Abstract
Adipose tissue has emerged as a major player in driving obesity-related inflammatory response. In obesity, chronic infiltration of macrophages in adipose tissue mediates local and systemic inflammation and acts as a key contributor to insulin resistance. In the past few years, adipose tissue plasticity and remodeling capacity has been studied extensively to develop therapeutic targets to combat obesity and related metabolic dysfunction. Progress in understanding the potential of adipocytes and contribution of macrophages and other immune cells to control immunometabolism in disease state has provided us new potential intervention targets to explore such as the formation of heat-producing beige adipocytes in white adipose tissue and the polarization of macrophages from an inflammatory toward an anti-inflammatory phenotype. Initiation and progression of inflammatory signaling in fat pads is complex, broad, and often functions in a tissue/cell type-specific manner. We have also realized the importance of location, coordinated role of tissue cross-talk, and physiological state of the fat pad in these processes. There has been significant progress in understanding how adipose tissue regulates these crucial processes and maintains metabolic homeostasis such as identification of fat depot-specific regulation of energy metabolism, mediators of macrophage polarization, role of gut-derived antigens, and consequences of diet and calorie restriction on adipose tissue metabolic and thermogenic potential.
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References
Rosen ED, Spiegelman BM (2014) What we talk about when we talk about fat. Cell 156(1-2):20–44. https://doi.org/10.1016/j.cell.2013.12.012
Hotamisligil GS, Shargill NS, Spiegelman BM (1993) Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259(5091):87–91. https://doi.org/10.1126/science.7678183
Pekala P, Kawakami M, Vine W, Lane MD, Cerami A (1983) Studies of insulin resistance in adipocytes induced by macrophage mediator. J Exp Med 157(4):1360–1365. https://doi.org/10.1084/jem.157.4.1360
Hotamisligil GS, Murray DL, Choy LN, Spiegelman BM (1994) Tumor necrosis factor alpha inhibits signaling from the insulin receptor. Proc Natl Acad Sci U S A 91(11):4854–4858. https://doi.org/10.1073/pnas.91.11.4854
Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS (1997) Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 389(6651):610–614. https://doi.org/10.1038/39335
Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RLet al. (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112(12):1796–1808. https://doi.org/10.1172/JCI200319246
Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112(12):1821–1830. https://doi.org/10.1172/JCI200319451
Morris DL, Singer K, Lumeng CN (2011) Adipose tissue macrophages: phenotypic plasticity and diversity in lean and obese states. Curr Opin Clin Nutr Metab Care 14(4):341–346. https://doi.org/10.1097/MCO.0b013e328347970b
Ferrante AW Jr (2013) The immune cells in adipose tissue. Diabetes Obes Metab 15(Suppl 3):34–38. https://doi.org/10.1111/dom.12154
Wajchenberg BL (2000) Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev 21(6):697–738. https://doi.org/10.1210/edrv.21.6.0415
Young SG, Zechner R (2013) Biochemistry and pathophysiology of intravascular and intracellular lipolysis. Genes Dev 27(5):459–484. https://doi.org/10.1101/gad.209296.112
Ryden M, Arner P (2007) Tumour necrosis factor-alpha in human adipose tissue—from signalling mechanisms to clinical implications. J Intern Med 262(4):431–438. https://doi.org/10.1111/j.1365-2796.2007.01854.x
Haemmerle G, Moustafa T, Woelkart G, Buttner S, Schmidt A et al (2011) ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-alpha and PGC-1. Nat Med 17(9):1076–1085. https://doi.org/10.1038/nm.2439
Czech MP, Tencerova M, Pedersen DJ, Aouadi M (2013) Insulin signalling mechanisms for triacylglycerol storage. Diabetologia 56(5):949–964. https://doi.org/10.1007/s00125-013-2869-1
Cinti S (2001) The adipose organ: morphological perspectives of adipose tissues. Proc Nutr Soc 60(03):319–328. https://doi.org/10.1079/PNS200192
Heaton JM (1972) The distribution of brown adipose tissue in the human. J Anat 112(Pt 1):35–39
Lean ME, James WP, Jennings G, Trayhurn P (1986) Brown adipose tissue uncoupling protein content in human infants, children and adults. Clin Sci (Lond) 71(3):291–297. https://doi.org/10.1042/cs0710291
Betz MJ, Enerback S (2015) Human brown adipose tissue: what we have learned so far. Diabetes 64(7):2352–2360. https://doi.org/10.2337/db15-0146
Cannon B, Nedergaard J (2004) Brown adipose tissue: function and physiological significance. Physiol Rev 84(1):277–359. https://doi.org/10.1152/physrev.00015.2003
