Skip to main content

Immune Cells and Metabolism

  • Chapter
Metabolic Control

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 233))

Abstract

Low-grade inflammation in the obese AT (AT) and the liver is a critical player in the development of obesity-related metabolic dysregulation, including insulin resistance, type 2 diabetes and non-alcoholic steatohepatitis (NASH). Myeloid as well as lymphoid cells infiltrate the AT and the liver and expand within these metabolic organs as a result of excessive nutrient intake, thereby exacerbating tissue inflammation. Macrophages are the paramount cell population in the field of metabolism-related inflammation; as obesity progresses, a switch takes place within the AT environment from an M2-alternatively activated macrophage state to an M1-inflammatory macrophage-dominated milieu. M1-polarized macrophages secrete inflammatory cytokines like TNF in the obese AT; such cytokines contribute to insulin resistance in adipocytes. Besides macrophages, also CD8+ T cells promote inflammation in the AT and the liver and thereby the deterioration of the metabolic balance in adipocytes and hepatocytes. Other cells of the innate immunity, such as neutrophils or mast cells, interfere with metabolic homeostasis as well. On the other hand, eosinophils or T-regulatory cells, the number of which in the AT decreases in the course of obesity, function to maintain metabolic balance by ameliorating inflammatory processes. In addition, eosinophils and M2-polarized macrophages may contribute to “beige” adipogenesis under lean conditions; beige adipocytes are located predominantly in the subcutaneous AT and have thermogenic and optimal energy-dispensing properties like brown adipocytes. This chapter will summarize the different aspects of the regulation of homeostasis of metabolic tissues by immune cells.

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

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Adler M, Taylor S, Okebugwu K, Yee H, Fielding C, Fielding G, Poles M (2011) Intrahepatic natural killer T cell populations are increased in human hepatic steatosis. World J Gastroenterol 17:1725–1731

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Altintas MM, Azad A, Nayer B, Contreras G, Zaias J, Faul C, Reiser J, Nayer A (2011a) Mast cells, macrophages, and crown-like structures distinguish subcutaneous from visceral fat in mice. J Lipid Res 52:480–488

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Altintas MM, Rossetti MA, Nayer B, Puig A, Zagallo P, Ortega LM, Johnson KB, McNamara G, Reiser J, Mendez AJ, Nayer A (2011b) Apoptosis, mastocytosis, and diminished adipocytokine gene expression accompany reduced epididymal fat mass in long-standing diet-induced obese mice. Lipids Health Dis 10:198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Altintas MM, Nayer B, Walford EC, Johnson KB, Gaidosh G, Reiser J, De La Cruz-Munoz N, Ortega LM, Nayer A (2012) Leptin deficiency-induced obesity affects the density of mast cells in abdominal fat depots and lymph nodes in mice. Lipids Health Dis 11:21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Annunziato F, Romagnani C, Romagnani S (2014) The 3 major types of innate and adaptive cell-mediated effector immunity. J Allergy Clin Immunol 135:626–635

    Article  PubMed  CAS  Google Scholar 

  • Arkan MC, Hevener AL, Greten FR, Maeda S, Li ZW, Long JM, Wynshaw-Boris A, Poli G, Olefsky J, Karin M (2005) IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med 11:191–198

    Article  CAS  PubMed  Google Scholar 

  • Bai Y, Sun Q (2015) Macrophage recruitment in obese adipose tissue. Obes Rev 16:127–136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bertola A, Ciucci T, Rousseau D, Bourlier V, Duffaut C, Bonnafous S, Blin-Wakkach C, Anty R, Iannelli A, Gugenheim J, Tran A, Bouloumie A, Gual P, Wakkach A (2012) Identification of adipose tissue dendritic cells correlated with obesity-associated insulin-resistance and inducing Th17 responses in mice and patients. Diabetes 61:2238–2247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bieghs V, Walenbergh SM, Hendrikx T, van Gorp PJ, Verheyen F, Olde Damink SW, Masclee AA, Koek GH, Hofker MH, Binder CJ, Shiri-Sverdlov R (2013) Trapping of oxidized LDL in lysosomes of Kupffer cells is a trigger for hepatic inflammation. Liver Int 33:1056–1061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Borg NA, Wun KS, Kjer-Nielsen L, Wilce MC, Pellicci DG, Koh R, Besra GS, Bharadwaj M, Godfrey DI, McCluskey J, Rossjohn J (2007) CD1d-lipid-antigen recognition by the semi-invariant NKT T-cell receptor. Nature 448:44–49

    Article  CAS  PubMed  Google Scholar 

  • Brestoff JR, Kim BS, Saenz SA, Stine RR, Monticelli LA, Sonnenberg GF, Thome JJ, Farber DL, Lutfy K, Seale P, Artis D (2014) Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity. Nature 519:242–246

    Google Scholar 

  • Chatzigeorgiou A, Karalis KP, Bornstein SR, Chavakis T (2012) Lymphocytes in obesity-related adipose tissue inflammation. Diabetologia 55:2583–2592

    Article  CAS  PubMed  Google Scholar 

  • Chatzigeorgiou A, Chung KJ, Garcia-Martin R, Alexaki VI, Klotzsche-von Ameln A, Phieler J, Sprott D, Kanczkowski W, Tzanavari T, Bdeir M, Bergmann S, Cartellieri M, Bachmann M, Nikolakopoulou P, Androutsellis-Theotokis A, Siegert G, Bornstein SR, Muders MH, Boon L, Karalis KP, Lutgens E, Chavakis T (2014a) Dual role of B7 costimulation in obesity-related nonalcoholic steatohepatitis and metabolic dysregulation. Hepatology 60:1196–1210

    Article  CAS  PubMed  Google Scholar 

  • Chatzigeorgiou A, Seijkens T, Zarzycka B, Engel D, Poggi M, van den Berg S, van den Berg S, Soehnlein O, Winkels H, Beckers L, Lievens D, Driessen A, Kusters P, Biessen E, Garcia-Martin R, Klotzsche-von Ameln A, Gijbels M, Noelle R, Boon L, Hackeng T, Schulte KM, Xu A, Vriend G, Nabuurs S, Chung KJ, Willems van Dijk K, Rensen PC, Gerdes N, de Winther M, Block NL, Schally AV, Weber C, Bornstein SR, Nicolaes G, Chavakis T, Lutgens E (2014b) Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance. Proc Natl Acad Sci U S A 111:2686–2691

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chawla A, Nguyen KD, Goh YP (2011) Macrophage-mediated inflammation in metabolic disease. Nat Rev Immunol 11:738–749

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen X, Wu Y, Wang L (2013) Fat-resident Tregs: an emerging guard protecting from obesity-associated metabolic disorders. Obes Rev 14:568–578

    Article  CAS  PubMed  Google Scholar 

  • Chen Y, Tian J, Tian X, Tang X, Rui K, Tong J, Lu L, Xu H, Wang S (2014) Adipose tissue dendritic cells enhances inflammation by prompting the generation of Th17 cells. PLoS One 9:e92450

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chmelar J, Chung KJ, Chavakis T (2013) The role of innate immune cells in obese adipose tissue inflammation and development of insulin resistance. Thromb Haemost 109:399–406

    Article  CAS  PubMed  Google Scholar 

  • Cho KW, Morris DL, DelProposto JL, Geletka L, Zamarron B, Martinez-Santibanez G, Meyer KA, Singer K, O’Rourke RW, Lumeng CN (2014) An MHC II-dependent activation loop between adipose tissue macrophages and CD4+ T cells controls obesity-induced inflammation. Cell Rep 9:605–617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cildir G, Akincilar SC, Tergaonkar V (2014) Chronic adipose tissue inflammation: all immune cells on the stage. Trends Mol Med 19:487–500

