2.Hotamisligil, GS (2006) Inflammation and metabolic disorders. Nature 444, 860–867.
3.Donath, MY & Shoelson, SE (2011) Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 11, 98–107.
4.Hansson, GK & Libby, P (2006) The immune response in atherosclerosis: A double-edged sword. Nat Rev Immunol 6, 508–519.
5.Zimmet, P, Alberti, KG & Shaw, J (2001) Global and societal implications of the diabetes epidemic. Nature 414, 782–787.
6.Weisberg, SP, McCann, D, Desai, M et al. (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112, 1796–1808.
7.Xu, H, Barnes, GT, Yang, Q et al. (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112, 1821–1830.
8.Hotamisligil, GS, Shargill, NS & Spiegelman, BM (1993) Adipose expression of tumor necrosis factor-alpha: Direct role in obesity-linked insulin resistance. Science 259, 87–91.
9.Lumeng, CN, Deyoung, SM, Bodzin, JL et al. (2007) Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity. Diabetes 56, 16–23.
10.Nathan, C (2008) Metchnikoff's Legacy in 2008. Nat Immunol 9, 695–698.
11.Geissmann, F, Manz, MG, Jung, S et al. (2011) Development of monocytes, macrophages, and dendritic cells. Science 327, 656–661.
12.Kono, H & Rock, KL (2008) How dying cells alert the immune system to danger. Nat Rev Immunol 8, 279–289.
13.Bryant, P & Ploegh, H (2004) Class II MHC peptide loading by the professionals. Curt Opin Immunol 16, 96–102.
14.Trayhurn, P (2007) Adipocyte biology. Obes Rev 8, 41–44.
15.Lagathu, C, Yvan-Charvet, L, Bastard, JP et al. (2006) Long-term treatment with interleukin-1beta induces insulin resistance in murine and human adipocytes. Diabetologia 49, 2162–2173.
16.Maffei, M, Fei, H, Lee, GH, et al. . (1995) Increased expression in adipocytes of ob RNA in mice with lesions of the hypothalamus and with mutations at the db locus. Proc Natl Acad Sci USA 92, 6957–6960.
17.Beltowski, J (2003) Adiponectin and resistin–new hormones of white adipose tissue. Med Sci Monit 9, 55–61.
18.Abel, ED, Peroni, O, Kim, JK et al. . (2001) Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver. Nature 409, 729–733.
19.Lumeng, CN, Deyoung, SM & Saltiel, AR (2007) Macrophages block insulin action in adipocytes by altering expression of signaling and glucose transport proteins. Am J Physiol 292, E166–E174.
20.Suganami, T, Nishida, J & Ogawa, Y (2005) A paracrine loop between adipocytes and macrophages aggravates inflammatory changes: Role of free fatty acids and tumor necrosis factor alpha. Arterioscler Thromb Vasc Biol 25, 2062–2068.
21.Hirosumi, J, Tuncman, G, Chang, L et al. (2002) A central role for JNK in obesity and insulin resistance. Nature 420, 333–336.
22.Bandyopadhyay, GK, Yu, JG, Ofrecio, J et al. (2005) Increased p85/55/50 expression and decreased phosphotidylinositol 3-kinase activity in insulin-resistant human skeletal muscle. Diabetes 54, 2351–2359.
23.Arkan, MC, Hevener, AL, Greten, FR et al. (2005) IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med 11, 191–198.
24.Tuncman, G, Hirosumi, J, Solinas, G et al. (2006) Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance. Proc Natl Acad Sci USA. 103, 10741–10746.
25.Kawai, T & Akira, S (2007) TLR signaling. Semin Immunol 19, 24–32.
26.Kim, JK (2006) Fat uses a TOLL-road to connect inflammation and diabetes. Cell Metab 4, 417–419.
27.Shi, H, Kokoeva, MV, Inouye, K et al. (2006) TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 116, 3015–3025.
28.Tsukumo, DM, Carvalho-Filho, MA, Carvalheira, JB et al. (2007) Loss-of-function mutation in Toll-like receptor 4 prevents diet-induced obesity and insulin resistance. Diabetes 56, 1986–1998.
29.de Luca, C & Olefsky, JM (2008) Inflammation and insulin resistance. FEBS Lett 582, 97–105.
30.Cinti, S, Mitchell, G, Barbatelli, G et al. (2005) Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res 46, 2347–2355.
31.Ye, J, Gao, Z, Yin, J et al. (2007) Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am J Physiol Endocrinol Metab 293, 1118–1128.
32.O'Rourke, RW, White, AE, Metcalf, MD et al. . (2011) Hypoxia-induced inflammatory cytokine secretion in human adipose tissue stromovascular cells. Diabetologia 54, 1480–1490.
