease of asymmetric dimethyl arginine after anti-TNF therapy in patients with rheumatoid arthritis. Drug Dev. Res. 75, S67–S69 (2014).

    Article  CAS  PubMed  Google Scholar 

  57. Francisco, V. et al. Adipokines: linking metabolic syndrome, the immune system, and arthritic diseases. Biochem. Pharmacol. 165, 196–206 (2019).

    Article  CAS  PubMed  Google Scholar 

  58. Everett, B. M. et al. Inhibition of Interleukin-1β and reduction in atherothrombotic cardiovascular events in the CANTOS trial. J. Am. Coll. Cardiol. 76, 1660–1670 (2020).

    Article  CAS  PubMed  Google Scholar 

  59. Nguyen, J. C., Killcross, A. S. & Jenkins, T. A. Obesity and cognitive decline: role of inflammation and vascular changes. Front. Neurosci. 8, 375 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Pugazhenthi, S., Qin, L. & Reddy, P. H. Common neurodegenerative pathways in obesity, diabetes, and Alzheimer’s disease. Biochim. Biophys. Acta, Mol. Basis Dis. 1037–1045, 2017 (1863).

    Google Scholar 

  61. Bomfim, T. R. et al. An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease–associated Aβ oligomers. J. Clin. Invest. 122, 1339–1353 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ferreira, S. T., Clarke, J. R. & Bomfim, T. R. & De Felice, F. G. Inflammation, defective insulin signaling, and neuronal dysfunction in Alzheimer’s disease. Alzheimers Dement. 10, S76–S83 (2014).

    Article  PubMed  Google Scholar 

  63. de la Monte, S. M. & Wands, J. R. Alzheimer’s disease is type 3 diabetes-evidence reviewed. J. Diabetes Sci. Technol. 2, 1101–1113 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Aggarwal, B. B. et al. in Cytokines as Potential Therapeutic Targets for Inflammatory Skin Diseases (Ernst Schering Research Foundation Workshops, vol. 56) (eds. Numerof, R., Dinarello, C. A. & Asadullah, K.) 161–186 (Springer, 2006).

  65. Sethi, G., Sung, B. & Aggarwal, B. B. TNF: a master switch for inflammation to cancer. Front. Biosci. 13, 5094–5107 (2008).

    Article  CAS  PubMed  Google Scholar 

  66. Lou, J., Lucas, R. & Grau, G. E. Pathogenesis of cerebral malaria: recent experimental data and possible applications for humans. Clin. Microbiol. Rev. 14, 810–820 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Jacobs, M. et al. Tumor necrosis factor is critical to control tuberculosis infection. Microbes Infect. 9, 623–628 (2007).

    Article  CAS  PubMed  Google Scholar 

  68. Del Valle, D. M. et al. An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat. Med. 26, 1636–1643 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Robinson, P. C., Richards, D., Tanner, H. L. & Feldmann, M. Accumulating evidence suggests anti-TNF therapy needs to be given trial priority in COVID-19 treatment. Lancet Rheumatol 2, e653–e655 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Feldmann, M. et al. Trials of anti-tumour necrosis factor therapy for COVID-19 are urgently needed. Lancet 395, 1407–1409 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Mahase, E. Covid-19: anti-TNF drug adalimumab to be trialled for patients in the community. Br. Med. J. 371, m3847 (2020).

    Article  Google Scholar 

  72. Sethi, J. K. & Hotamisligil, G. S. The role of TNF alpha in adipocyte metabolism. Semin. Cell Dev. Biol. 10, 19–29 (1999).

    Article  CAS  PubMed  Google Scholar 

  73. Cawthorn, W. P. & Sethi, J. K. TNF-alpha and adipocyte biology. FEBS Lett. 582, 117–131 (2008).

    Article  CAS  PubMed  Google Scholar 

  74. Sethi, J. K. & Vidal-Puig, A. J. Thematic review series: adipocyte biology. Adipose tissue function and plasticity orchestrate nutritional adaptation. J. Lipid Res. 48, 1253–1262 (2007).