Bartelt A, Bruns OT, Reimer R, Hohenberg H, Ittrich H, Peldschus K, Kaul MG, Tromsdorf UI, Weller H, Waurisch C, Eychmüller A, Gordts PLSM, Rinninger F, Bruegelmann K, Freund B, Nielsen P, Merkel M, Heeren J (2011) Brown adipose tissue activity controls triglyceride clearance. Nat Med 17(2):200–205. https://doi.org/10.1038/nm.2297
Stanford KI, Middelbeek RJ, Townsend KL, An D, Nygaard EB, Hitchcox KM et al (2013) Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. J Clin Invest 123(1):215–223. https://doi.org/10.1172/JCI62308
Cannon B, Nedergaard J (2011) Nonshivering thermogenesis and its adequate measurement in metabolic studies. J Exp Biol 214(2):242–253. https://doi.org/10.1242/jeb.050989
Hanssen MJ, van der Lans AA, Brans B, Hoeks J, Jardon KM et al (2016) Short-term cold acclimation recruits brown adipose tissue in obese humans. Diabetes 65(5):1179–1189. https://doi.org/10.2337/db15-1372
Kingma BR, Frijns AJ, Saris WH, van Steenhoven AA, Lichtenbelt WD (2011) Increased systolic blood pressure after mild cold and rewarming: relation to cold-induced thermogenesis and age. Acta Physiol (Oxf) 203(4):419–427. https://doi.org/10.1111/j.1748-1716.2011.02336.x
Wijers SL, Saris WH, van Marken Lichtenbelt WD (2010) Cold-induced adaptive thermogenesis in lean and obese. Obesity (Silver Spring) 18(6):1092–1099. https://doi.org/10.1038/oby.2010.74
Bartelt A, Heeren J (2014) Adipose tissue browning and metabolic health. Nat Rev Endocrinol 10(1):24–36. https://doi.org/10.1038/nrendo.2013.204
Berry DC, Jiang Y, Graff JM (2016) Emerging roles of adipose progenitor cells in tissue development, homeostasis, expansion and thermogenesis. Trends Endocrinol Metab 27(8):574–585. https://doi.org/10.1016/j.tem.2016.05.001
Wu J, Cohen P, Spiegelman BM (2013) Adaptive thermogenesis in adipocytes: is beige the new brown? Genes Dev 27(3):234–250. https://doi.org/10.1101/gad.211649.112
Sidossis LS, Porter C, Saraf MK, Borsheim E, Radhakrishnan RS et al (2015) Browning of subcutaneous white adipose tissue in humans after severe adrenergic stress. Cell Metab 22(2):219–227. https://doi.org/10.1016/j.cmet.2015.06.022
Frontini A, Vitali A, Perugini J, Murano I, Romiti C, Ricquier D, Guerrieri M, Cinti S (2013) White-to-brown transdifferentiation of omental adipocytes in patients affected by pheochromocytoma. Biochim Biophys Acta 1831(5):950–959. https://doi.org/10.1016/j.bbalip.2013.02.005
Kiefer FW (2017) The significance of beige and brown fat in humans. Endocr Connect 6(5):R70–R79. https://doi.org/10.1530/EC-17-0037
Czech MP (2017) Insulin action and resistance in obesity and type 2 diabetes. Nat Med 23(7):804–814. https://doi.org/10.1038/nm.4350
Samuel VT, Petersen KF, Shulman GI (2010) Lipid-induced insulin resistance: unravelling the mechanism. Lancet 375(9733):2267–2277. https://doi.org/10.1016/S0140-6736(10)60408-4
Chaurasia B, Summers SA (2015) Ceramides—lipotoxic inducers of metabolic disorders. Trends Endocrinol Metab 26(10):538–550. https://doi.org/10.1016/j.tem.2015.07.006
Arner E, Westermark PO, Spalding KL, Britton T, Ryden M, Frisen J, Bernard S, Arner P (2010) Adipocyte turnover: relevance to human adipose tissue morphology. Diabetes 59(1):105–109. https://doi.org/10.2337/db09-0942
Isakson P, Hammarstedt A, Gustafson B, Smith U (2009) Impaired preadipocyte differentiation in human abdominal obesity: role of Wnt, tumor necrosis factor-alpha, and inflammation. Diabetes 58(7):1550–1557. https://doi.org/10.2337/db08-1770
Taylor R, Holman RR (2015) Normal weight individuals who develop type 2 diabetes: the personal fat threshold. Clin Sci (Lond) 128(7):405–410. https://doi.org/10.1042/CS20140553
Tchernof A, Despres JP (2013) Pathophysiology of human visceral obesity: an update. Physiol Rev 93(1):359–404. https://doi.org/10.1152/physrev.00033.2011
Wang QA, Tao C, Gupta RK, Scherer PE (2013) Tracking adipogenesis during white adipose tissue development, expansion and regeneration. Nat Med 19(10):1338–1344. https://doi.org/10.1038/nm.3324
Jeffery E, Wing A, Holtrup B, Sebo Z, Kaplan JL, Saavedra-Peña R, Church CD, Colman L, Berry R, Rodeheffer MS (2016) The adipose tissue microenvironment regulates depot-specific adipogenesis in obesity. Cell Metab 24(1):142–150. https://doi.org/10.1016/j.cmet.2016.05.012
Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi Eet al. (2005) Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res 46(11):2347–2355. https://doi.org/10.1194/jlr.M500294-JLR200
Takahashi K, Yamaguchi S, Shimoyama T, Seki H, Miyokawa K, Katsuta H, Tanaka T, Yoshimoto K, Ohno H, Nagamatsu S, Ishida H (2008) JNK- and IkappaB-dependent pathways regulate MCP-1 but not adiponectin release from artificially hypertrophied 3T3-L1 adipocytes preloaded with palmitate in vitro. Am J Physiol Endocrinol Metab 294(5):E898–E909. https://doi.org/10.1152/ajpendo.00131.2007