    Article  CAS  Google Scholar 

  • Cipolletta D, Feuerer M, Li A, Kamei N, Lee J, Shoelson SE, Benoist C, Mathis D (2012) PPAR-gamma is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature 486:549–553

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cipolletta D, Cohen P, Spiegelman BM, Benoist C, Mathis D (2015) Appearance and disappearance of the mRNA signature characteristic of Treg cells in visceral adipose tissue: age, diet, and PPARgamma effects. Proc Natl Acad Sci U S A 112:482–487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cohen JC, Horton JD, Hobbs HH (2011) Human fatty liver disease: old questions and new insights. Science 332:1519–1523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cua DJ, Tato CM (2010) Innate IL-17-producing cells: the sentinels of the immune system. Nat Rev Immunol 10:479–489

    Article  CAS  PubMed  Google Scholar 

  • De Rosa V, Procaccini C, Cali G, Pirozzi G, Fontana S, Zappacosta S, La Cava A, Matarese G (2007) A key role of leptin in the control of regulatory T cell proliferation. Immunity 26:241–255

    Article  PubMed  CAS  Google Scholar 

  • De Taeye BM, Novitskaya T, McGuinness OP, Gleaves L, Medda M, Covington JW, Vaughan DE (2007) Macrophage TNF-alpha contributes to insulin resistance and hepatic steatosis in diet-induced obesity. Am J Physiol Endocrinol Metab 293:E713–E725

    Article  PubMed  CAS  Google Scholar 

  • DeFuria J, Belkina AC, Jagannathan-Bogdan M, Snyder-Cappione J, Carr JD, Nersesova YR, Markham D, Strissel KJ, Watkins AA, Zhu M, Allen J, Bouchard J, Toraldo G, Jasuja R, Obin MS, McDonnell ME, Apovian C, Denis GV, Nikolajczyk BS (2013) B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile. Proc Natl Acad Sci U S A 110:5133–5138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Deiuliis J, Shah Z, Shah N, Needleman B, Mikami D, Narula V, Perry K, Hazey J, Kampfrath T, Kollengode M, Sun Q, Satoskar AR, Lumeng C, Moffatt-Bruce S, Rajagopalan S (2011) Visceral adipose inflammation in obesity is associated with critical alterations in t regulatory cell numbers. PLoS One 6:e16376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Drechsler M, Megens RT, van Zandvoort M, Weber C, Soehnlein O (2010) Hyperlipidemia-triggered neutrophilia promotes early atherosclerosis. Circulation 122:1837–1845

    Article  CAS  PubMed  Google Scholar 

  • Duffaut C, Galitzky J, Lafontan M, Bouloumie A (2009a) Unexpected trafficking of immune cells within the adipose tissue during the onset of obesity. Biochem Biophys Res Commun 384:482–485

    Article  CAS  PubMed  Google Scholar 

  • Duffaut C, Zakaroff-Girard A, Bourlier V, Decaunes P, Maumus M, Chiotasso P, Sengenes C, Lafontan M, Galitzky J, Bouloumie A (2009b) Interplay between human adipocytes and T lymphocytes in obesity: CCL20 as an adipochemokine and T lymphocytes as lipogenic modulators. Arterioscler Thromb Vasc Biol 29:1608–1614

    Article  CAS  PubMed  Google Scholar 

  • Eguchi K, Manabe I (2013) Macrophages and islet inflammation in type 2 diabetes. Diabetes Obes Metab 15(Suppl 3):152–158

    Article  CAS  PubMed  Google Scholar 

  • Eguchi K, Manabe I, Oishi-Tanaka Y, Ohsugi M, Kono N, Ogata F, Yagi N, Ohto U, Kimoto M, Miyake K, Tobe K, Arai H, Kadowaki T, Nagai R (2012) Saturated fatty acid and TLR signaling link beta cell dysfunction and islet inflammation. Cell Metab 15:518–533

    Article  CAS  PubMed  Google Scholar 

  • Ehses JA, Perren A, Eppler E, Ribaux P, Pospisilik JA, Maor-Cahn R, Gueripel X, Ellingsgaard H, Schneider MK, Biollaz G, Fontana A, Reinecke M, Homo-Delarche F, Donath MY (2007) Increased number of islet-associated macrophages in type 2 diabetes. Diabetes 56:2356–2370

    Article  CAS  PubMed  Google Scholar 

  • Elgazar-Carmon V, Rudich A, Hadad N, Levy R (2008) Neutrophils transiently infiltrate intra-abdominal fat early in the course of high-fat feeding. J Lipid Res 49:1894–1903

    Article  CAS  PubMed  Google Scholar 

  • Elinav E, Pappo O, Sklair-Levy M, Margalit M, Shibolet O, Gomori M, Alper R, Thalenfeld B, Engelhardt D, Rabbani E, Ilan Y (2006) Adoptive transfer of regulatory NKT lymphocytes ameliorates non-alcoholic steatohepatitis and glucose intolerance in ob/ob mice and is associated with intrahepatic CD8 trapping. J Pathol 209:121–128

    Article  CAS  PubMed  Google Scholar 

  • Ericksen RE, Rose S, Westphalen CB, Shibata W, Muthupalani S, Tailor Y, Friedman RA, Han W, Fox JG, Ferrante AW Jr, Wang TC (2014) Obesity accelerates Helicobacter felis-induced gastric carcinogenesis by enhancing immature myeloid cell trafficking and TH17 response. Gut 63:385–394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eskan MA, Jotwani R, Abe T, Chmelar J, Lim JH, Liang S, Ciero PA, Krauss JL, Li F, Rauner M, Hofbauer LC, Choi EY, Chung KJ, Hashim A, Curtis MA, Chavakis T, Hajishengallis G (2012) The leukocyte integrin antagonist Del-1 inhibits IL-17-mediated inflammatory bone loss. Nat Immunol 13:465–473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fabbrini E, Cella M, McCartney SA, Fuchs A, Abumrad NA, Pietka TA, Chen Z, Finck BN, Han DH, Magkos F, Conte C, Bradley D, Fraterrigo G, Eagon JC, Patterson BW, Colonna M, Klein S (2013) Association between specific adipose tissue CD4+ T-cell populations and insulin resistance in obese individuals. Gastroenterology 145:366–74.e1-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fabrizi M, Marchetti V, Mavilio M, Marino A, Casagrande V, Cavalera M, Moreno-Navarrete JM, Mezza T, Sorice GP, Fiorentino L, Menghini R, Lauro R, Monteleone G, Giaccari A, Fernandez Real JM, Federici M (2014) IL-21 is a major negative regulator of IRF4-dependent lipolysis affecting Tregs in adipose tissue and systemic insulin sensitivity. Diabetes 63:2086–2096

    Article  CAS  PubMed  Google Scholar 

  • Fantuzzi G, Faggioni R (2000) Leptin in the regulation of immunity, inflammation, and hematopoiesis. J Leukoc Biol 68:437–446

    CAS  PubMed  Google Scholar 

  • Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J, Nayer A, Lee J, Goldfine AB, Benoist C, Shoelson S, Mathis D (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 

  • Fink LN, Costford SR, Lee YS, Jensen TE, Bilan PJ, Oberbach A, Bluher M, Olefsky JM, Sams A, Klip A (2014) Pro-inflammatory macrophages increase in skeletal muscle of high fat-Fed mice and correlate with metabolic risk markers in humans. Obesity (Silver Spring) 22:747–757

    Article  CAS  Google Scholar 

  • Finucane OM, Reynolds CM, McGillicuddy FC, Harford KA, Morrison M, Baugh J, Roche HM (2014) Macrophage migration inhibitory factor deficiency ameliorates high-fat diet induced insulin resistance in mice with reduced adipose inflammation and hepatic steatosis. PLoS One 9:e113369

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fromme T, Klingenspor M (2011) Uncoupling protein 1 expression and high-fat diets. Am J Physiol Regul Integr Comp Physiol 300:R1–R8