    Article  CAS  PubMed  Google Scholar 

  75. Cawthorn, W. P., Heyd, F., Hegyi, K. & Sethi, J. K. Tumour necrosis factor-alpha inhibits adipogenesis via a beta-catenin/TCF4(TCF7L2)-dependent pathway. Cell Death Differ. 14, 1361–1373 (2007).

    Article  CAS  PubMed  Google Scholar 

  76. Voloshyna, I. et al. Infliximab reverses suppression of cholesterol efflux proteins by TNF-α: a possible mechanism for modulation of atherogenesis. BioMed Res. Int. 2014, 312647 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Yanai, H. et al. The underlying mechanisms for development of hypertension in the metabolic syndrome. Nutr. J. 7, 10 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Fong, Y. et al. Antibodies to cachectin/tumor necrosis factor reduce interleukin 1 beta and interleukin 6 appearance during lethal bacteremia. J. Exp. Med. 170, 1627–1633 (1989).

    Article  CAS  PubMed  Google Scholar 

  79. Falvo, J. V., Tsytsykova, A. V. & Goldfeld, A. E. Transcriptional control of the TNF gene. Curr. Dir. Autoimmun. 11, 27–60 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Anderson, P. Post-transcriptional regulation of tumour necrosis factor alpha production. Ann. Rheum. Dis. 59, i3–i5 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Stamou, P. & Kontoyiannis, D. L. Posttranscriptional regulation of TNF mRNA: a paradigm of signal-dependent mRNA utilization and its relevance to pathology. Curr. Dir. Autoimmun. 11, 61–79 (2010).

    Article  CAS  PubMed  Google Scholar 

  82. Mazumder, B., Li, X. & Barik, S. Translation control: a multifaceted regulator of inflammatory response. J. Immunol. 184, 3311–3319 (2010).

    Article  CAS  PubMed  Google Scholar 

  83. Liu, J., Qian, C. & Cao, X. Post-translational modification control of innate immunity. Immunity 45, 15–30 (2016).

    Article  PubMed  CAS  Google Scholar 

  84. Xu, H., Sethi, J. K. & Hotamisligil, G. S. Transmembrane tumor necrosis factor (TNF)-alpha inhibits adipocyte differentiation by selectively activating TNF receptor 1. J. Biol. Chem. 274, 26287–26295 (1999).

    Article  CAS  PubMed  Google Scholar 

  85. Xu, H., Uysal, K. T., Becherer, J. D., Arner, P. & Hotamisligil, G. S. Altered tumor necrosis factor-alpha (TNF-alpha) processing in adipocytes and increased expression of transmembrane TNF-alpha in obesity. Diabetes 51, 1876–1883 (2002).

    Article  CAS  PubMed  Google Scholar 

  86. Black, R. A. et al. A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature 385, 729–733 (1997).

    Article  CAS  PubMed  Google Scholar 

  87. Serino, M. et al. Mice heterozygous for tumor necrosis factor-alpha converting enzyme are protected from obesity-induced insulin resistance and diabetes. Diabetes 56, 2541–2546 (2007).

    Article  CAS  PubMed  Google Scholar 

  88. Medler, J. & Wajant, H. Tumor necrosis factor receptor-2 (TNFR2): an overview of an emerging drug target. Expert Opin. Ther. Targets 23, 295–307 (2019).

    Article  CAS  PubMed  Google Scholar 

  89. Tartaglia, L. A., Pennica, D. & Goeddel, D. V. Ligand passing: the 75-kDa tumor necrosis factor (TNF) receptor recruits TNF for signaling by the 55-kDa TNF receptor. J. Biol. Chem. 268, 18542–18548 (1993).

    Article  CAS  PubMed  Google Scholar 

  90. Hotamisligil, G. S., Arner, P., Atkinson, R. L. & Spiegelman, B. M. Differential regulation of the p80 tumor necrosis factor receptor in human obesity and insulin resistance. Diabetes 46, 451–455 (1997).