Halberg N, Khan T, Trujillo ME, Wernstedt-Asterholm I, Attie AD, Sherwani S, Wang ZV, Landskroner-Eiger S, Dineen S, Magalang UJ, Brekken RA, Scherer PE (2009) Hypoxia-inducible factor 1alpha induces fibrosis and insulin resistance in white adipose tissue. Mol Cell Biol 29(16):4467–4483. https://doi.org/10.1128/MCB.00192-09
Shan B, Wang X, Wu Y, Xu C, Xia Z, Dai J, Shao M, Zhao F, He S, Yang L, Zhang M, Nan F, Li J, Liu J, Liu J, Jia W, Qiu Y, Song B, Han JDJ, Rui L, Duan SZ, Liu Y (2017) The metabolic ER stress sensor IRE1alpha suppresses alternative activation of macrophages and impairs energy expenditure in obesity. Nat Immunol 18(5):519–529. https://doi.org/10.1038/ni.3709
Garcia-Martin R, Alexaki VI, Qin N, Rubin de Celis MF, Economopoulou M et al (2015) Adipocyte-specific hypoxia-inducible factor 2alpha deficiency exacerbates obesity-induced Brown adipose tissue dysfunction and metabolic dysregulation. Mol Cell Biol 36(3):376–393. https://doi.org/10.1128/MCB.00430-15
Lee YS, Kim JW, Osborne O, Oh DY, Sasik R et al (2014) Increased adipocyte O2 consumption triggers HIF-1alpha, causing inflammation and insulin resistance in obesity. Cell 157(6):1339–1352. https://doi.org/10.1016/j.cell.2014.05.012
Giordano A, Murano I, Mondini E, Perugini J, Smorlesi A, Severi I, Barazzoni R, Scherer PE, Cinti S (2013) Obese adipocytes show ultrastructural features of stressed cells and die of pyroptosis. J Lipid Res 54(9):2423–2436. https://doi.org/10.1194/jlr.M038638
Sharma NS, Nagrath D, Yarmush ML (2010) Adipocyte-derived basement membrane extract with biological activity: applications in hepatocyte functional augmentation in vitro. FASEB J 24(7):2364–2374. https://doi.org/10.1096/fj.09-135095
Sun K, Tordjman J, Clement K, Scherer PE (2013) Fibrosis and adipose tissue dysfunction. Cell Metab 18(4):470–477. https://doi.org/10.1016/j.cmet.2013.06.016
Spencer M, Yao-Borengasser A, Unal R, Rasouli N, Gurley CM, Zhu B, Peterson CA, Kern PA (2010) Adipose tissue macrophages in insulin-resistant subjects are associated with collagen VI and fibrosis and demonstrate alternative activation. Am J Physiol Endocrinol Metab 299(6):E1016–E1027. https://doi.org/10.1152/ajpendo.00329.2010
Wernstedt Asterholm I, Tao C, Morley TS, Wang QA, Delgado-Lopez F et al (2014) Adipocyte inflammation is essential for healthy adipose tissue expansion and remodeling. Cell Metab 20(1):103–118. https://doi.org/10.1016/j.cmet.2014.05.005
Lancha A, Rodriguez A, Catalan V, Becerril S, Sainz N et al (2014) Osteopontin deletion prevents the development of obesity and hepatic steatosis via impaired adipose tissue matrix remodeling and reduced inflammation and fibrosis in adipose tissue and liver in mice. PLoS One 9(5):e98398. https://doi.org/10.1371/journal.pone.0098398
Klingberg F, Hinz B, White ES (2013) The myofibroblast matrix: implications for tissue repair and fibrosis. J Pathol 229(2):298–309. https://doi.org/10.1002/path.4104
Keophiphath M, Achard V, Henegar C, Rouault C, Clement K et al (2009) Macrophage-secreted factors promote a profibrotic phenotype in human preadipocytes. Mol Endocrinol 23(1):11–24. https://doi.org/10.1210/me.2008-0183
Bourlier V, Sengenes C, Zakaroff-Girard A, Decaunes P, Wdziekonski B et al (2012) TGFbeta family members are key mediators in the induction of myofibroblast phenotype of human adipose tissue progenitor cells by macrophages. PLoS One 7(2):e31274. https://doi.org/10.1371/journal.pone.0031274
Alessi MC, Bastelica D, Morange P, Berthet B, Leduc I, Verdier M, Geel O, Juhan-Vague I (2000) Plasminogen activator inhibitor 1, transforming growth factor-beta1, and BMI are closely associated in human adipose tissue during morbid obesity. Diabetes 49(8):1374–1380. https://doi.org/10.2337/diabetes.49.8.1374
Yadav H, Quijano C, Kamaraju AK, Gavrilova O, Malek R, Chen W, Zerfas P, Zhigang D, Wright EC, Stuelten C, Sun P, Lonning S, Skarulis M, Sumner AE, Finkel T, Rane SG (2011) Protection from obesity and diabetes by blockade of TGF-beta/Smad3 signaling. Cell Metab 14(1):67–79. https://doi.org/10.1016/j.cmet.2011.04.013
Jeffery E, Church CD, Holtrup B, Colman L, Rodeheffer MS (2015) Rapid depot-specific activation of adipocyte precursor cells at the onset of obesity. Nat Cell Biol 17(4):376–385. https://doi.org/10.1038/ncb3122
Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444(7121):860–867. https://doi.org/10.1038/nature05485
Crewe C, An YA, Scherer PE (2017) The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. J Clin Invest 127(1):74–82. https://doi.org/10.1172/JCI88883
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(9):1894–1903. https://doi.org/10.1194/jlr.M800132-JLR200