    Article  CAS  PubMed  Google Scholar 

  • Fuster JJ, Zuriaga MA, Thi-Minh Ngo D, Farb MG, Aprahamian T, Yamaguchi TP, Gokce N, Walsh K (2014) Non-canonical Wnt signaling promotes obesity-induced adipose tissue inflammation and metabolic dysfunction independent of adipose tissue expansion. Diabetes 64: 1235–1248

    Google Scholar 

  • Gadd VL, Skoien R, Powell EE, Fagan KJ, Winterford C, Horsfall L, Irvine K, Clouston AD (2014) The portal inflammatory infiltrate and ductular reaction in human nonalcoholic fatty liver disease. Hepatology 59:1393–1405

    Article  PubMed  Google Scholar 

  • Getz GS, Vanderlaan PA, Reardon CA (2011) Natural killer T cells in lipoprotein metabolism and atherosclerosis. Thromb Haemost 106:814–819

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3:23–35

    Article  CAS  PubMed  Google Scholar 

  • Gordon S, Martinez FO (2010) Alternative activation of macrophages: mechanism and functions. Immunity 32:593–604

    Article  CAS  PubMed  Google Scholar 

  • Gri G, Frossi B, D’Inca F, Danelli L, Betto E, Mion F, Sibilano R, Pucillo C (2012) Mast cell: an emerging partner in immune interaction. Front Immunol 3:120

    Article  PubMed  PubMed Central  Google Scholar 

  • Hamada M, Abe M, Miyake T, Kawasaki K, Tada F, Furukawa S, Matsuura B, Hiasa Y, Onji M (2011) B cell-activating factor controls the production of adipokines and induces insulin resistance. Obesity (Silver Spring) 19:1915–1922

    Article  CAS  Google Scholar 

  • Harley IT, Stankiewicz TE, Giles DA, Softic S, Flick LM, Cappelletti M, Sheridan R, Xanthakos SA, Steinbrecher KA, Sartor RB, Kohli R, Karp CL, Divanovic S (2014) IL-17 signaling accelerates the progression of nonalcoholic fatty liver disease in mice. Hepatology 59:1830–1839

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harms M, Seale P (2013) Brown and beige fat: development, function and therapeutic potential. Nat Med 19:1252–1263

    Article  CAS  PubMed  Google Scholar 

  • Henning JR, Graffeo CS, Rehman A, Fallon NC, Zambirinis CP, Ochi A, Barilla R, Jamal M, Deutsch M, Greco S, Ego-Osuala M, Bin-Saeed U, Rao RS, Badar S, Quesada JP, Acehan D, Miller G (2013) Dendritic cells limit fibroinflammatory injury in nonalcoholic steatohepatitis in mice. Hepatology 58:589–602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hirai S, Ohyane C, Kim YI, Lin S, Goto T, Takahashi N, Kim CS, Kang J, Yu R, Kawada T (2014) Involvement of mast cells in adipose tissue fibrosis. Am J Physiol Endocrinol Metab 306:E247–E255

    Article  CAS  PubMed  Google Scholar 

  • Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS (2002) A central role for JNK in obesity and insulin resistance. Nature 420:333–336

    Article  CAS  PubMed  Google Scholar 

  • Hivroz C, Chemin K, Tourret M, Bohineust A (2012) Crosstalk between T lymphocytes and dendritic cells. Crit Rev Immunol 32:139–155

    Article  CAS  PubMed  Google Scholar 

  • Huang W, Metlakunta A, Dedousis N, Zhang P, Sipula I, Dube JJ, Scott DK, O’Doherty RM (2010) Depletion of liver Kupffer cells prevents the development of diet-induced hepatic steatosis and insulin resistance. Diabetes 59:347–357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ibusuki R, Uto H, Arima S, Mawatari S, Setoguchi Y, Iwashita Y, Hashimoto S, Maeda T, Tanoue S, Kanmura S, Oketani M, Ido A, Tsubouchi H (2013) Transgenic expression of human neutrophil peptide-1 enhances hepatic fibrosis in mice fed a choline-deficient, L-amino acid-defined diet. Liver Int 33:1549–1556

    CAS  PubMed  Google Scholar 

  • Ichiki T, Sunagawa K (2014) Novel roles of hypoxia response system in glucose metabolism and obesity. Trends Cardiovasc Med 24:197–201

    Article  CAS  PubMed  Google Scholar 

  • Ichimura A, Hirasawa A, Poulain-Godefroy O, Bonnefond A, Hara T, Yengo L, Kimura I, Leloire A, Liu N, Iida K, Choquet H, Besnard P, Lecoeur C, Vivequin S, Ayukawa K, Takeuchi M, Ozawa K, Tauber M, Maffeis C, Morandi A, Buzzetti R, Elliott P, Pouta A, Jarvelin MR, Korner A, Kiess W, Pigeyre M, Caiazzo R, Van Hul W, Van Gaal L, Horber F, Balkau B, Levy-Marchal C, Rouskas K, Kouvatsi A, Hebebrand J, Hinney A, Scherag A, Pattou F, Meyre D, Koshimizu TA, Wolowczuk I, Tsujimoto G, Froguel P (2012) Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human. Nature 483:350–354

    Article  CAS  PubMed  Google Scholar 

  • Ilan Y, Maron R, Tukpah AM, Maioli TU, Murugaiyan G, Yang K, Wu HY, Weiner HL (2010) Induction of regulatory T cells decreases adipose inflammation and alleviates insulin resistance in ob/ob mice. Proc Natl Acad Sci U S A 107:9765–9770

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Inouye KE, Shi H, Howard JK, Daly CH, Lord GM, Rollins BJ, Flier JS (2007) Absence of CC chemokine ligand 2 does not limit obesity-associated infiltration of macrophages into adipose tissue. Diabetes 56:2242–2250

    Article  CAS  PubMed  Google Scholar 

  • Inzaugarat ME, Ferreyra Solari NE, Billordo LA, Abecasis R, Gadano AC, Chernavsky AC (2011) Altered phenotype and functionality of circulating immune cells characterize adult patients with nonalcoholic steatohepatitis. J Clin Immunol 31:1120–1130

    Article  PubMed  Google Scholar 

  • Ioan-Facsinay A, Kwekkeboom JC, Westhoff S, Giera M, Rombouts Y, van Harmelen V, Huizinga TW, Deelder A, Kloppenburg M, Toes RE (2013) Adipocyte-derived lipids modulate CD4+ T-cell function. Eur J Immunol 43:1578–1587

    Article  CAS  PubMed  Google Scholar 

  • Ishijima Y, Ohmori S, Ohneda K (2014) Mast cell deficiency results in the accumulation of preadipocytes in adipose tissue in both obese and non-obese mice. FEBS Open Bio 4:18–24

    Article  CAS  PubMed Central  Google Scholar 

  • Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR (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 

  • Iyer A, Lim J, Poudyal H, Reid RC, Suen JY, Webster J, Prins JB, Whitehead JP, Fairlie DP, Brown L (2012) An inhibitor of phospholipase A2 group IIA modulates adipocyte signaling and protects against diet-induced metabolic syndrome in rats. Diabetes 61:2320–2329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jaensson E, Uronen-Hansson H, Pabst O, Eksteen B, Tian J, Coombes JL, Berg PL, Davidsson T, Powrie F, Johansson-Lindbom B, Agace WW (2008) Small intestinal CD103+ dendritic cells display unique functional properties that are conserved between mice and humans. J Exp Med 205:2139–2149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang E, Perrard XD, Yang D, Khan IM, Perrard JL, Smith CW, Ballantyne CM, Wu H (2014) Essential role of CD11a in CD8+ T-cell accumulation and activation in adipose tissue. Arterioscler Thromb Vasc Biol 34:34–43