    Article  CAS  PubMed  Google Scholar 

  91. Rönnemaa, T., Pulkki, K. & Kaprio, J. Serum soluble tumor necrosis factor-alpha receptor 2 is elevated in obesity but is not related to insulin sensitivity: a study in identical twins discordant for obesity. J. Clin. Endocrinol. Metab. 85, 2728–2732 (2000).

    PubMed  Google Scholar 

  92. Good, M. et al. TNF and TNF receptor expression and insulin sensitivity in human omental and subcutaneous adipose tissue—influence of BMI and adipose distribution. Diab. Vasc. Dis. Res. 3, 26–33 (2006).

    Article  PubMed  Google Scholar 

  93. Kohno, T. et al. A second tumor necrosis factor receptor gene product can shed a naturally occurring tumor necrosis factor inhibitor. Proc. Natl Acad. Sci. USA 87, 8331–8335 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Aderka, D., Engelmann, H., Maor, Y., Brakebusch, C. & Wallach, D. Stabilization of the bioactivity of tumor necrosis factor by its soluble receptors. J. Exp. Med. 175, 323–329 (1992).

    Article  CAS  PubMed  Google Scholar 

  95. Peraldi, P., Hotamisligil, G. S., Buurman, W. A., White, M. F. & Spiegelman, B. M. Tumor necrosis factor (TNF)-alpha inhibits insulin signaling through stimulation of the p55 TNF receptor and activation of sphingomyelinase. J. Biol. Chem. 271, 13018–13022 (1996).

    Article  CAS  PubMed  Google Scholar 

  96. Sethi, J. K. et al. Characterisation of receptor-specific TNFalpha functions in adipocyte cell lines lacking type 1 and 2 TNF receptors. FEBS Lett. 469, 77–82 (2000).

    Article  CAS  PubMed  Google Scholar 

  97. Martins, L. B. et al. Paradoxical role of tumor necrosis factor on metabolic dysfunction and adipose tissue expansion in mice. Nutrition 50, 1–7 (2018).

    Article  CAS  PubMed  Google Scholar 

  98. Sethi, J. K., Xu, H. Y. & Hotamisligil, G. S. Roles of tumor necrosis factor receptor 1 and receptor 2 in insulin receptor signaling. Diabetes 48, A219–A219 (1999).

    Google Scholar 

  99. Aquilano, K. et al. Adipocyte metabolism is improved by TNF receptor-targeting small RNAs identified from dried nuts. Commun. Biol. 2, 317 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Liu, L. S., Spelleken, M., Röhrig, K., Hauner, H. & Eckel, J. Tumor necrosis factor-alpha acutely inhibits insulin signaling in human adipocytes: implication of the p80 tumor necrosis factor receptor. Diabetes 47, 515–522 (1998).

    Article  CAS  PubMed  Google Scholar 

  101. Wu, S., Dong, K., Wang, J. & Bi, Y. Tumor necrosis factor alpha improves glucose homeostasis in diabetic mice independent with tumor necrosis factor receptor 1 and tumor necrosis factor receptor 2. Endocr. J. 65, 601–609 (2018).

    Article  CAS  PubMed  Google Scholar 

  102. Wajant, H. & Siegmund, D. TNFR1 and TNFR2 in the control of the life and death balance of macrophages. Front. Cell Dev. Biol. 7, 91 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Karunakaran, D. et al. RIPK1 gene variants associate with obesity in humans and can be therapeutically silenced to reduce obesity in mice. Nat. Metab. 2, 1113–1125 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Sabio, G. & Davis, R. J. TNF and MAP kinase signalling pathways. Semin. Immunol. 26, 237–245 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Leiva, M., Matesanz, N., Pulgarín-Alfaro, M., Nikolic, I. & Sabio, G. Uncovering the role of p38 family members in adipose tissue physiology. Front. Endocrinol. 11, 572089 (2020).

    Article  Google Scholar 

  106. Hirosumi, J. et al. A central role for JNK in obesity and insulin resistance. Nature 420, 333–336 (2002).

    Article  CAS  PubMed  Google Scholar 

  107. Tuncman, G. et al. Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance. Proc. Natl Acad. Sci. U.S.A. 103, 10741–10746 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Waeber, G. et al. The gene MAPK8IP1, encoding islet-brain-1, is a candidate for type 2 diabetes. Nat. Genet. 24, 291–295 (2000).

