Skip to main content

Advertisement

SpringerLink
Log in

The obesity-related pathology and Th17 cells

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Chronic inflammation associated with obesity plays a major role in the development of metabolic diseases, cancer, and autoimmune diseases. Among Th subsets, Th17 cells are involved in the pathogenesis of autoimmune disorders such as psoriasis, rheumatoid arthritis, inflammatory bowel disease, steroid-resistant asthma, and multiple sclerosis. Accumulating data suggest that reciprocal interactions between the metabolic systems and immune system play pivotal roles in the pathogenesis of obesity-associated diseases. We herein outline the developing principles in the control of T cell differentiation and function via their cellular metabolism. Also discussed are recent findings that changes in the intracellular metabolism, including fatty acid metabolism, affect the Th17 cell function in obese individuals. Finally, we will also highlight the unique molecular mechanism involved in the activation of retinoid-related orphan receptor-gamma-t (RORγt) by intracellular metabolism and discuss a new therapeutic approach for treating autoimmune disorders through the inhibition of RORγt.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

RORγt:

Retinoid-related orphan receptor-gamma-t

Th:

Helper T cell

ATMs:

Adipose tissue macrophages

VAT:

Visceral adipose tissue

SAT:

Subcutaneous adipose tissue

ILC2s:

Group 2 innate lymphoid cells

MS:

Multiple sclerosis, psoriasis

IBD:

Inflammatory bowel disease

RA:

Rheumatoid arthritis

MMPs:

Matrix metalloproteases

SVCs:

Stromal vascular cells

DTR:

Diphtheria toxin receptor

MSC:

Mesenchymal stem cell

CNS:

Central nervous system

GWAS:

Genome-wide association study

OXPHOS:

Oxidative phosphorylation

STAT:

Transcription factor signal transducer and activator

BATF:

Basic leucine zipper transcription factor ATF-like

IRF:

Interferon-regulatory factor

SREBP:

Sterol regulatory element-binding protein

ERRα:

Estrogen related receptor-alpha

LXR:

Liver X receptor

FAO:

Fatty acid oxidation

SRC-1:

Steroid receptor coactivator 1 (SRC-1)

Dig (dhd):

20,22-Dihydrodigoxin-21,23-diol

Dig (sal):

Digoxin-21-salicylidene

ChIP:

Chromatin immunoprecipitation

CBIs:

Cholesterol biosynthetic intermediates

References

  1. Gregor MF, Hotamisligil GS (2011) Inflammatory mechanisms in obesity. Annu Rev Immunol 29:415–445

    Article  CAS  PubMed  Google Scholar 

  2. Ng M et al (2014) Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 384:766–781

    Article  PubMed  PubMed Central  Google Scholar 

  3. Kanneganti TD, Dixit VD (2012) Immunological complications of obesity. Nat Immunol 13:707–712

    Article  CAS  PubMed  Google Scholar 

  4. Kim HY et al (2014) Interleukin-17-producing innate lymphoid cells and the NLRP3 inflammasome facilitate obesity-associated airway hyperreactivity. Nat Med 20:54–61

    Article  CAS  PubMed  Google Scholar 

  5. Osborn O, Olefsky JM (2012) The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med 18:363–374

    Article  CAS  PubMed  Google Scholar 

  6. Winer S et al (2009) Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med 15:921–929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kaminski DA, Randall TD (2010) Adaptive immunity and adipose tissue biology. Trends Immunol 31:384–390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Mauer J et al (2014) Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin. Nat Immunol 15:423–430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Stienstra R et al (2012) The inflammasome puts obesity in the danger zone. Cell Metab 15:10–18

    Article  CAS  PubMed  Google Scholar 

  10. Winer DA et al (2011) B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat Med 17:610–617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. O’Shea JJ, Paul WE (2010) Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 327:1098–1102

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Reiner SL (2007) Development in motion: helper T cells at work. Cell 129:33–36