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kahn SE, Hull RL, Utzschneider KM (2006) Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444:840–846

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, Kitazawa S, Miyachi H, Maeda S, Egashira K, Kasuga M (2006) MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 116:1494–1505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kang K, Reilly SM, Karabacak V, Gangl MR, Fitzgerald K, Hatano B, Lee CH (2008) Adipocyte-derived Th2 cytokines and myeloid PPARdelta regulate macrophage polarization and insulin sensitivity. Cell Metab 7:485–495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kawasaki K, Abe M, Tada F, Tokumoto Y, Chen S, Miyake T, Furukawa S, Matsuura B, Hiasa Y, Onji M (2013) Blockade of B-cell-activating factor signaling enhances hepatic steatosis induced by a high-fat diet and improves insulin sensitivity. Lab Invest 93:311–321

    Article  CAS  PubMed  Google Scholar 

  • Kelly A, Fahey R, Fletcher JM, Keogh C, Carroll AG, Siddachari R, Geoghegan J, Hegarty JE, Ryan EJ, O’Farrelly C (2014) CD141(+) myeloid dendritic cells are enriched in healthy human liver. J Hepatol 60:135–142

    Article  CAS  PubMed  Google Scholar 

  • Khan IM, Dai Perrard XY, Perrard JL, Mansoori A, Smith CW, Wu H, Ballantyne CM (2014a) Attenuated adipose tissue and skeletal muscle inflammation in obese mice with combined CD4+ and CD8+ T cell deficiency. Atherosclerosis 233:419–428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Khan MT, Nieuwdorp M, Backhed F (2014b) Microbial modulation of insulin sensitivity. Cell Metab 20:753–760

    Article  CAS  PubMed  Google Scholar 

  • Kim DH, Do MS (2015) BAFF knockout improves systemic inflammation via regulating adipose tissue distribution in high-fat diet-induced obesity. Exp Mol Med 47:e129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kintscher U, Hartge M, Hess K, Foryst-Ludwig A, Clemenz M, Wabitsch M, Fischer-Posovszky P, Barth TF, Dragun D, Skurk T, Hauner H, Bluher M, Unger T, Wolf AM, Knippschild U, Hombach V, Marx N (2008) T-lymphocyte infiltration in visceral adipose tissue: a primary event in adipose tissue inflammation and the development of obesity-mediated insulin resistance. Arterioscler Thromb Vasc Biol 28:1304–1310

    Article  CAS  PubMed  Google Scholar 

  • Kita H (2011) Eosinophils: multifaceted biological properties and roles in health and disease. Immunol Rev 242:161–177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Koenen TB, Stienstra R, van Tits LJ, Joosten LA, van Velzen JF, Hijmans A, Pol JA, van der Vliet JA, Netea MG, Tack CJ, Stalenhoef AF, de Graaf J (2011) The inflammasome and caspase-1 activation: a new mechanism underlying increased inflammatory activity in human visceral adipose tissue. Endocrinology 152:3769–3778

    Article  CAS  PubMed  Google Scholar 

  • Kondo T, Toyoshima Y, Ishii Y, Kyuwa S (2013) Natural killer T cells in adipose tissue are activated in lean mice. Exp Anim 62:319–328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kordonowy LL, Burg E, Lenox CC, Gauthier LM, Petty JM, Antkowiak M, Palvinskaya T, Ubags N, Rincon M, Dixon AE, Vernooy JH, Fessler MB, Poynter ME, Suratt BT (2012) Obesity is associated with neutrophil dysfunction and attenuation of murine acute lung injury. Am J Respir Cell Mol Biol 47:120–127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Korn T, Bettelli E, Oukka M, Kuchroo VK (2009) IL-17 and Th17 cells. Annu Rev Immunol 27:485–517

    Article  CAS  PubMed  Google Scholar 

  • Kraakman MJ, Murphy AJ, Jandeleit-Dahm K, Kammoun HL (2014) Macrophage polarization in obesity and type 2 diabetes: weighing down our understanding of macrophage function? Front Immunol 5:470

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kwon H, Pessin JE (2013) Adipokines mediate inflammation and insulin resistance. Front Endocrinol (Lausanne) 4:71

    Google Scholar 

  • Lanthier N, Molendi-Coste O, Horsmans Y, van Rooijen N, Cani PD, Leclercq IA (2010) Kupffer cell activation is a causal factor for hepatic insulin resistance. Am J Physiol Gastrointest Liver Physiol 298:G107–G116

    Article  CAS  PubMed  Google Scholar 

  • Lee BC, Lee J (2014) Cellular and molecular players in adipose tissue inflammation in the development of obesity-induced insulin resistance. Biochim Biophys Acta 1842:446–462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee MW, Odegaard JI, Mukundan L, Qiu Y, Molofsky AB, Nussbaum JC, Yun K, Locksley RM, Chawla A (2015) Activated type 2 innate lymphoid cells regulate beige fat biogenesis. Cell 160:74–87

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leroux A, Ferrere G, Godie V, Cailleux F, Renoud ML, Gaudin F, Naveau S, Prevot S, Makhzami S, Perlemuter G, Cassard-Doulcier AM (2012) Toxic lipids stored by Kupffer cells correlates with their pro-inflammatory phenotype at an early stage of steatohepatitis. J Hepatol 57:141–149

    Article  CAS  PubMed  Google Scholar 

  • Li L, Huang L, Vergis AL, Ye H, Bajwa A, Narayan V, Strieter RM, Rosin DL, Okusa MD (2010) IL-17 produced by neutrophils regulates IFN-gamma-mediated neutrophil migration in mouse kidney ischemia-reperfusion injury. J Clin Invest 120:331–342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liang W, Lindeman JH, Menke AL, Koonen DP, Morrison M, Havekes LM, van den Hoek AM, Kleemann R (2014) Metabolically induced liver inflammation leads to NASH and differs from LPS- or IL-1beta-induced chronic inflammation. Lab Invest 94:491–502

    Article  CAS  PubMed  Google Scholar 

  • Liao X, Sharma N, Kapadia F, Zhou G, Lu Y, Hong H, Paruchuri K, Mahabeleshwar GH, Dalmas E, Venteclef N, Flask CA, Kim J, Doreian BW, Lu KQ, Kaestner KH, Hamik A, Clement K, Jain MK (2011) Kruppel-like factor 4 regulates macrophage polarization. J Clin Invest 121:2736–2749

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lidell ME, Betz MJ, Dahlqvist Leinhard O, Heglind M, Elander L, Slawik M, Mussack T, Nilsson D, Romu T, Nuutila P, Virtanen KA, Beuschlein F, Persson A, Borga M, Enerback S (2013) Evidence for two types of brown adipose tissue in humans. Nat Med 19:631–634

    Article  CAS  PubMed  Google Scholar 

  • Lim J, Iyer A, Liu L, Suen JY, Lohman RJ, Seow V, Yau MK, Brown L, Fairlie DP (2013) Diet-induced obesity, adipose inflammation, and metabolic dysfunction correlating with PAR2 expression are attenuated by PAR2 antagonism. FASEB J 27:4757–4767

    Article  CAS  PubMed  Google Scholar 

  • Liu J, Divoux A, Sun J, Zhang J, Clement K, Glickman JN, Sukhova GK, Wolters PJ, Du J, Gorgun CZ, Doria A, Libby P, Blumberg RS, Kahn BB, Hotamisligil GS, Shi GP (2009) Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice. Nat Med 15:940–945

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Locatelli I, Sutti S, Vacchiano M, Bozzola C, Albano E (2013) NF-kappaB1 deficiency stimulates the progression of non-alcoholic steatohepatitis (NASH) in mice by promoting NKT-cell-mediated responses. Clin Sci (Lond) 124:279–287