    Article  CAS  PubMed  Google Scholar 

  109. Weston, C. R. & Davis, R. J. The JNK signal transduction pathway. Curr. Opin. Cell Biol. 19, 142–149 (2007).

    Article  CAS  PubMed  Google Scholar 

  110. Hotamisligil, G. S. & Davis, R. J. Cell signaling and stress responses. Cold Spring Harb. Perspect. Biol. 8, a006072 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Hotamisligil, G. S. et al. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science 271, 665–670 (1996).

    Article  CAS  PubMed  Google Scholar 

  112. Kanety, H., Feinstein, R., Papa, M. Z., Hemi, R. & Karasik, A. Tumor necrosis factor alpha-induced phosphorylation of insulin receptor substrate-1 (IRS-1). Possible mechanism for suppression of insulin-stimulated tyrosine phosphorylation of IRS-1. J. Biol. Chem. 270, 23780–23784 (1995).

    Article  CAS  PubMed  Google Scholar 

  113. Aguirre, V. et al. Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action. J. Biol. Chem. 277, 1531–1537 (2002).

    Article  CAS  PubMed  Google Scholar 

  114. Copps, K. D. & White, M. F. Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. Diabetologia 55, 2565–2582 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Gao, Z. et al. Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex. J. Biol. Chem. 277, 48115–48121 (2002).

    Article  CAS  PubMed  Google Scholar 

  116. Austin, R. L., Rune, A., Bouzakri, K., Zierath, J. R. & Krook, A. siRNA-mediated reduction of inhibitor of nuclear factor-kappaB kinase prevents tumor necrosis factor-alpha-induced insulin resistance in human skeletal muscle. Diabetes 57, 2066–2073 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Jiang, S. & Messina, J. L. Role of inhibitory κB kinase and c-Jun NH2-terminal kinase in the development of hepatic insulin resistance in critical illness diabetes. Am. J. Physiol. Gastrointest. Liver Physiol. 301, G454–G463 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Li, Y. et al. Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101). J. Biol. Chem. 279, 45304–45307 (2004).

    Article  CAS  PubMed  Google Scholar 

  119. Kim, J. K. et al. PKC-theta knockout mice are protected from fat-induced insulin resistance. J. Clin. Invest. 114, 823–827 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Nawaratne, R. et al. Regulation of insulin receptor substrate 1 pleckstrin homology domain by protein kinase C: role of serine 24 phosphorylation. Mol. Endocrinol. 20, 1838–1852 (2006).

    Article  CAS  PubMed  Google Scholar 

  121. De Fea, K. & Roth, R. A. Modulation of insulin receptor substrate-1 tyrosine phosphorylation and function by mitogen-activated protein kinase. J. Biol. Chem. 272, 31400–31406 (1997).

    Article  PubMed  Google Scholar 

  122. Engelman, J. A., Berg, A. H., Lewis, R. Y., Lisanti, M. P. & Scherer, P. E. Tumor necrosis factor alpha-mediated insulin resistance, but not dedifferentiation, is abrogated by MEK1/2 inhibitors in 3T3-L1 adipocytes. Mol. Endocrinol. 14, 1557–1569 (2000).

    CAS  PubMed  Google Scholar 

  123. Bouzakri, K. & Zierath, J. R. MAP4K4 gene silencing in human skeletal muscle prevents tumor necrosis factor-alpha-induced insulin resistance. J. Biol. Chem. 282, 7783–7789 (2007).

    Article  CAS  PubMed  Google Scholar 

  124. Danai, L. V. et al. Inducible deletion of protein kinase Map4k4 in obese mice improves insulin sensitivity in liver and adipose tissues. Mol. Cell. Biol. 35, 2356–2365 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Chiang, S. H. et al. The protein kinase IKKepsilon regulates energy balance in obese mice. Cell 138, 961–975 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Patel, M. N. et al. Hematopoietic IKBKE limits the chronicity of inflammasome priming and metaflammation. Proc. Natl Acad. Sci. U.S.A. 112, 506–511 (2015).