Talukdar S, Oh DY, 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(9):1407–1412. https://doi.org/10.1038/nm.2885
Cho KW, Zamarron BF, Muir LA, Singer K, Porsche CE, DelProposto JB, Geletka L, Meyer KA, O’Rourke RW, Lumeng CN (2016) Adipose tissue dendritic cells are independent contributors to obesity-induced inflammation and insulin resistance. J Immunol 197(9):3650–3661. https://doi.org/10.4049/jimmunol.1600820
Hellman B, Larsson S, Westman S (1963) Mast cell content and fatty acid metabolism in the epididymal fat pad of obese mice. Acta Physiol Scand 58(2-3):255–262. https://doi.org/10.1111/j.1748-1716.1963.tb02647.x
Liu J, Divoux A, Sun J, Zhang J, Clement K et al (2009) Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice. Nat Med 15(8):940–945. https://doi.org/10.1038/nm.1994
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(6026):243–247. https://doi.org/10.1126/science.1201475
Chawla A, Nguyen KD, Goh YP (2011) Macrophage-mediated inflammation in metabolic disease. Nat Rev Immunol 11(11):738–749. https://doi.org/10.1038/nri3071
Boutens L, Stienstra R (2016) Adipose tissue macrophages: going off track during obesity. Diabetologia 59(5):879–894. https://doi.org/10.1007/s00125-016-3904-9
Harman-Boehm I, Bluher M, Redel H, Sion-Vardy N, Ovadia S et al (2007) Macrophage infiltration into omental versus subcutaneous fat across different populations: effect of regional adiposity and the comorbidities of obesity. J Clin Endocrinol Metab 92(6):2240–2247. https://doi.org/10.1210/jc.2006-1811
Lee YH, Petkova AP, Granneman JG (2013) Identification of an adipogenic niche for adipose tissue remodeling and restoration. Cell Metab 18(3):355–367. https://doi.org/10.1016/j.cmet.2013.08.003
Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3(1):23–35. https://doi.org/10.1038/nri978
Lumeng CN, Bodzin JL, Saltiel AR (2007) Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 117(1):175–184. https://doi.org/10.1172/JCI29881
Lumeng CN, Deyoung SM, Bodzin JL, Saltiel AR (2007) Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity. Diabetes 56(1):16–23. https://doi.org/10.2337/db06-1076
Chavez-Galan L, Olleros ML, Vesin D, Garcia I (2015) Much more than M1 and M2 macrophages, there are also CD169(+) and TCR(+) macrophages. Front Immunol 6:263. https://doi.org/10.3389/fimmu.2015.00263
Stienstra R, Duval C, Keshtkar S, van der Laak J, Kersten S, Müller M (2008) Peroxisome proliferator-activated receptor gamma activation promotes infiltration of alternatively activated macrophages into adipose tissue. J Biol Chem 283(33):22620–22627. https://doi.org/10.1074/jbc.M710314200
Cancello R, Tordjman J, Poitou C, Guilhem G, Bouillot JL, Hugol D, Coussieu C, Basdevant A, Hen AB, Bedossa P, Guerre-Millo M, Clement K (2006) Increased infiltration of macrophages in omental adipose tissue is associated with marked hepatic lesions in morbid human obesity. Diabetes 55(6):1554–1561. https://doi.org/10.2337/db06-0133
Wentworth JM, Naselli G, Brown WA, Doyle L, Phipson B, Smyth GK, Wabitsch M, O'Brien PE, Harrison LC (2010) Pro-inflammatory CD11c+CD206+ adipose tissue macrophages are associated with insulin resistance in human obesity. Diabetes 59(7):1648–1656. https://doi.org/10.2337/db09-0287
Aron-Wisnewsky J, Tordjman J, Poitou C, Darakhshan F, Hugol D, Basdevant A, Aissat A, Guerre-Millo M, Clément K (2009) Human adipose tissue macrophages: m1 and m2 cell surface markers in subcutaneous and omental depots and after weight loss. J Clin Endocrinol Metab 94(11):4619–4623. https://doi.org/10.1210/jc.2009-0925
Nakajima S, Koh V, Kua LF, So J, Davide L, Lim KS, Petersen SH, Yong WP, Shabbir A, Kono K (2016) Accumulation of CD11c+CD163+ adipose tissue macrophages through upregulation of intracellular 11beta-HSD1 in human obesity. J Immunol 197(9):3735–3745. https://doi.org/10.4049/jimmunol.1600895
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(5):610–617. https://doi.org/10.1038/nm.2353
Wu H, Ghosh S, Perrard XD, Feng L, Garcia GE, Perrard JL, Sweeney JF, Peterson LE, Chan L, Smith CW, Ballantyne CM (2007) T-cell accumulation and regulated on activation, normal T cell expressed and secreted upregulation in adipose tissue in obesity. Circulation 115(8):1029–1038. https://doi.org/10.1161/CIRCULATIONAHA.106.638379
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(8):914–920. https://doi.org/10.1038/nm.1964
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 (2009) Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med 15(8):921–929. https://doi.org/10.1038/nm.2001
Strissel KJ, DeFuria J, Shaul ME, Bennett G, Greenberg AS, Obin MS (2010) T-cell recruitment and Th1 polarization in adipose tissue during diet-induced obesity in C57BL/6 mice. Obesity (Silver Spring) 18(10):1918–1925. https://doi.org/10.1038/oby.2010.1