33.Robidoux, J, Cao, W, Quan, H et al. (2005) Selective activation of mitogen-activated protein (MAP) kinase kinase 3 and p38alpha MAP kinase is essential for cyclic AMP-dependent UCP1 expression in adipocytes. Mol Cell Biol 25, 5466–5479.
34.Surmi, BK & Hasty, AH (2008) Macrophage infiltration into adipose tissue: Initiation, propagation and remodeling. Future Lipidol 3, 545–556.
35.Bruun, JM, Lihn, AS, Pedersen, SB et al. (2005) Monocyte chemoattractant protein-1 release is higher in visceral than subcutaneous human adipose tissue (AT): Implication of macrophages resident in the AT. J Clin Endocrinol Metab 90, 2282–2289.
36.Weisberg, SP, Hunter, D, Huber, R et al. (2006) CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest 116, 115–124.
37.Kamei, N, Tobe, K, Suzuki, R et al. (2006) Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance. J Biol Chem 281, 26602–26614.
38.Chen, A, Mumick, S, Zhang, C et al. (2005) Diet induction of monocyte chemoattractant protein-1 and its impact on obesity. Obes Res 13, 1311–1320.
39.Inouye, KE, Shi, H, Howard, JK et al. (2007) Absence of CC chemokine ligand 2 does not limit obesity-associated infiltration of macrophages into adipose tissue. Diabetes 56, 2242–2250.
40.Mantovani, A, Sica, A & Locati, M (2005) Macrophage polarization comes of age. Immunity 23, 344–346.
41.Lumeng, CN, Bodzin, JL & Saltiel, AR (2007) Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 117, 175–184.
42.Edwards, JP, Zhang, X, Frauwirth, KA et al. (2006) Biochemical and functional characterization of three activated macrophage populations. J Leukoc Biol 80, 1298–1307.
43.Gerber, JS & Mosser, DM (2001) Reversing lipopolysaccharide toxicity by ligating the macrophage Fc gamma receptors. J Immunol 166, 6861–6868.
44.Frankenberger, M, Haussinger, K & Ziegler-Heitbrock, L (2005) Liposomal methylprednisolone differentially regulates the expression of TNF and IL-10 in human alveolar macrophages. Int Immunopharmacol 5, 289–299.
45.Strassmann, G, Patil-Koota, V, Finkelman, F et al. (1994) Evidence for the involvement of interleukin 10 in the differential deactivation of murine peritoneal macrophages by prostaglandin E2. J Exp Med 180, 2365–2370.
46.Anderson, CF & Mosser, DM (2002) Cutting edge: Biasing immune responses by directing antigen to macrophage Fc gamma receptors. J Immunol 168, 3697–3701.
47.Mantovani, A, Sica, A, Sozzani, S et al. (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trend Immunol 25, 677–686.
48.Nguyen, MT, Favelyukis, S, Nguyen, AK et al. (2007) A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-dependent pathways. J Biol Chem 282, 35279–35292.
49.Patsouris, D, Li, PP, Thapar, D et al. (2008) Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell Metab 8, 301–309.
50.Li, P, Lu, M, Nguyen, MT et al. (2011) Functional heterogeneity of CD11c-positive adipose tissue macrophages in diet-induced obese mice. J Biol Chem 285, 15333–15345.
51.Heilbronn, LK & Campbell, LV (2008) Adipose tissue macrophages, low grade inflammation and insulin resistance in human obesity. Curr Pharm Des 14, 1225–1230.
52.Odegaard, JI, Ricardo-Gonzalez, RR, Goforth, MH et al. (2007) Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature 447, 1116–1120.
53.Hevener, AL, Olefsky, JM, Reichart, D et al. (2007) Macrophage PPAR gamma is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones. J Clin Invest 117, 1658–1669.
54.Stienstra, R, Duval, C, Keshtkar, S et al. (2008) Peroxisome proliferator-activated receptor gamma activation promotes infiltration of alternatively activated macrophages into adipose tissue. J Biol Chem 283, 22620–22627.
55.Bouhlel, MA, Derudas, B, Rigamonti, E et al. (2007) PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metab 6, 137–143.
56.Kang, K, Reilly, SM, Karabacak, V et al. (2008) Adipocyte-derived Th2 cytokines and myeloid PPARdelta regulate macrophage polarization and insulin sensitivity. Cell Metab 7, 485–495.
57.Guri, AJ, Hontecillas, R, Ferrer, G et al. (2008) Loss of PPARγ in immune cells impairs the ability of abscisic acid to improve insulin sensitivity by supressing monocyte chemoattractant protein-1 expression and macrophage infiltration into white adipose tissue. J Nutr Biochem 19, 216–228.