    Article  CAS  Google Scholar 

  • Lumeng CN, Bodzin JL, Saltiel AR (2007) Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 117:175–184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lumeng CN, DelProposto JB, Westcott DJ, Saltiel AR (2008) Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes. Diabetes 57:3239–3246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lumeng CN, Maillard I, Saltiel AR (2009) T-ing up inflammation in fat. Nat Med 15:846–847

    Article  CAS  PubMed  Google Scholar 

  • Ma X, Hua J, Mohamood AR, Hamad AR, Ravi R, Li Z (2007) A high-fat diet and regulatory T cells influence susceptibility to endotoxin-induced liver injury. Hepatology 46:1519–1529

    Article  CAS  PubMed  Google Scholar 

  • Mallevaey T, Clarke AJ, Scott-Browne JP, Young MH, Roisman LC, Pellicci DG, Patel O, Vivian JP, Matsuda JL, McCluskey J, Godfrey DI, Marrack P, Rossjohn J, Gapin L (2011) A molecular basis for NKT cell recognition of CD1d-self-antigen. Immunity 34:315–326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mantell BS, Stefanovic-Racic M, Yang X, Dedousis N, Sipula IJ, O’Doherty RM (2011) Mice lacking NKT cells but with a complete complement of CD8+ T-cells are not protected against the metabolic abnormalities of diet-induced obesity. PLoS One 6:e19831

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25:677–686

    Article  CAS  PubMed  Google Scholar 

  • Mantovani A, Cassatella MA, Costantini C, Jaillon S (2011) Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol 11:519–531

    Article  CAS  PubMed  Google Scholar 

  • Martinez FO, Helming L, Gordon S (2009) Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol 27:451–483

    Article  CAS  PubMed  Google Scholar 

  • Martin-Murphy BV, You Q, Wang H, De La Houssaye BA, Reilly TP, Friedman JE, Ju C (2014) Mice lacking natural killer T cells are more susceptible to metabolic alterations following high fat diet feeding. PLoS One 9:e80949

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Matarese G, Di Giacomo A, Sanna V, Lord GM, Howard JK, Di Tuoro A, Bloom SR, Lechler RI, Zappacosta S, Fontana S (2001) Requirement for leptin in the induction and progression of autoimmune encephalomyelitis. J Immunol 166:5909–5916

    Article  CAS  PubMed  Google Scholar 

  • Mazza C, Malissen B (2007) What guides MHC-restricted TCR recognition? Semin Immunol 19:225–235

    Article  CAS  PubMed  Google Scholar 

  • McLaughlin T, Liu LF, Lamendola C, Shen L, Morton J, Rivas H, Winer D, Tolentino L, Choi O, Zhang H, Hui Yen Chng M, Engleman E (2014) T-cell profile in adipose tissue is associated with insulin resistance and systemic inflammation in humans. Arterioscler Thromb Vasc Biol 34:2637–2643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meng F, Wang K, Aoyama T, Grivennikov SI, Paik Y, Scholten D, Cong M, Iwaisako K, Liu X, Zhang M, Osterreicher CH, Stickel F, Ley K, Brenner DA, Kisseleva T (2012) Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice. Gastroenterology 143:765–76.e1-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Merad M, Manz MG (2009) Dendritic cell homeostasis. Blood 113:3418–3427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miura K, Yang L, van Rooijen N, Ohnishi H, Seki E (2012) Hepatic recruitment of macrophages promotes nonalcoholic steatohepatitis through CCR2. Am J Physiol Gastrointest Liver Physiol 302:G1310–G1321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miyake T, Akbar SM, Yoshida O, Chen S, Hiasa Y, Matsuura B, Abe M, Onji M (2010) Impaired dendritic cell functions disrupt antigen-specific adaptive immune responses in mice with nonalcoholic fatty liver disease. J Gastroenterol 45:859–867

    Article  CAS  PubMed  Google Scholar 

  • Molofsky AB, Nussbaum JC, Liang HE, Van Dyken SJ, Cheng LE, Mohapatra A, Chawla A, Locksley RM (2013) Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages. J Exp Med 210:535–549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Monk JM, Hou TY, Turk HF, Weeks B, Wu C, McMurray DN, Chapkin RS (2013) Dietary n-3 polyunsaturated fatty acids (PUFA) decrease obesity-associated Th17 cell-mediated inflammation during colitis. PLoS One 7:e49739

    Article  CAS  Google Scholar 

  • Morris DL, Cho KW, Delproposto JL, Oatmen KE, Geletka LM, Martinez-Santibanez G, Singer K, Lumeng CN (2013) Adipose tissue macrophages function as antigen-presenting cells and regulate adipose tissue CD4+ T cells in mice. Diabetes 62:2762–2772

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murahovschi V, Pivovarova O, Ilkavets I, Dmitrieva RM, Docke S, Keyhani-Nejad F, Gogebakan O, Osterhoff M, Kemper M, Hornemann S, Markova M, Kloting N, Stockmann M, Weickert MO, Lamounier-Zepter V, Neuhaus P, Konradi A, Dooley S, von Loeffelholz C, Bluher M, Pfeiffer AF, Rudovich N (2014) WISP1 is a novel adipokine linked to inflammation in obesity. Diabetes 64:856–866

    Article  PubMed  CAS  Google Scholar 

  • Musilli C, Paccosi S, Pala L, Gerlini G, Ledda F, Mugelli A, Rotella CM, Parenti A (2011) Characterization of circulating and monocyte-derived dendritic cells in obese and diabetic patients. Mol Immunol 49:234–238

    Article  CAS  PubMed  Google Scholar 

  • Myers MG Jr, Leibel RL, Seeley RJ, Schwartz MW (2010) Obesity and leptin resistance: distinguishing cause from effect. Trends Endocrinol Metab 21:643–651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nguyen KD, Qiu Y, Cui X, Goh YP, Mwangi J, David T, Mukundan L, Brombacher F, Locksley RM, Chawla A (2011) Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature 480:104–108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nijhuis J, Rensen SS, Slaats Y, van Dielen FM, Buurman WA, Greve JW (2009) Neutrophil activation in morbid obesity, chronic activation of acute inflammation. Obesity (Silver Spring) 17:2014–2018

    Article  CAS  Google Scholar 

  • Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M, Otsu M, Hara K, Ueki K, Sugiura S, Yoshimura K, Kadowaki T, Nagai R (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 

  • O’Rourke RW, Metcalf MD, White AE, Madala A, Winters BR, Maizlin II, Jobe BA, Roberts CT Jr, Slifka MK, Marks DL (2009) Depot-specific differences in inflammatory mediators and a role for NK cells and IFN-gamma in inflammation in human adipose tissue. Int J Obes (Lond) 33:978–990

    Article  CAS  Google Scholar 

  • O’Shea D, Corrigan M, Dunne MR, Jackson R, Woods C, Gaoatswe G, Moynagh PN, O’Connell J, Hogan AE (2013) Changes in human dendritic cell number and function in severe obesity may contribute to increased susceptibility to viral infection. Int J Obes (Lond) 37:1510–1513

    Article  CAS  Google Scholar 

  • Odegaard JI, Ricardo-Gonzalez RR, Goforth MH, Morel CR, Subramanian V, Mukundan L, Red Eagle A, Vats D, Brombacher F, Ferrante AW, Chawla A (2007) Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature 447:1116–1120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ohmura K, Ishimori N, Ohmura Y, Tokuhara S, Nozawa A, Horii S, Andoh Y, Fujii S, Iwabuchi K, Onoe K, Tsutsui H (2010) Natural killer T cells are involved in adipose tissues inflammation and glucose intolerance in diet-induced obese mice. Arterioscler Thromb Vasc Biol 30:193–199

    Article  CAS  PubMed  Google Scholar 

  • Orr JS, Puglisi MJ, Ellacott KL, Lumeng CN, Wasserman DH, Hasty AH (2012) Toll-like receptor 4 deficiency promotes the alternative activation of adipose tissue macrophages. Diabetes 61:2718–2727