Ballak DB, Stienstra R, Hijmans A, Joosten LA, Netea MG et al (2013) Combined B- and T-cell deficiency does not protect against obesity-induced glucose intolerance and inflammation. Cytokine 62(1):96–103. https://doi.org/10.1016/j.cyto.2013.02.009
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(8):930–939. https://doi.org/10.1038/nm.2002
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(7404):549–553. https://doi.org/10.1038/nature11132
Lynch L, Michelet X, Zhang S, Brennan PJ, Moseman A, Lester C, Besra G, Vomhof-Dekrey EE, Tighe M, Koay HF, Godfrey DI, Leadbetter EA, Sant'Angelo DB, von Andrian U, Brenner MB (2015) Regulatory iNKT cells lack expression of the transcription factor PLZF and control the homeostasis of T(reg) cells and macrophages in adipose tissue. Nat Immunol 16(1):85–95. https://doi.org/10.1038/ni.3047
Bapat SP, Myoung Suh J, Fang S, Liu S, Zhang Y, Cheng A, Zhou C, Liang Y, LeBlanc M, Liddle C, Atkins AR, Yu RT, Downes M, Evans RM, Zheng Y (2015) Depletion of fat-resident Treg cells prevents age-associated insulin resistance. Nature 528(7580):137–141. https://doi.org/10.1038/nature16151
Huehn J, Beyer M (2015) Epigenetic and transcriptional control of Foxp3+ regulatory T cells. Semin Immunol 27(1):10–18. https://doi.org/10.1016/j.smim.2015.02.002
Cipolletta D (2014) Adipose tissue-resident regulatory T cells: phenotypic specialization, functions and therapeutic potential. Immunology 142(4):517–525. https://doi.org/10.1111/imm.12262
Glass CK, Olefsky JM (2012) Inflammation and lipid signaling in the etiology of insulin resistance. Cell Metab 15(5):635–645. https://doi.org/10.1016/j.cmet.2012.04.001
Li C, Ying W, Huang Z, Brehm T, Morin A, Vella AT, Zhou B (2017) IRF6 regulates alternative activation by suppressing PPARgamma in male murine macrophages. Endocrinology 158(9):2837–2847. https://doi.org/10.1210/en.2017-00053
Odegaard JI, Ricardo-Gonzalez RR, Red Eagle A, Vats D, Morel CR, Goforth MH, Subramanian V, Mukundan L, Ferrante AW, Chawla A (2008) Alternative M2 activation of Kupffer cells by PPARdelta ameliorates obesity-induced insulin resistance. Cell Metab 7(6):496–507. https://doi.org/10.1016/j.cmet.2008.04.003
Ohashi K, Parker JL, Ouchi N, Higuchi A, Vita JA, Gokce N, Pedersen AA, Kalthoff C, Tullin S, Sams A, Summer R, Walsh K (2010) Adiponectin promotes macrophage polarization toward an anti-inflammatory phenotype. J Biol Chem 285(9):6153–6160. https://doi.org/10.1074/jbc.M109.088708
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(6):485–495. https://doi.org/10.1016/j.cmet.2008.04.002
Ji Y, Sun S, Xu A, Bhargava P, Yang L, Lam KSL, Gao B, Lee CH, Kersten S, Qi L (2012) Activation of natural killer T cells promotes M2 macrophage polarization in adipose tissue and improves systemic glucose tolerance via interleukin-4 (IL-4)/STAT6 protein signaling axis in obesity. J Biol Chem 287(17):13561–13571. https://doi.org/10.1074/jbc.M112.350066
De Boer AA, Monk JM, Robinson LE (2014) Docosahexaenoic acid decreases pro-inflammatory mediators in an in vitro murine adipocyte macrophage co-culture model. PLoS One 9(1):e85037. https://doi.org/10.1371/journal.pone.0085037
Lee JY, Sohn KH, Rhee SH, Hwang D (2001) Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4. J Biol Chem 276(20):16683–16689. https://doi.org/10.1074/jbc.M011695200
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(11):3015–3025. https://doi.org/10.1172/JCI28898
Poggi M, Bastelica D, Gual P, Iglesias MA, Gremeaux T, Knauf C, Peiretti F, Verdier M, Juhan-Vague I, Tanti JF, Burcelin R, Alessi MC (2007) C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet. Diabetologia 50(6):1267–1276. https://doi.org/10.1007/s00125-007-0654-8
Suganami T, Mieda T, Itoh M, Shimoda Y, Kamei Y, Ogawa Y (2007) Attenuation of obesity-induced adipose tissue inflammation in C3H/HeJ mice carrying a Toll-like receptor 4 mutation. Biochem Biophys Res Commun 354(1):45–49. https://doi.org/10.1016/j.bbrc.2006.12.190
Tsukumo DM, Carvalho-Filho MA, Carvalheira JB, Prada PO, Hirabara SM et al (2007) Loss-of-function mutation in Toll-like receptor 4 prevents diet-induced obesity and insulin resistance. Diabetes 56(8):1986–1998. https://doi.org/10.2337/db06-1595
Orr JS, Puglisi MJ, Ellacott KL, Lumeng CN, Wasserman DH et al (2012) Toll-like receptor 4 deficiency promotes the alternative activation of adipose tissue macrophages. Diabetes 61(11):2718–2727. https://doi.org/10.2337/db11-1595
Jia L, Vianna CR, Fukuda M, Berglund ED, Liu C, Tao C, Sun K, Liu T, Harper MJ, Lee CE, Lee S, Scherer PE, Elmquist JK (2014) Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance. Nat Commun 5:3878. https://doi.org/10.1038/ncomms4878