58.Bassaganya-Riera, J, Misyak, S, Guri, AJ et al. (2009) PPAR gamma is highly expressed in F4/80(hi) adipose tissue macrophages and dampens adipose-tissue inflammation. Cell Immunol 258, 138–146.
59.Nicholls, HT, Kowalski, G, Kennedy, DJ et al. (2011) Hematopoietic cell-restricted deletion of CD36 reduces high-fat diet-induced macrophage infiltration and improves insulin signaling in adipose tissue. Diabetes 60, 1100–1110.
60.Prieur, X, Mok, CY, Velagapudi, VR et al. (2011) Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice. Diabetes 60, 797–809.
61.Yen, CL, Stone, SJ, Koliwad, S et al. (2008) Thematic review series: Glycerolipids. DGAT enzymes and triacylglycerol biosynthesis. J lipid Res 49, 2283–2301.
62.Chen, HC, Ladha, Z, Farese, RV et al. (2002) Deficiency of acyl coenzyme a:diacylglycerol acyltransferase 1 increases leptin sensitivity in murine obesity models. Endocrinology 143, 2893–2898.
63.Levin, MC, Monetti, M, Watt, MJ et al. (2007) Increased lipid accumulation and insulin resistance in transgenic mice expressing DGAT2 in glycolytic (type II) muscle. Am J Physiol Endocrinol Metab 293, 1772–1781.
64.Monetti, M, Levin, MC, Watt, MJ et al. (2007) Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver. Cell Metab 6, 69–78.
65.Ruan, H, Pownall, HJ & Lodish, HF (2003) Troglitazone antagonizes tumor necrosis factor-alpha-induced reprogramming of adipocyte gene expression by inhibiting the transcriptional regulatory functions of NF-kappaB. J Biol Chem 278, 28181–28192.
66.Kim, JY, van de Wall, E, Laplante, M et al. (2007) Obesity-associated improvements in metabolic profile through expansion of adipose tissue. J Clin Invest 117, 2621–2637.
67.Ranganathan, G, Unal, R, Pokrovskaya, I et al. (2006) The lipogenic enzymes DGAT1, FAS, and LPL in adipose tissue: Effects of obesity, insulin resistance, and TZD treatment. J Lipid Res 47, 2444–2450.
68.Koliwad, SK, Streeper, RS, Monetti, M et al. (2011) DGAT1-dependent triacylglycerol storage by macrophages protects mice from diet-induced insulin resistance and inflammation. J Clin Invest 120, 756–767.
69.Gutcher, I & Becher, B (2007) APC-derived cytokines and T cell polarization in autoimmune inflammation. J Clin Invest 117, 1119–1127.
70.Sarkar, S, Kalia, V, Haining, W et al. . (2008) Functional and genomic profiling of effector CD8 T cell subsets with distinct memory fates. J Exp Med 205, 625–640.
71.Rausch, ME, Weisberg, S, Vardhana, P et al. (2008) Obesity in C57BL/6J mice is characterized by adipose tissue hypoxia and cytotoxic T-cell infiltration. Int J Obes (Lond) 32, 451–463.
72.Wu, H, Ghosh, S, Perrard, XD et al. (2007) T-cell accumulation and regulated on activation, normal T cell expressed and secreted upregulation in adipose tissue in obesity. Circulation 115, 1029–1038.
73.Monney, L, Sabatos, CA, Gaglia, JL et al. (2002) Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 415, 536–541.
74.Kintscher, U, Hartge, M, Hess, K et al. (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.
75.Rocha, VZ, Folco, EJ, Sukhova, G et al. (2008) Interferon-gamma, a Th1 cytokine, regulates fat inflammation: A role for adaptive immunity in obesity. Circulation Res 103, 467–476.
76.McGillicuddy, FC, Chiquoine, EH, Hinkle, CC et al. (2009) Interferon gamma attenuates insulin signaling, lipid storage, and differentiation in human adipocytes via activation of the JAK/STAT pathway. J Biol Chem 284, 31936–31944.
77.Nishimura, S, Manabe, I, Nagasaki, M et al. (2009) CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med 15, 914–920.
78.Zheng, Y & Rudensky, AY (2007) Foxp3 in control of the regulatory T cell lineage. Nat Immunol 8, 457–462.
79.Sakaguchi, S, Yamaguchi, T, Nomura, T et al. (2008) Regulatory T cells and immune tolerance. Cell 133, 775–787.
80.Ait-Oufella, H, Salomon, BL, Potteaux, S et al. (2006) Natural regulatory T cells control the development of atherosclerosis in mice. Nat Med 12, 178–180.
81.Winer, S, Chan, Y, Paltser, G et al. (2009) Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med 15, 921–929.
82.Feuerer, M, Herrero, L, Cipolletta, D et al. (2009) Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 15, 930–939.