    Article  CAS  PubMed  Google Scholar 

  127. Guney, E. et al. Aberrant Ca2+ homeostasis in adipocytes links inflammation to metabolic dysregulation in obesity. Preprint in bioRxiv at https://doi.org/10.1101/2020.10.28.360008 (2020).

  128. Illario, M. et al. Calcium-calmodulin-dependent kinase II (CaMKII) mediates insulin-stimulated proliferation and glucose uptake. Cell. Signal. 21, 786–792 (2009).

    Article  CAS  PubMed  Google Scholar 

  129. Shungin, D. et al. New genetic loci link adipose and insulin biology to body fat distribution. Nature 518, 187–196 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Mao, L., Fang, Y., Campbell, M. & Southerland, W. M. Population differentiation in allele frequencies of obesity-associated SNPs. BMC Genomics 18, 861 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Wiegmann, K., Schütze, S., Machleidt, T., Witte, D. & Krönke, M. Functional dichotomy of neutral and acidic sphingomyelinases in tumor necrosis factor signaling. Cell 78, 1005–1015 (1994).

    Article  CAS  PubMed  Google Scholar 

  132. Aerts, J. M. et al. Pharmacological inhibition of glucosylceramide synthase enhances insulin sensitivity. Diabetes 56, 1341–1349 (2007).

    Article  CAS  PubMed  Google Scholar 

  133. Petersen, M. C. & Shulman, G. I. Mechanisms of insulin action and insulin resistance. Physiol. Rev. 98, 2133–2223 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Sethi, J. K. & Vidal-Puig, A. Wnt signalling and the control of cellular metabolism. Biochem. J. 427, 1–17 (2010).

    Article  CAS  PubMed  Google Scholar 

  135. Lagathu, C. et al. Dact1, a nutritionally regulated preadipocyte gene, controls adipogenesis by coordinating the Wnt/beta-catenin signaling network. Diabetes 58, 609–619 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Lagathu, C. et al. Secreted frizzled-related protein 1 regulates adipose tissue expansion and is dysregulated in severe obesity. Int. J. Obes. 34, 1695–1705 (2010).

    Article  CAS  Google Scholar 

  137. Isakson, P., Hammarstedt, A., Gustafson, B. & Smith, U. Impaired preadipocyte differentiation in human abdominal obesity: role of Wnt, tumor necrosis factor-alpha, and inflammation. Diabetes 58, 1550–1557 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Gustafson, B. et al. Inflammation and impaired adipogenesis in hypertrophic obesity in man. Am. J. Physiol. Endocrinol. Metab. 297, E999–E1003 (2009).

    Article  CAS  PubMed  Google Scholar 

  139. Roubert, A. et al. The influence of tumor necrosis factor-α on the tumorigenic Wnt-signaling pathway in human mammary tissue from obese women. Oncotarget 8, 36127–36136 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Guo, C. et al. Genetic ablation of tumor necrosis factor-alpha attenuates the promoted colonic Wnt signaling in high fat diet-induced obese mice. J. Nutr. Biochem. 77, 108302 (2020).

    Article  CAS  PubMed  Google Scholar 

  141. Verjee, L. S. et al. Unraveling the signaling pathways promoting fibrosis in Dupuytren’s disease reveals TNF as a therapeutic target. Proc. Natl Acad. Sci. U.S.A. 110, E928–E937 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Ruan, H., Hacohen, N., Golub, T. R., Van Parijs, L. & Lodish, H. F. Tumor necrosis factor-alpha suppresses adipocyte-specific genes and activates expression of preadipocyte genes in 3T3-L1 adipocytes: nuclear factor-kappaB activation by TNF-alpha is obligatory. Diabetes 51, 1319–1336 (2002).