    Article  CAS  PubMed  Google Scholar 

  13. Endo Y et al (2014) Pathogenic memory type Th2 cells in allergic inflammation. Trends Immunol 35:69–78

    Article  CAS  PubMed  Google Scholar 

  14. Bettelli E et al (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441:235–238

    Article  CAS  PubMed  Google Scholar 

  15. Ivanov II et al (2006) The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126:1121–1133

    Article  CAS  PubMed  Google Scholar 

  16. Leonardi C et al (2012) Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N Engl J Med 366:1190–1199

    Article  CAS  PubMed  Google Scholar 

  17. McGeachy MJ, Cua DJ (2008) Th17 cell differentiation: the long and winding road. Immunity 28:445–453

    Article  CAS  PubMed  Google Scholar 

  18. Nylander A, Hafler DA (2012) Multiple sclerosis. J Clin Invest 122:1180–1188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Stockinger B et al (2007) Th17 T cells: linking innate and adaptive immunity. Semin Immunol 19:353–361

    Article  CAS  PubMed  Google Scholar 

  20. Sundrud MS et al (2009) Halofuginone inhibits TH17 cell differentiation by activating the amino acid starvation response. Science 324:1334–1338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Yang J et al (2014) Targeting Th17 cells in autoimmune diseases. Trends Pharmacol Sci 35:493–500

    Article  CAS  PubMed  Google Scholar 

  22. Chawla A et al (2011) Macrophage-mediated inflammation in metabolic disease. Nat Rev Immunol 11:738–749

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Spiegelman BM, Hotamisligil GS (1993) Through thick and thin: wasting, obesity, and TNF alpha. Cell 73:625–627

    Article  CAS  PubMed  Google Scholar 

  24. Lumeng CN et al (2007) Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity. Diabetes 56:16–23

    Article  CAS  PubMed  Google Scholar 

  25. Weisberg SP et al (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112:1796–1808

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lumeng CN et al (2007) Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 117:175–184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Nguyen MT et al (2007) A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-dependent pathways. J Biol Chem 282:35279–35292

    Article  CAS  PubMed  Google Scholar 

  28. Kratz M et al (2014) Metabolic dysfunction drives a mechanistically distinct proinflammatory phenotype in adipose tissue macrophages. Cell Metab 20:614–625

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Patsouris D et al (2008) Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell Metab 8:301–309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Weisberg SP et al (2006) CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest 116:115–124

    Article  CAS  PubMed  Google Scholar 

  31. Feuerer M et al (2009) Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 15:930–939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Nishimura S et al (2009) CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med 15:914–920

    Article  CAS  PubMed  Google Scholar 

  33. Brestoff JR et al (2015) Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity. Nature 519:242–246

    Article  CAS  PubMed  Google Scholar 

  34. Nussbaum JC et al (2013) Type 2 innate lymphoid cells control eosinophil homeostasis. Nature 502:245–248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Winer S et al (2009) Obesity predisposes to Th17 bias. Eur J Immunol 39:2629–2635

    Article  CAS  PubMed  Google Scholar 

  36. Zuniga LA et al (2010) IL-17 regulates adipogenesis, glucose homeostasis, and obesity. J Immunol 185:6947–6959

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Shin JH et al (2009) Interleukin-17A inhibits adipocyte differentiation in human mesenchymal stem cells and regulates pro-inflammatory responses in adipocytes. Biochem Pharmacol 77:1835–1844

    Article  CAS  PubMed  Google Scholar 

  38. Ghannam S et al (2010) Mesenchymal stem cells inhibit human Th17 cell differentiation and function and induce a T regulatory cell phenotype. J Immunol 185:302–312

    Article  CAS  PubMed  Google Scholar 

  39. Sumarac-Dumanovic M et al (2009) Increased activity of interleukin-23/interleukin-17 proinflammatory axis in obese women. Int J Obes 33:151–156

    Article  CAS  Google Scholar 

  40. Zapata-Gonzalez F et al (2015) Interleukin-17A gene expression in morbidly obese women. Int J Mol Sci 16:17469–17481

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Pandolfi JB et al (2016) ATP-induced inflammation drives tissue-resident Th17 cells in metabolically unhealthy obesity. J Immunol 196:3287–3296

    Article  CAS  PubMed  Google Scholar 

  42. Panduro M et al (2016) Tissue Tregs. Annu Rev Immunol 34:609–633

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Eller K et al (2011) Potential role of regulatory T cells in reversing obesity-linked insulin resistance and diabetic nephropathy. Diabetes 60:2954–2962

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Bapat SP et al (2015) Depletion of fat-resident Treg cells prevents age-associated insulin resistance. Nature 528:137–141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Milner JD et al (2008) Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 452:773–776

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Korn T et al (2009) IL-17 and Th17 cells. Annu Rev Immunol 27:485–517