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 

  • Ouchi N, Parker JL, Lugus JJ, Walsh K (2011) Adipokines in inflammation and metabolic disease. Nat Rev Immunol 11:85–97

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pal D, Dasgupta S, Kundu R, Maitra S, Das G, Mukhopadhyay S, Ray S, Majumdar SS, Bhattacharya S (2012) Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat Med 18:1279–1285

    Article  CAS  PubMed  Google Scholar 

  • Patsouris D, Li PP, Thapar D, Chapman J, Olefsky JM, Neels JG (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 

  • Phieler J, Chung KJ, Chatzigeorgiou A, Klotzsche-von Ameln A, Garcia-Martin R, Sprott D, Moisidou M, Tzanavari T, Ludwig B, Baraban E, Ehrhart-Bornstein M, Bornstein SR, Mziaut H, Solimena M, Karalis KP, Economopoulou M, Lambris JD, Chavakis T (2013) The complement anaphylatoxin C5a receptor contributes to obese adipose tissue inflammation and insulin resistance. J Immunol 191:4367–4374

    Article  CAS  PubMed  Google Scholar 

  • Piccirillo CA, d’Hennezel E, Sgouroudis E, Yurchenko E (2008) CD4+Foxp3+ regulatory T cells in the control of autoimmunity: in vivo veritas. Curr Opin Immunol 20:655–662

    Article  CAS  PubMed  Google Scholar 

  • Pulendran B, Artis D (2012) New paradigms in type 2 immunity. Science 337:431–435

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qiu Y, Nguyen KD, Odegaard JI, Cui X, Tian X, Locksley RM, Palmiter RD, Chawla A (2014) Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat. Cell 157:1292–1308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ramkhelawon B, Hennessy EJ, Menager M, Ray TD, Sheedy FJ, Hutchison S, Wanschel A, Oldebeken S, Geoffrion M, Spiro W, Miller G, McPherson R, Rayner KJ, Moore KJ (2014) Netrin-1 promotes adipose tissue macrophage retention and insulin resistance in obesity. Nat Med 20:377–384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rao RR, Long JZ, White JP, Svensson KJ, Lou J, Lokurkar I, Jedrychowski MP, Ruas JL, Wrann CD, Lo JC, Camera DM, Lachey J, Gygi S, Seehra J, Hawley JA, Spiegelman BM (2014) Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis. Cell 157:1279–1291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Raphael I, Nalawade S, Eagar TN, Forsthuber TG (2014) T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine doi: 10.1016/j.cyto.2014.09.011 (Epub ahead of print)

  • Rausch ME, Weisberg S, Vardhana P, Tortoriello DV (2008) Obesity in C57BL/6J mice is characterized by adipose tissue hypoxia and cytotoxic T-cell infiltration. Int J Obes (Lond) 32:451–463

    Article  CAS  Google Scholar 

  • Rensen SS, Slaats Y, Nijhuis J, Jans A, Bieghs V, Driessen A, Malle E, Greve JW, Buurman WA (2009) Increased hepatic myeloperoxidase activity in obese subjects with nonalcoholic steatohepatitis. Am J Pathol 175:1473–1482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rensen SS, Bieghs V, Xanthoulea S, Arfianti E, Bakker JA, Shiri-Sverdlov R, Hofker MH, Greve JW, Buurman WA (2012) Neutrophil-derived myeloperoxidase aggravates non-alcoholic steatohepatitis in low-density lipoprotein receptor-deficient mice. PLoS One 7:e52411

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ricardo-Gonzalez RR, Red Eagle A, Odegaard JI, Jouihan H, Morel CR, Heredia JE, Mukundan L, Wu D, Locksley RM, Chawla A (2010) IL-4/STAT6 immune axis regulates peripheral nutrient metabolism and insulin sensitivity. Proc Natl Acad Sci U S A 107:22617–22622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ricciardi-Castagnoli P, Granucci F (2002) Opinion: interpretation of the complexity of innate immune responses by functional genomics. Nat Rev Immunol 2:881–889

    Article  CAS  PubMed  Google Scholar 

  • Rocha VZ, Folco EJ, Sukhova G, Shimizu K, Gotsman I, Vernon AH, Libby P (2008) Interferon-gamma, a Th1 cytokine, regulates fat inflammation: a role for adaptive immunity in obesity. Circ Res 103:467–476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rossato M, Granzotto M, Macchi V, Porzionato A, Petrelli L, Calcagno A, Vencato J, De Stefani D, Silvestrin V, Rizzuto R, Bassetto F, De Caro R, Vettor R (2014) Human white adipocytes express the cold receptor TRPM8 which activation induces UCP1 expression, mitochondrial activation and heat production. Mol Cell Endocrinol 383:137–146

    Article  CAS  PubMed  Google Scholar 

  • Saito M, Okamatsu-Ogura Y, Matsushita M, Watanabe K, Yoneshiro T, Nio-Kobayashi J, Iwanaga T, Miyagawa M, Kameya T, Nakada K, Kawai Y, Tsujisaki M (2009) High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 58:1526–1531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schenk S, Saberi M, Olefsky JM (2008) Insulin sensitivity: modulation by nutrients and inflammation. J Clin Invest 118:2992–3002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Seijkens T, Kusters P, Chatzigeorgiou A, Chavakis T, Lutgens E (2014) Immune cell crosstalk in obesity: a key role for costimulation? Diabetes 63:3982–3991

    Article  CAS  PubMed  Google Scholar 

  • Seth RK, Das S, Kumar A, Chanda A, Kadiiska MB, Michelotti G, Manautou J, Diehl AM, Chatterjee S (2014) CYP2E1-dependent and leptin-mediated hepatic CD57 expression on CD8+ T cells aid progression of environment-linked nonalcoholic steatohepatitis. Toxicol Appl Pharmacol 274:42–54

    Article  CAS  PubMed  Google Scholar 

  • Shan J, Feng L, Sun G, Chen P, Zhou Y, Xia M, Li H, Li Y (2014) Interplay between mTOR and STAT5 signaling modulates the balance between regulatory and effective T cells. Immunobiology 220:510–517

    Article  PubMed  CAS  Google Scholar 

  • Shen L, Chng MH, Alonso MN, Yuan R, Winer DA, Engleman EG (2014) B-1a lymphocytes attenuate insulin resistance. Diabetes 64:593–603

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS (2006) TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 116:3015–3025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shin JH, Shin DW, Noh M (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 

  • Sim AT, Ludowyke RI, Verrills NM (2006) Mast cell function: regulation of degranulation by serine/threonine phosphatases. Pharmacol Ther 112:425–439

    Article  CAS  PubMed  Google Scholar 

  • Soderberg C, Marmur J, Eckes K, Glaumann H, Sallberg M, Frelin L, Rosenberg P, Stal P, Hultcrantz R (2011) Microvesicular fat, inter cellular adhesion molecule-1 and regulatory T-lymphocytes are of importance for the inflammatory process in livers with non-alcoholic steatohepatitis. APMIS 119:412–420

    Article  PubMed  Google Scholar 

  • Spencer LA, Weller PF (2010) Eosinophils and Th2 immunity: contemporary insights. Immunol Cell Biol 88:250–256

    Article  PubMed  PubMed Central  Google Scholar 

  • Stefanovic-Racic M, Yang X, Turner MS, Mantell BS, Stolz DB, Sumpter TL, Sipula IJ, Dedousis N, Scott DK, Morel PA, Thomson AW, O’Doherty RM (2012) Dendritic cells promote macrophage infiltration and comprise a substantial proportion of obesity-associated increases in CD11c+ cells in adipose tissue and liver. Diabetes 61:2330–2339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stein M, Keshav S, Harris N, Gordon S (1992) Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation. J Exp Med 176:287–292