Stienstra R, Joosten LA, Koenen T, van Tits B, van Diepen JA et al (2010) The inflammasome-mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity. Cell Metab 12(6):593–605. https://doi.org/10.1016/j.cmet.2010.11.011
Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, Ravussin E, Stephens JM, Dixit VD (2011) The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med 17(2):179–188. https://doi.org/10.1038/nm.2279
Chiang SH, Bazuine M, Lumeng CN, Geletka LM, Mowers J, White NM, Ma JT, Zhou J, Qi N, Westcott D, Delproposto JB, Blackwell TS, Yull FE, Saltiel AR (2009) The protein kinase IKKepsilon regulates energy balance in obese mice. Cell 138(5):961–975. https://doi.org/10.1016/j.cell.2009.06.046
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(2):191–198. https://doi.org/10.1038/nm1185
Gao Z, Zhang J, Henagan TM, Lee JH, Ye X, Wang H, Ye J (2015) P65 inactivation in adipocytes and macrophages attenuates adipose inflammatory response in lean but not in obese mice. Am J Physiol Endocrinol Metab 308(6):E496–E505. https://doi.org/10.1152/ajpendo.00532.2014
Tang T, Zhang J, Yin J, Staszkiewicz J, Gawronska-Kozak B, Jung DY, Ko HJ, Ong H, Kim JK, Mynatt R, Martin RJ, Keenan M, Gao Z, Ye J (2010) Uncoupling of inflammation and insulin resistance by NF-kappaB in transgenic mice through elevated energy expenditure. J Biol Chem 285(7):4637–4644. https://doi.org/10.1074/jbc.M109.068007
Berg AH, Lin Y, Lisanti MP, Scherer PE (2004) Adipocyte differentiation induces dynamic changes in NF-kappaB expression and activity. Am J Physiol Endocrinol Metab 287(6):E1178–E1188. https://doi.org/10.1152/ajpendo.00002.2004
Kumari M, Wang X, Lantier L, Lyubetskaya A, Eguchi J, Kang S, Tenen D, Roh HC, Kong X, Kazak L, Ahmad R, Rosen ED (2016) IRF3 promotes adipose inflammation and insulin resistance and represses browning. J Clin Invest 126(8):2839–2854. https://doi.org/10.1172/JCI86080
Freaney JE, Kim R, Mandhana R, Horvath CM (2013) Extensive cooperation of immune master regulators IRF3 and NFkappaB in RNA pol II recruitment and pause release in human innate antiviral transcription. Cell Rep 4(5):959–973. https://doi.org/10.1016/j.celrep.2013.07.043
Wietek C, Miggin SM, Jefferies CA, O'Neill LA (2003) Interferon regulatory factor-3-mediated activation of the interferon-sensitive response element by Toll-like receptor (TLR) 4 but not TLR3 requires the p65 subunit of NF-kappa. J Biol Chem 278(51):50923–50931. https://doi.org/10.1074/jbc.M308135200
Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT et al (2002) A central role for JNK in obesity and insulin resistance. Nature 420(6913):333–336. https://doi.org/10.1038/nature01137
Han MS, Jung DY, Morel C, Lakhani SA, Kim JK, Flavell RA, Davis RJ (2013) JNK expression by macrophages promotes obesity-induced insulin resistance and inflammation. Science 339(6116):218–222. https://doi.org/10.1126/science.1227568
Saraswathi V, Hasty AH (2006) The role of lipolysis in mediating the proinflammatory effects of very low density lipoproteins in mouse peritoneal macrophages. J Lipid Res 47(7):1406–1415. https://doi.org/10.1194/jlr.M600159-JLR200
Anderson EK, Hill AA, Hasty AH (2012) Stearic acid accumulation in macrophages induces toll-like receptor 4/2-independent inflammation leading to endoplasmic reticulum stress-mediated apoptosis. Arterioscler Thromb Vasc Biol 32(7):1687–1695. https://doi.org/10.1161/ATVBAHA.112.250142
Lee JY, Ye J, Gao Z, Youn HS, Lee WH, Zhao L, Sizemore N, Hwang DH (2003) Reciprocal modulation of Toll-like receptor-4 signaling pathways involving MyD88 and phosphatidylinositol 3-kinase/AKT by saturated and polyunsaturated fatty acids. J Biol Chem 278(39):37041–37051. https://doi.org/10.1074/jbc.M305213200
Suganami T, Tanimoto-Koyama K, Nishida J, Itoh M, Yuan X, Mizuarai S, Kotani H, Yamaoka S, Miyake K, Aoe S, Kamei Y, Ogawa Y (2007) Role of the Toll-like receptor 4/NF-kappaB pathway in saturated fatty acid-induced inflammatory changes in the interaction between adipocytes and macrophages. Arterioscler Thromb Vasc Biol 27(1):84–91. https://doi.org/10.1161/01.ATV.0000251608.09329.9a
Xu X, Grijalva A, Skowronski A, van Eijk M, Serlie MJ et al (2013) Obesity activates a program of lysosomal-dependent lipid metabolism in adipose tissue macrophages independently of classic activation. Cell Metab 18(6):816–830. https://doi.org/10.1016/j.cmet.2013.11.001
Prieur X, Mok CY, Velagapudi VR, Nunez V, Fuentes L et al (2011) Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice. Diabetes 60(3):797–809. https://doi.org/10.2337/db10-0705
Koliwad SK, Streeper RS, Monetti M, Cornelissen I, Chan L, Terayama K, Naylor S, Rao M, Hubbard B, Farese RV Jr (2010) DGAT1-dependent triacylglycerol storage by macrophages protects mice from diet-induced insulin resistance and inflammation. J Clin Invest 120(3):756–767. https://doi.org/10.1172/JCI36066