    Article  CAS  PubMed  Google Scholar 

  143. Bhatnagar, S. et al. Tumor necrosis factor-α regulates distinct molecular pathways and gene networks in cultured skeletal muscle cells. PLoS One 5, e13262 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Cheshire, J. L. & Baldwin, A. S. Jr. Synergistic activation of NF-kappaB by tumor necrosis factor alpha and gamma interferon via enhanced I kappaB alpha degradation and de novo I kappaBbeta degradation. Mol. Cell. Biol. 17, 6746–6754 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Wright, H. L., Thomas, H. B., Moots, R. J. & Edwards, S. W. RNA-seq reveals activation of both common and cytokine-specific pathways following neutrophil priming. PLoS One 8, e58598 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. McGeough, M. D. et al. TNF regulates transcription of NLRP3 inflammasome components and inflammatory molecules in cryopyrinopathies. J. Clin. Invest. 127, 4488–4497 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Peraldi, P., Xu, M. & Spiegelman, B. M. Thiazolidinediones block tumor necrosis factor-alpha-induced inhibition of insulin signaling. J. Clin. Invest. 100, 1863–1869 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Cerami, A. TNF and EPO: major players in the innate immune response: their discovery. Ann. Rheum. Dis. 71, i55–i59 (2012).

    Article  CAS  PubMed  Google Scholar 

  149. Moreira, A. L. et al. Thalidomide exerts its inhibitory action on tumor necrosis factor alpha by enhancing mRNA degradation. J. Exp. Med. 177, 1675–1680 (1993).

    Article  CAS  PubMed  Google Scholar 

  150. Kruys, V., Marinx, O., Shaw, G., Deschamps, J. & Huez, G. Translational blockade imposed by cytokine-derived UA-rich sequences. Science 245, 852–855 (1989).

    Article  CAS  PubMed  Google Scholar 

  151. Belarbi, K. et al. TNF-α protein synthesis inhibitor restores neuronal function and reverses cognitive deficits induced by chronic neuroinflammation. J. Neuroinflammation 9, 23 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Wong, E. et al. Harnessing the natural inhibitory domain to control TNFα converting enzyme (TACE) activity in vivo. Sci Rep. 6, 35598 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Cui, X. et al. Trivalent soluble TNF receptor, a potent TNF-α antagonist for the treatment collagen-induced arthritis. Sci Rep. 8, 7327 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  154. Shepard, H. M., Phillips, G. L., D Thanos, C. & Feldmann, M. Developments in therapy with monoclonal antibodies and related proteins. Clin. Med. (Lond.) 17, 220–232 (2017).

    Article  Google Scholar 

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Acknowledgements

J.K.S. is funded by the Welcome Trust (grant number 206453/Z/17/Z) and the UK National Institute for Health Research Southampton Biomedical Research Centre. G.S.H. is funded by grants from the US National Institutes of Health (grant numbers DK123458 and HL125753), the Juvenile Diabetes Research Foundation and Lab1636.

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Authors and Affiliations

  1. Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK

    Jaswinder K. Sethi

  2. National Institute for Health Research Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton National Health Service (NHS) Foundation Trust, Southampton, UK

    Jaswinder K. Sethi

  3. Institute for Life Sciences, University of Southampton, Southampton, UK

    Jaswinder K. Sethi

  4. Sabri Ülker Center for Metabolic Research, Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Gökhan S. Hotamisligil

  5. Harvard-MIT Broad Institute, Boston, MA, USA

    Gökhan S. Hotamisligil

  6. Harvard Stem Cell Institute, Boston, MA, USA

    Gökhan S. Hotamisligil

  7. The Joslin Diabetes Center, Boston, MA, USA

    Gökhan S. Hotamisligil

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  1. Jaswinder K. Sethi
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  2. Gökhan S. Hotamisligil
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Correspondence to Jaswinder K. Sethi or Gökhan S. Hotamisligil.

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Peer review information Nature Metabolism thanks Mark Febbraio and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editors: George Caputa; Ashley Castellanos-Jankiewicz.

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Sethi, J.K., Hotamisligil, G.S. Metabolic Messengers: tumour necrosis factor. Nat Metab 3, 1302–1312 (2021). https://doi.org/10.1038/s42255-021-00470-z

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