    Article  CAS  PubMed  Google Scholar 

  • Stienstra R, Saudale F, Duval C, Keshtkar S, Groener JE, van Rooijen N, Staels B, Kersten S, Muller M (2010) Kupffer cells promote hepatic steatosis via interleukin-1beta-dependent suppression of peroxisome proliferator-activated receptor alpha activity. Hepatology 51:511–522

    Article  CAS  PubMed  Google Scholar 

  • Stockinger B, Veldhoen M (2007) Differentiation and function of Th17 T cells. Curr Opin Immunol 19:281–286

    Article  CAS  PubMed  Google Scholar 

  • Stolarczyk E, Vong CT, Perucha E, Jackson I, Cawthorne MA, Wargent ET, Powell N, Canavan JB, Lord GM, Howard JK (2013) Improved insulin sensitivity despite increased visceral adiposity in mice deficient for the immune cell transcription factor T-bet. Cell Metab 17:520–533

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Subramanian S, Chait A (2012) Hypertriglyceridemia secondary to obesity and diabetes. Biochim Biophys Acta 1821:819–825

    Article  CAS  PubMed  Google Scholar 

  • Surmi BK, Hasty AH (2008) Macrophage infiltration into adipose tissue: initiation, propagation and remodeling. Futur Lipidol 3:545–556

    Article  CAS  Google Scholar 

  • Sutti S, Jindal A, Locatelli I, Vacchiano M, Gigliotti L, Bozzola C, Albano E (2014) Adaptive immune responses triggered by oxidative stress contribute to hepatic inflammation in NASH. Hepatology 59:886–897

    Article  CAS  PubMed  Google Scholar 

  • Sutton CE, Mielke LA, Mills KH (2012) IL-17-producing gammadelta T cells and innate lymphoid cells. Eur J Immunol 42:2221–2231

    Article  CAS  PubMed  Google Scholar 

  • Syn WK, Oo YH, Pereira TA, Karaca GF, Jung Y, Omenetti A, Witek RP, Choi SS, Guy CD, Fearing CM, Teaberry V, Pereira FE, Adams DH, Diehl AM (2010) Accumulation of natural killer T cells in progressive nonalcoholic fatty liver disease. Hepatology 51:1998–2007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Syn WK, Agboola KM, Swiderska M, Michelotti GA, Liaskou E, Pang H, Xie G, Philips G, Chan IS, Karaca GF, Pereira Tde A, Chen Y, Mi Z, Kuo PC, Choi SS, Guy CD, Abdelmalek MF, Diehl AM (2012) NKT-associated hedgehog and osteopontin drive fibrogenesis in non-alcoholic fatty liver disease. Gut 61:1323–1329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tajiri K, Shimizu Y, Tsuneyama K, Sugiyama T (2009) Role of liver-infiltrating CD3+CD56+ natural killer T cells in the pathogenesis of nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol 21:673–680

    Article  CAS  PubMed  Google Scholar 

  • Taleb S, Herbin O, Ait-Oufella H, Verreth W, Gourdy P, Barateau V, Merval R, Esposito B, Clement K, Holvoet P, Tedgui A, Mallat Z (2007) Defective leptin/leptin receptor signaling improves regulatory T cell immune response and protects mice from atherosclerosis. Arterioscler Thromb Vasc Biol 27:2691–2698

    Article  CAS  PubMed  Google Scholar 

  • Talukdar S, da Oh Y, Bandyopadhyay G, Li D, Xu J, McNelis J, Lu M, Li P, Yan Q, Zhu Y, Ofrecio J, Lin M, Brenner MB, Olefsky JM (2012) Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat Med 18:1407–1412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tanaka A, Nomura Y, Matsuda A, Ohmori K, Matsuda H (2011) Mast cells function as an alternative modulator of adipogenesis through 15-deoxy-delta-12, 14-prostaglandin J2. Am J Physiol Cell Physiol 301:C1360–C1367

    Article  CAS  PubMed  Google Scholar 

  • Tang Y, Bian Z, Zhao L, Liu Y, Liang S, Wang Q, Han X, Peng Y, Chen X, Shen L, Qiu D, Li Z, Ma X (2011) Interleukin-17 exacerbates hepatic steatosis and inflammation in non-alcoholic fatty liver disease. Clin Exp Immunol 166:281–290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tashiro K, Takai S, Jin D, Yamamoto H, Komeda K, Hayashi M, Tanaka K, Tanigawa N, Miyazaki M (2010) Chymase inhibitor prevents the nonalcoholic steatohepatitis in hamsters fed a methionine- and choline-deficient diet. Hepatol Res 40:514–523

    Article  CAS  PubMed  Google Scholar 

  • Tosello-Trampont AC, Landes SG, Nguyen V, Novobrantseva TI, Hahn YS (2012) Kupffer cells trigger nonalcoholic steatohepatitis development in diet-induced mouse model through tumor necrosis factor-alpha production. J Biol Chem 287:40161–40172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Triggiani M, Granata F, Frattini A, Marone G (2006) Activation of human inflammatory cells by secreted phospholipases A2. Biochim Biophys Acta 1761:1289–1300

    Article  CAS  PubMed  Google Scholar 

  • Tsuruda T, Kato J, Hatakeyama K, Kojima K, Yano M, Yano Y, Nakamura K, Nakamura-Uchiyama F, Matsushima Y, Imamura T, Onitsuka T, Asada Y, Nawa Y, Eto T, Kitamura K (2008) Adventitial mast cells contribute to pathogenesis in the progression of abdominal aortic aneurysm. Circ Res 102:1368–1377

    Article  CAS  PubMed  Google Scholar 

  • van den Berg SM, Seijkens TT, Kusters PJ, Zarzycka B, Beckers L, den Toom M, Gijbels MJ, Chatzigeorgiou A, Weber C, de Winther MP, Chavakis T, Nicolaes GA, Lutgens E (2014) Blocking CD40-TRAF6 interactions by small-molecule inhibitor 6860766 ameliorates the complications of diet-induced obesity in mice. Int J Obes (Lond) doi: 10.1038/ijo.2014.198 (Epub ahead of print)

  • Van Dyken SJ, Locksley RM (2013) Interleukin-4- and interleukin-13-mediated alternatively activated macrophages: roles in homeostasis and disease. Annu Rev Immunol 31:317–343

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Vasanthakumar A, Moro K, Xin A, Liao Y, Gloury R, Kawamoto S, Fagarasan S, Mielke LA, Afshar-Sterle S, Masters SL, Nakae S, Saito H, Wentworth JM, Li P, Liao W, Leonard WJ, Smyth GK, Shi W, Nutt SL, Koyasu S, Kallies A (2015) The transcriptional regulators IRF4, BATF and IL-33 orchestrate development and maintenance of adipose tissue-resident regulatory T cells. Nat Immunol 16:276–285

    Article  CAS  PubMed  Google Scholar 

  • Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, Taittonen M, Laine J, Savisto NJ, Enerback S, Nuutila P (2009) Functional brown adipose tissue in healthy adults. N Engl J Med 360:1518–1525

    Article  CAS  PubMed  Google Scholar 

  • Wagner NM, Brandhorst G, Czepluch F, Lankeit M, Eberle C, Herzberg S, Faustin V, Riggert J, Oellerich M, Hasenfuss G, Konstantinides S, Schafer K (2013) Circulating regulatory T cells are reduced in obesity and may identify subjects at increased metabolic and cardiovascular risk. Obesity (Silver Spring) 21:461–468

    Article  CAS  Google Scholar 

  • Wan YY, Flavell RA (2009) How diverse–CD4 effector T cells and their functions. J Mol Cell Biol 1:20–36