Vessby B, Uusitupa M, Hermansen K, Riccardi G, Rivellese AA, Tapsell LC, Nälsén C, Berglund L, Louheranta A, Rasmussen BM, Calvert GD, Maffetone A, Pedersen E, Gustafsson IB, Storlien LH, KANWU Study (2001) Substituting dietary saturated for monounsaturated fat impairs insulin sensitivity in healthy men and women: the KANWU study. Diabetologia 44(3):312–319. https://doi.org/10.1007/s001250051620
Summers LK, Fielding BA, Bradshaw HA, Ilic V, Beysen C et al (2002) Substituting dietary saturated fat with polyunsaturated fat changes abdominal fat distribution and improves insulin sensitivity. Diabetologia 45(3):369–377. https://doi.org/10.1007/s00125-001-0768-3
Surwit RS, Kuhn CM, Cochrane C, McCubbin JA, Feinglos MN (1988) Diet-induced type II diabetes in C57BL/6J mice. Diabetes 37(9):1163–1167. https://doi.org/10.2337/diab.37.9.1163
Ikemoto S, Takahashi M, Tsunoda N, Maruyama K, Itakura H, Ezaki O (1996) High-fat diet-induced hyperglycemia and obesity in mice: differential effects of dietary oils. Metabolism 45(12):1539–1546. https://doi.org/10.1016/S0026-0495(96)90185-7
Yang ZH, Miyahara H, Hatanaka A (2011) Chronic administration of palmitoleic acid reduces insulin resistance and hepatic lipid accumulation in KK-Ay ice with genetic type 2 diabetes. Lipids Health Dis 10(1):120. https://doi.org/10.1186/1476-511X-10-120
Flachs P, Ruhl R, Hensler M, Janovska P, Zouhar P et al (2011) Synergistic induction of lipid catabolism and anti-inflammatory lipids in white fat of dietary obese mice in response to calorie restriction and n-3 fatty acids. Diabetologia 54(10):2626–2638. https://doi.org/10.1007/s00125-011-2233-2
Oh DY, Talukdar S, Bae EJ, Imamura T, Morinaga H, Fan WQ, Li P, Lu WJ, Watkins SM, Olefsky JM (2010) GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 142(5):687–698. https://doi.org/10.1016/j.cell.2010.07.041
Paerregaard SI, Agerholm M, Serup AK, Ma T, Kiens B et al (2016) FFAR4 (GPR120) signaling is not required for anti-inflammatory and insulin-sensitizing effects of omega-3 fatty acids. Mediat Inflamm 2016:1536047
Titos E, Rius B, Gonzalez-Periz A, Lopez-Vicario C, Moran-Salvador E et al (2011) Resolvin D1 and its precursor docosahexaenoic acid promote resolution of adipose tissue inflammation by eliciting macrophage polarization toward an M2-like phenotype. J Immunol 187(10):5408–5418. https://doi.org/10.4049/jimmunol.1100225
van Dijk SJ, Feskens EJ, Bos MB, Hoelen DW, Heijligenberg R, Bromhaar MG, de Groot LC, de Vries JH, Muller M, Afman LA (2009) A saturated fatty acid-rich diet induces an obesity-linked proinflammatory gene expression profile in adipose tissue of subjects at risk of metabolic syndrome. Am J Clin Nutr 90(6):1656–1664. https://doi.org/10.3945/ajcn.2009.27792
Itariu BK, Zeyda M, Hochbrugger EE, Neuhofer A, Prager G, Schindler K, Bohdjalian A, Mascher D, Vangala S, Schranz M, Krebs M, Bischof MG, Stulnig TM (2012) Long-chain n-3 PUFAs reduce adipose tissue and systemic inflammation in severely obese nondiabetic patients: a randomized controlled trial. Am J Clin Nutr 96(5):1137–1149. https://doi.org/10.3945/ajcn.112.037432
Tierney AC, McMonagle J, Shaw DI, Gulseth HL, Helal O, Saris WHM, Paniagua JA, Gołąbek-Leszczyñska I, Defoort C, Williams CM, Karsltröm B, Vessby B, Dembinska-Kiec A, López-Miranda J, Blaak EE, Drevon CA, Gibney MJ, Lovegrove JA, Roche HM (2011) Effects of dietary fat modification on insulin sensitivity and on other risk factors of the metabolic syndrome—LIPGENE: a European randomized dietary intervention study. Int J Obes 35(6):800–809. https://doi.org/10.1038/ijo.2010.209
Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C, Waget A, Delmee E, Cousin B, Sulpice T, Chamontin B, Ferrieres J, Tanti JF, Gibson GR, Casteilla L, Delzenne NM, Alessi MC, Burcelin R (2007) Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56(7):1761–1772. https://doi.org/10.2337/db06-1491
Amar J, Burcelin R, Ruidavets JB, Cani PD, Fauvel J, Alessi MC, Chamontin B, Ferriéres J (2008) Energy intake is associated with endotoxemia in apparently healthy men. Am J Clin Nutr 87(5):1219–1223
Pendyala S, Walker JM, Holt PR (2012) A high-fat diet is associated with endotoxemia that originates from the gut. Gastroenterology 142(1100–1):e2
Vors C, Pineau G, Drai J, Meugnier E, Pesenti S, Laville M, Laugerette F, Malpuech-Brugère C, Vidal H, Michalski MC (2015) Postprandial endotoxemia linked with chylomicrons and lipopolysaccharides handling in obese versus lean men: a lipid dose-effect trial. J Clin Endocrinol Metab 100(9):3427–3435. https://doi.org/10.1210/jc.2015-2518
Serino M, Luche E, Gres S, Baylac A, Berge M et al (2012) Metabolic adaptation to a high-fat diet is associated with a change in the gut microbiota. Gut 61(4):543–553. https://doi.org/10.1136/gutjnl-2011-301012