    Article  CAS  PubMed  Google Scholar 

  47. Koenders MI et al (2005) Interleukin-17 receptor deficiency results in impaired synovial expression of interleukin-1 and matrix metalloproteinases 3, 9, and 13 and prevents cartilage destruction during chronic reactivated streptococcal cell wall-induced arthritis. Arthritis Rheum 52:3239–3247

    Article  CAS  PubMed  Google Scholar 

  48. Sarkar S, Fox DA (2010) Targeting IL-17 and Th17 cells in rheumatoid arthritis. Rheum Dis Clin North Am 36:345–366

    Article  PubMed  Google Scholar 

  49. Langrish CL et al (2005) IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 201:233–240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Hofstetter HH et al (2005) Therapeutic efficacy of IL-17 neutralization in murine experimental autoimmune encephalomyelitis. Cell Immunol 237:123–130

    Article  CAS  PubMed  Google Scholar 

  51. McGeachy MJ et al (2007) TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol 8:1390–1397

    Article  CAS  PubMed  Google Scholar 

  52. Hueber W et al (2012) Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut 61:1693–1700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Codarri L et al (2011) RORgammat drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat Immunol 12:560–567

    Article  CAS  PubMed  Google Scholar 

  54. Duvallet E et al (2011) Interleukin-23: a key cytokine in inflammatory diseases. Ann Med 43:503–511

    Article  CAS  PubMed  Google Scholar 

  55. Cargill M et al (2007) A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet 80:273–290

    Article  CAS  PubMed  Google Scholar 

  56. Rahman P et al (2009) Association of interleukin 23 receptor variants with psoriatic arthritis. J Rheumatol 36:137–140

    CAS  PubMed  Google Scholar 

  57. Huber AK et al (2008) Interleukin (IL)-23 receptor is a major susceptibility gene for Graves’ ophthalmopathy: the IL-23/T-helper 17 axis extends to thyroid autoimmunity. J Clin Endocrinol Metab 93:1077–1081

    Article  CAS  PubMed  Google Scholar 

  58. Nunez C et al (2008) IL23R: a susceptibility locus for celiac disease and multiple sclerosis? Genes Immun 9:289–293

    Article  CAS  PubMed  Google Scholar 

  59. Jager A et al (2009) Th1, Th17, and Th9 effector cells induce experimental autoimmune encephalomyelitis with different pathological phenotypes. J Immunol 183:7169–7177

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Lee Y et al (2012) Induction and molecular signature of pathogenic TH17 cells. Nat Immunol 13:991–999

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Ghoreschi K et al (2010) Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling. Nature 467:967–971

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Kleinewietfeld M et al (2013) Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature 496:518–522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Wu C et al (2013) Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature 496:513–517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Endo Y et al (2015) Obesity drives Th17 cell differentiation by inducing the lipid metabolic kinase, ACC1. Cell Rep 12:1042–1055

    Article  CAS  PubMed  Google Scholar 

  65. Smith-Garvin JE et al (2009) T cell activation. Annu Rev Immunol 27:591–619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Pearce EL, Pearce EJ (2013) Metabolic pathways in immune cell activation and quiescence. Immunity 38:633–643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Pollizzi KN, Powell JD (2014) Integrating canonical and metabolic signalling programmes in the regulation of T cell responses. Nat Rev Immunol 14:435–446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Vander Heiden MG et al (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–1033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. MacIver NJ et al (2013) Metabolic regulation of T lymphocytes. Annu Rev Immunol 31:259–283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Carr EL et al (2010) Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation. J Immunol 185:1037–1044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Frauwirth KA et al (2002) The CD28 signaling pathway regulates glucose metabolism. Immunity 16:769–777

    Article  CAS  PubMed  Google Scholar 

  72. Macintyre AN et al (2014) The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab 20:61–72

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Wang R et al (2011) The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35:871–882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Michalek RD et al (2011) Estrogen-related receptor-alpha is a metabolic regulator of effector T-cell activation and differentiation. Proc Natl Acad Sci USA 108:18348–18353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Kidani Y et al (2013) Sterol regulatory element-binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity. Nat Immunol 14:489–499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Bensinger SJ et al (2008) LXR signaling couples sterol metabolism to proliferation in the acquired immune response. Cell 134:97–111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Waickman AT, Powell JD (2012) mTOR, metabolism, and the regulation of T-cell differentiation and function. Immunol Rev 249:43–58