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Q, Xie Z, Zhang W, Zhou J, Wu Y, Zhang M, Zhu H, Zou MH (2014) Myeloperoxidase deletion prevents high-fat diet-induced obesity and insulin resistance. Diabetes 63:4172–4185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wehr A, Baeck C, Heymann F, Niemietz PM, Hammerich L, Martin C, Zimmermann HW, Pack O, Gassler N, Hittatiya K, Ludwig A, Luedde T, Trautwein C, Tacke F (2013) Chemokine receptor CXCR6-dependent hepatic NK T cell accumulation promotes inflammation and liver fibrosis. J Immunol 190:5226–5236

    Article  CAS  PubMed  Google Scholar 

  • Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112:1796–1808

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weitman ES, Aschen SZ, Farias-Eisner G, Albano N, Cuzzone DA, Ghanta S, Zampell JC, Thorek D, Mehrara BJ (2013) Obesity impairs lymphatic fluid transport and dendritic cell migration to lymph nodes. PLoS One 8:e70703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Westcott DJ, Delproposto JB, Geletka LM, Wang T, Singer K, Saltiel AR, Lumeng CN (2009) MGL1 promotes adipose tissue inflammation and insulin resistance by regulating 7/4hi monocytes in obesity. J Exp Med 206:3143–3156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Winer S, Chan Y, Paltser G, Truong D, Tsui H, Bahrami J, Dorfman R, Wang Y, Zielenski J, Mastronardi F, Maezawa Y, Drucker DJ, Engleman E, Winer D, Dosch HM (2009a) Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med 15:921–929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Winer S, Paltser G, Chan Y, Tsui H, Engleman E, Winer D, Dosch HM (2009b) Obesity predisposes to Th17 bias. Eur J Immunol 39:2629–2635

    Article  CAS  PubMed  Google Scholar 

  • Winer DA, Winer S, Shen L, Wadia PP, Yantha J, Paltser G, Tsui H, Wu P, Davidson MG, Alonso MN, Leong HX, Glassford A, Caimol M, Kenkel JA, Tedder TF, McLaughlin T, Miklos DB, Dosch HM, Engleman EG (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 

  • Winer DA, Winer S, Chng MH, Shen L, Engleman EG (2014) B Lymphocytes in obesity-related adipose tissue inflammation and insulin resistance. Cell Mol Life Sci 71:1033–1043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wing JB, Sakaguchi S (2012) Multiple treg suppressive modules and their adaptability. Front Immunol 3:178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wolf MJ, Adili A, Piotrowitz K, Abdullah Z, Boege Y, Stemmer K, Ringelhan M, Simonavicius N, Egger M, Wohlleber D, Lorentzen A, Einer C, Schulz S, Clavel T, Protzer U, Thiele C, Zischka H, Moch H, Tschop M, Tumanov AV, Haller D, Unger K, Karin M, Kopf M, Knolle P, Weber A, Heikenwalder M (2014) Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes. Cancer Cell 26:549–564

    Article  CAS  PubMed  Google Scholar 

  • Wong VW, Wong GL, Choi PC, Chan AW, Li MK, Chan HY, Chim AM, Yu J, Sung JJ, Chan HL (2010) Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years. Gut 59:969–974

    Article  PubMed  Google Scholar 

  • Wree A, Broderick L, Canbay A, Hoffman HM, Feldstein AE (2013) From NAFLD to NASH to cirrhosis-new insights into disease mechanisms. Nat Rev Gastroenterol Hepatol 10:627–636

    Article  CAS  PubMed  Google Scholar 

  • Wu D, Molofsky AB, Liang HE, Ricardo-Gonzalez RR, Jouihan HA, Bando JK, Chawla A, Locksley RM (2011) Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science 332:243–247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu J, Bostrom P, Sparks LM, Ye L, Choi JH, Giang AH, Khandekar M, Virtanen KA, Nuutila P, Schaart G, Huang K, Tu H, van Marken Lichtenbelt WD, Hoeks J, Enerback S, Schrauwen P, Spiegelman BM (2012a) Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 150:366–376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu L, Parekh VV, Gabriel CL, Bracy DP, Marks-Shulman PA, Tamboli RA, Kim S, Mendez-Fernandez YV, Besra GS, Lomenick JP, Williams B, Wasserman DH, Van Kaer L (2012b) Activation of invariant natural killer T cells by lipid excess promotes tissue inflammation, insulin resistance, and hepatic steatosis in obese mice. Proc Natl Acad Sci U S A 109:E1143–E1152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu JM, Shi GP (2012) Emerging role of mast cells and macrophages in cardiovascular and metabolic diseases. Endocr Rev 33:71–108

    Article  PubMed  PubMed Central  Google Scholar 

  • Yamagata H, Ikejima K, Takeda K, Aoyama T, Kon K, Okumura K, Watanabe S (2013) Altered expression and function of hepatic natural killer T cells in obese and diabetic KK-A(y) mice. Hepatol Res 43:276–288

    Article  CAS  PubMed  Google Scholar 

  • Yekollu SK, Thomas R, O’Sullivan B (2011) Targeting curcusomes to inflammatory dendritic cells inhibits NF-kappaB and improves insulin resistance in obese mice. Diabetes 60:2928–2938

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yilmaz H, Ucan B, Sayki M, Unsal I, Sahin M, Ozbek M, Delibasi T (2014) Usefulness of the neutrophil-to-lymphocyte ratio to prediction of type 2 diabetes mellitus in morbid obesity. Diabetes Metab Syndr doi: 10.1016/j.dsx.2014.04.009 (Epub ahead of print)

  • Yoshimura A, Suzuki M, Sakaguchi R, Hanada T, Yasukawa H (2012) SOCS, inflammation, and autoimmunity. Front Immunol 3:20

    Article  PubMed  PubMed Central  Google Scholar 

  • Yu Y, Liu Y, Shi FD, Zou H, Matarese G, La Cava A (2013) Cutting edge: leptin-induced RORgammat expression in CD4+ T cells promotes Th17 responses in systemic lupus erythematosus. J Immunol 190:3054–3058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zeyda M, Huber J, Prager G, Stulnig TM (2011) Inflammation correlates with markers of T-cell subsets including regulatory T cells in adipose tissue from obese patients. Obesity (Silver Spring) 19:743–748

    Article  CAS  Google Scholar 

  • Zhao L, de Qiu K, Ma X (2010) Th17 cells: the emerging reciprocal partner of regulatory T cells in the liver. J Dig Dis 11:126–133

    Article  PubMed  CAS  Google Scholar 

  • Zhong J, Rao X, Braunstein Z, Taylor A, Narula V, Hazey J, Mikami D, Needleman B, Rutsky J, Sun Q, Deiuliis JA, Satoskar AR, Rajagopalan S (2014) T-cell costimulation protects obesity-induced adipose inflammation and insulin resistance. Diabetes 63:1289–1302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu J, Yamane H, Paul WE (2010) Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol 28:445–489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu L, Wu Y, Wei H, Xing X, Zhan N, Xiong H, Peng B (2011) IL-17R activation of human periodontal ligament fibroblasts induces IL-23 p19 production: differential involvement of NF-kappaB versus JNK/AP-1 pathways. Mol Immunol 48:647–656

    Article  CAS  PubMed  Google Scholar 

  • Zuniga LA, Shen WJ, Joyce-Shaikh B, Pyatnova EA, Richards AG, Thom C, Andrade SM, Cua DJ, Kraemer FB, Butcher EC (2010) IL-17 regulates adipogenesis, glucose homeostasis, and obesity. J Immunol 185:6947–6959

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Antonios Chatzigeorgiou .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Chatzigeorgiou, A., Chavakis, T. (2015). Immune Cells and Metabolism. In: Herzig, S. (eds) Metabolic Control. Handbook of Experimental Pharmacology, vol 233. Springer, Cham. https://doi.org/10.1007/164_2015_8

Download citation

Publish with us

Policies and ethics