Colman RJ, Beasley TM, Kemnitz JW, Johnson SC, Weindruch R, Anderson RM (2014) Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys. Nat Commun 5:3557. https://doi.org/10.1038/ncomms4557
De Guzman JM, Ku G, Fahey R, Youm YH, Kass I, Ingram DK, Dixit VD, Kheterpal I (2013) Chronic caloric restriction partially protects against age-related alteration in serum metabolome. Age (Dordr) 35(4):1091–1104. https://doi.org/10.1007/s11357-012-9430-x
Canto C, Auwerx J (2011) Calorie restriction: is AMPK a key sensor and effector? Physiology (Bethesda) 26(4):214–224. https://doi.org/10.1152/physiol.00010.2011
Fabbiano S, Suarez-Zamorano N, Rigo D, Veyrat-Durebex C, Stevanovic Dokic A et al (2016) Caloric restriction leads to browning of white adipose tissue through type 2 immune signaling. Cell Metab 24(3):434–446. https://doi.org/10.1016/j.cmet.2016.07.023
Kosteli A, Sugaru E, Haemmerle G, Martin JF, Lei J, Zechner R, Ferrante AW Jr (2010) Weight loss and lipolysis promote a dynamic immune response in murine adipose tissue. J Clin Invest 120(10):3466–3479. https://doi.org/10.1172/JCI42845
Mottillo EP, Shen XJ, Granneman JG (2007) Role of hormone-sensitive lipase in beta-adrenergic remodeling of white adipose tissue. Am J Physiol Endocrinol Metab 293(5):E1188–E1197. https://doi.org/10.1152/ajpendo.00051.2007
Li P, Lu M, Nguyen MT, Bae EJ, Chapman J et al (2010) Functional heterogeneity of CD11c-positive adipose tissue macrophages in diet-induced obese mice. J Biol Chem 285(20):15333–15345. https://doi.org/10.1074/jbc.M110.100263
Kurki E, Shi J, Martonen E, Finckenberg P, Mervaala E (2012) Distinct effects of calorie restriction on adipose tissue cytokine and angiogenesis profiles in obese and lean mice. Nutr Metab (Lond) 9(1):64. https://doi.org/10.1186/1743-7075-9-64
Kovacikova M, Sengenes C, Kovacova Z, Siklova-Vitkova M, Klimcakova E et al (2011) Dietary intervention-induced weight loss decreases macrophage content in adipose tissue of obese women. Int J Obes 35(1):91–98. https://doi.org/10.1038/ijo.2010.112
Fischer K, Ruiz HH, Jhun K, Finan B, Oberlin DJ, van der Heide V, Kalinovich AV, Petrovic N, Wolf Y, Clemmensen C, Shin AC, Divanovic S, Brombacher F, Glasmacher E, Keipert S, Jastroch M, Nagler J, Schramm KW, Medrikova D, Collden G, Woods SC, Herzig S, Homann D, Jung S, Nedergaard J, Cannon B, Tschöp MH, Müller TD, Buettner C (2017) Alternatively activated macrophages do not synthesize catecholamines or contribute to adipose tissue adaptive thermogenesis. Nat Med 23(5):623–630. https://doi.org/10.1038/nm.4316
Nguyen KD, Qiu Y, Cui X, Goh YP, Mwangi J et al (2011) Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature 480(7375):104–108. https://doi.org/10.1038/nature10653
Wolf Y, Boura-Halfon S, Cortese N, Haimon Z, Sar Shalom H, Kuperman Y, Kalchenko V, Brandis A, David E, Segal-Hayoun Y, Chappell-Maor L, Yaron A, Jung S (2017) Brown-adipose-tissue macrophages control tissue innervation and homeostatic energy expenditure. Nat Immunol 18(6):665–674. https://doi.org/10.1038/ni.3746
Shimizu I, Aprahamian T, Kikuchi R, Shimizu A, Papanicolaou KN, MacLauchlan S, Maruyama S, Walsh K (2014) Vascular rarefaction mediates whitening of brown fat in obesity. J Clin Invest 124(5):2099–2112. https://doi.org/10.1172/JCI71643
Polyak A, Winkler Z, Kuti D, Ferenczi S, Kovacs KJ (2016) Brown adipose tissue in obesity: Fractalkine-receptor dependent immune cell recruitment affects metabolic-related gene expression. Biochim Biophys Acta 1861(11):1614–1622. https://doi.org/10.1016/j.bbalip.2016.07.002
Le Barz M, Anhe FF, Varin TV, Desjardins Y, Levy E et al (2015) Probiotics as complementary treatment for metabolic disorders. Diabetes Metab J 39(4):291–303. https://doi.org/10.4093/dmj.2015.39.4.291
Li J, Lin S, Vanhoutte PM, Woo CW, Xu A (2016) Akkermansia muciniphila protects against atherosclerosis by preventing metabolic endotoxemia-induced inflammation in Apoe−/− mice. Circulation 133(24):2434–2446. https://doi.org/10.1161/CIRCULATIONAHA.115.019645
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The authors were supported by an Alexander von Humboldt postdoctoral fellowship to MK and by a grant funded by the Deutsche Forschungsgemeinschaft (HE3645/7-1) to JH.
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This article is a contribution to the special issue on Dietary Control of Immunometabolism - Guest Editors: Joerg Heeren and Ludger Scheja
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Kumari, M., Heeren, J. & Scheja, L. Regulation of immunometabolism in adipose tissue. Semin Immunopathol 40, 189–202 (2018). https://doi.org/10.1007/s00281-017-0668-3
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DOI: https://doi.org/10.1007/s00281-017-0668-3