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Mondino A, Mueller DL (2007) mTOR at the crossroads of T cell proliferation and tolerance. Semin Immunol 19:162–172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Chi H (2012) Regulation and function of mTOR signalling in T cell fate decisions. Nat Rev Immunol 12:325–338

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Duvel K et al (2010) Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol Cell 39:171–183

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Wang R, Green DR (2012) Metabolic checkpoints in activated T cells. Nat Immunol 13:907–915

    Article  CAS  PubMed  Google Scholar 

  82. Yang L et al (2008) IL-21 and TGF-beta are required for differentiation of human T(H)17 cells. Nature 454:350–352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Durant L et al (2010) Diverse targets of the transcription factor STAT3 contribute to T cell pathogenicity and homeostasis. Immunity 32:605–615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Wang X et al (2012) Transcription of Il17 and Il17f is controlled by conserved noncoding sequence 2. Immunity 36:23–31

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Ciofani M et al (2012) A validated regulatory network for Th17 cell specification. Cell 151:289–303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Gaffen SL et al (2014) The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing. Nat Rev Immunol 14:585–600

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Brustle A et al (2007) The development of inflammatory T(H)-17 cells requires interferon-regulatory factor 4. Nat Immunol 8:958–966

    Article  PubMed  CAS  Google Scholar 

  88. Schraml BU et al (2009) The AP-1 transcription factor Batf controls T(H)17 differentiation. Nature 460:405–409

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Dang EV et al (2011) Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell 146:772–784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Jain R et al (2016) Interleukin-23-induced transcription factor blimp-1 promotes pathogenicity of T helper 17 cells. Immunity 44:131–142

    Article  CAS  PubMed  Google Scholar 

  91. Delgoffe GM et al (2009) The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30:832–844

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Delgoffe GM et al (2011) The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat Immunol 12:295–303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Lee K et al (2010) Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways. Immunity 32:743–753

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Michalek RD et al (2011) Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J Immunol 186:3299–3303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Shi LZ et al (2011) HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med 208:1367–1376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Jacobs SR et al (2008) Glucose uptake is limiting in T cell activation and requires CD28-mediated Akt-dependent and independent pathways. J Immunol 180:4476–4486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Ikejiri A et al (2012) Dynamic regulation of Th17 differentiation by oxygen concentrations. Int Immunol 24:137–146

    Article  CAS  PubMed  Google Scholar 

  98. Klotz L et al (2009) The nuclear receptor PPAR gamma selectively inhibits Th17 differentiation in a T cell-intrinsic fashion and suppresses CNS autoimmunity. J Exp Med 206:2079–2089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Li B et al (2009) Regulation of Th17 differentiation by epidermal fatty acid-binding protein. J Immunol 182:7625–7633

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Reynolds JM et al (2007) Deficiency of fatty acid-binding proteins in mice confers protection from development of experimental autoimmune encephalomyelitis. J Immunol 179:313–321

    Article  CAS  PubMed  Google Scholar 

  101. Cui G et al (2011) Liver X receptor (LXR) mediates negative regulation of mouse and human Th17 differentiation. J Clin Invest 121:658–670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Quintana FJ et al (2008) Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature 453:65–71

    Article  CAS  PubMed  Google Scholar 

  103. Veldhoen M et al (2008) The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453:106–109

    Article  CAS  PubMed  Google Scholar 

  104. Veldhoen M et al (2009) Natural agonists for aryl hydrocarbon receptor in culture medium are essential for optimal differentiation of Th17 T cells. J Exp Med 206:43–49

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Ao A et al (2008) Involvement of estrogen-related receptors in transcriptional response to hypoxia and growth of solid tumors. Proc Natl Acad Sci USA 105:7821–7826

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Gerriets VA et al (2015) Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation. J Clin Invest 125:194–207

    Article  PubMed  Google Scholar 

  107. Berod L et al (2014) De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat Med 20:1327–1333

    Article  CAS  PubMed  Google Scholar 

  108. Matsuo S et al (2014) Fatty acid synthase inhibitor C75 ameliorates experimental colitis. Mol Med 20:1–9

    Article  PubMed  CAS  Google Scholar 

  109. Jetten AM (2009) Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism. Nucl Recept Signal 7:e003

    PubMed  PubMed Central  Google Scholar 

  110. Jetten AM et al (2001) The ROR nuclear orphan receptor subfamily: critical regulators of multiple biological processes. Prog Nucleic Acid Res Mol Biol 69:205–247

    Article  CAS  PubMed  Google Scholar 

  111. Steinmetz AC et al (2001) Binding of ligands and activation of transcription by nuclear receptors. Annu Rev Biophys Biomol Struct 30:329–359

    Article  CAS  PubMed  Google Scholar 

  112. Yang XO et al (2008) Regulation of inflammatory responses by IL-17F. J Exp Med 205:1063–1075

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Du J et al (2008) Isoform-specific inhibition of ROR alpha-mediated transcriptional activation by human FOXP3. J Immunol 180:4785–4792

    Article  CAS  PubMed  Google Scholar 

  114. Xiao S et al (2014) Small-molecule RORgammat antagonists inhibit T helper 17 cell transcriptional network by divergent mechanisms. Immunity 40:477–489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Solt LA et al (2011) Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. Nature 472:491–494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Huh JR et al (2011) Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORgammat activity. Nature 472:486–490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Xu T et al (2011) Ursolic acid suppresses interleukin-17 (IL-17) production by selectively antagonizing the function of RORgamma t protein. J Biol Chem 286:22707–22710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Kurebayashi Y et al (2012) PI3K-Akt-mTORC1-S6K1/2 axis controls Th17 differentiation by regulating Gfi1 expression and nuclear translocation of RORgamma. Cell Rep 1:360–373

    Article  CAS  PubMed  Google Scholar 

  119. Stehlin C et al (2001) X-ray structure of the orphan nuclear receptor RORbeta ligand-binding domain in the active conformation. EMBO J 20:5822–5831

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Slominski AT et al (2014) RORalpha and ROR gamma are expressed in human skin and serve as receptors for endogenously produced noncalcemic 20-hydroxy- and 20,23-dihydroxyvitamin D. FASEB J 28:2775–2789

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Soroosh P et al (2014) Oxysterols are agonist ligands of RORgammat and drive Th17 cell differentiation. Proc Natl Acad Sci USA 111:12163–12168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Santori FR et al (2015) Identification of natural RORgamma ligands that regulate the development of lymphoid cells. Cell Metab 21:286–297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Wang Y et al (2010) A second class of nuclear receptors for oxysterols: regulation of RORalpha and RORgamma activity by 24S-hydroxycholesterol (cerebrosterol). Biochim Biophys Acta 1801:917–923

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Wang Y et al (2010) Modulation of retinoic acid receptor-related orphan receptor alpha and gamma activity by 7-oxygenated sterol ligands. J Biol Chem 285:5013–5025

    Article  CAS  PubMed  Google Scholar 

  125. Haghikia A et al (2015) Dietary fatty acids directly impact central nervous system autoimmunity via the small intestine. Immunity 43:817–829

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Global COE Program (Global Center for Education and Research in Immune System Regulation and Treatment), and by grants from the Ministry of Education, Culture, Sports, Science and Technology (MEXT Japan) (Grants-in-Aid: for Scientific Research (S) #26221305, (B) #21390147 and #26293165, Young Scientists [A] #16H06224, and (B) #24790461, Challenging Exploratory Research #26670362 and #23659240, Grant-in-Aid for Scientific Research on Innovative Areas #16H01352, and Scientific Research on Innovative Areas ‘Stem Cell Aging’ #26115009), the Ministry of Health, Labor and Welfare, The Astellas Foundation for Research on Metabolic Disorders, The Uehara Memorial Foundation, Osaka Foundation for Promotion of Fundamental Medical Research, Kanae Foundation for the Promotion of Medical Science, Princes Takamatsu Cancer Research Fund and Takeda Science Foundation.

Author information

Authors and Affiliations

  1. Department of Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan

    Yusuke Endo & Toshinori Nakayama

  2. Department of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan

    Koutaro Yokote

  3. AMED-CREST, AMED, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan

    Toshinori Nakayama

Authors
  1. Yusuke Endo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Koutaro Yokote
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Toshinori Nakayama
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Toshinori Nakayama.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Endo, Y., Yokote, K. & Nakayama, T. The obesity-related pathology and Th17 cells. Cell. Mol. Life Sci. 74, 1231–1245 (2017). https://doi.org/10.1007/s00018-016-2399-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-016-2399-3

Keywords

Search

Navigation