Open access peer-reviewed chapter
Abstract
Adipose tissue (AT) is a very important endocrine and paracrine organ that regulates other tissues and organs. Dysfunction of AT leads to a wide range of disorders like obesity, insulin resistance, diabetes mellitus, cardiac disorders, tumors and others. Adipose tissue macrophages (ATMs) are the key actors in AT remodeling and dysfunction. Their role in AT dysfunction is nowadays increasingly investigated, but still their interplay and molecular mechanisms of actions have not been fully elucidated. In this chapter, we summarized the current knowledge about the role of macrophages in AT remodeling, dysfunction and related disorders and indicate the potential directions for future research.
Keywords
- Adipose tissue
- macrophages
- tissue remodeling
- adipose tissue dysfunctions
1. Introduction
Adipose tissue (AT) was previously considered to be only a fat depot. Today, it is well known that AT secretes a large number of proteins collectively termed as adipokines (adiponectin, leptin, resistin and inflammatory cytokines TNF-α, IL6, IL8, IL1, IL10, IL18 and TGF-β) that are responsible for many different processes in the body. Therefore, AT is considered to be a highly active metabolic, endocrine and paracrine organ that regulates other tissues and organs. AT is very heterogeneous and consists of different cell types such as: adipocytes, pre-adipocytes, endothelial cells, fibroblasts, mesenchymal stem cells and immune cells (mast cells, lymphocytes and macrophages). Adipose tissue macrophages (ATMs) are cells that are responsible for AT remodeling. There are two types of ATMs, M1 (classically activated) or inflammatory macrophages and M2 (alternatively activated), anti-inflammatory or reparatory macrophages. The role of ATMs in disorders such as obesity, insulin resistance, diabetes mellitus, cardiac disorders, tumors and others is nowadays increasingly investigated, but still their interplay and molecular mechanisms of actions have not been fully elucidated. This chapter provides an overview of current knowledge about the role of macrophages in AT remodeling, dysfunction and related disorders and indicates the potential directions for future research.
2. Adipose Tissue Macrophages (ATMs)
Although adipocytes play a central role in adipose tissue (AT) remodeling, an increasing attention is directed toward adipose tissue macrophages (ATMs). Since adipose tissue remodeling is nowadays considered as chronic inflammation, ATMs and their interaction with adipocytes are key events that orchestrate the adipose tissue remodeling process.
Resident ATMs are very heterogenic population of cells that is reflected on their function in AT [1, 2]. During AT remodeling, factors that are released from AT induce the recruitment of monocytes into AT. It has been shown that most of the macrophages in AT are derived from bone marrow [3, 4].
There are two types of ATMs: M1 (classically activated) and M2 (alternatively activated) macrophages. They are characterized based on their polarization state, the expression of particular antigens [2, 5, 6] and secretion products. M1 (classically activated) macrophages, also called pro-inflammatory macrophages, are dominant type of macrophages during AT expansion and inflammation. They are characteristic of obese AT. Classically activated macrophages can be induced by LPS and the Th1 cytokine IFN-γ and express high levels of pro-inflammatory mediators including F4/80, CD11c, TNF-α, IL-6, iNOS, CCR2, IL-12 and IL-23 [6–9]. M2 (alternatively activated) macrophages, also called reparatory or anti-inflammatory macrophages, are dominant in lean AT. M2 macrophages are responsible for AT homeostasis, tissue repair and immunosuppression. Exposure of macrophages to the TH2 cytokine IL-4 produces M2 phenotype. They express F4/80, CD301, arginase 1 [6, 7] and CD163 and high levels of scavenger, mannose, and galactose-type receptors. They secrete anti-inflammatory cytokines such as IL-10 and IL-1 receptor antagonist [8, 9] and are shown to inhibit NOS (iNOS) activity. M2 macrophages preserve normal adipocyte function by promoting tissue repair and angiogenesis in an increasing AT mass [2, 10].
3. The role of ATMs in adipose tissue dysfunction and related disorders
The exact role of ATMs in AT dysfunction and related disorders is still not known. In recent years, a lot of research has been done, and it has been shown that the balance between M1 and M2 macrophages is crucial for maintaining normal adipocyte function and AT homeostasis.
Obesity is a very common chronic disease that leads to the development of insulin resistance, diabetes mellitus, cardiac disorders and others [3, 4, 11–15]. Obesity is characterized as a low-grade chronic inflammation with unbalanced production of pro- and anti-inflammatory adipokines that contributes to the development of metabolic syndrome [4, 11–14, 16] and may be involved in a variety of physiologic and pathologic processes [17]. In obesity, the balance between M1 and M2 macrophages is disturbed and moved toward M1 inflammatory macrophages. There are two mechanisms of imbalance occurrence: infiltration of monocytes from circulation under the influence of molecules secreted from growing AT and “phenotypic switching” between M1 and M2 macrophages. During the AT growth, adipocytes secrete products that promote the production of macrophage inflammatory cytokines [18, 19]. These products influence the polarization of resident macrophages. A model of “phenotypic switching” of macrophages has been reported by Lumeng et al. in 2007 [6]. Their model emphasized that obesity is accompanied by a transformation in the polarized states of macrophages, from an “alternatively activated” M2 that primarily accumulates during negative energy balance to a more pro-inflammatory “classically activated” M1 macrophages. This phenotypic change from M2 to M1 polarization in obese adipose tissue leads to adipose tissue inflammation [20–23]. Macrophages that are infiltrated into AT from circulation are an important source of inflammation in obese AT. Chemokines are small pro-inflammatory molecules that promote macrophage mobilization from bone marrow into tissues. Increased expression of chemokines in obese adipose tissue has been implicated in the control of monocyte recruitment to the adipose tissue. During the expansion of AT, secretion of pro-inflammatory cytokines is upregulated and they are released into the circulation. It is shown that MCP-1/CCR2 pathways have pathophysiological role in macrophage infiltration into obese adipose tissue [24, 25]. MCP-1 plays a role in the recruitment of macrophages into obese adipose tissue. Increased levels of MCP-1, CXCL14, MIP-1α, MCP-2, MCP-3 and RANTES can be observed in AT of mice with genetic or DIO [15, 26]. CCR2 expressed in bone marrow cells is involved in macrophage infiltration into obese adipose tissue [27]. In addition to the MCP-1/CCR2 pathway, there are several reports suggesting the potential involvement of other chemotactic factors in obesity-induced macrophage infiltration such as osteopontin, angiopoietin-like protein 2 and CXCL14 [26, 28, 29]. Downregulation of MKP-1 is critical for increased production of MCP-1 during adipocyte hypertrophy [30]. Increased number of pro-inflammatory CD11c+ M1-like ATMs in established obesity is a result of increased monocyte migration into AT, polarization of ATMs toward the M1 and a low level of proliferation of these cells after they become ATMs [31]. Adipocyte hyperplasia and hypertrophy both contribute to the expansion of AT that leads to hypoxia, adipocyte cell death, enhanced chemokine secretion and dysregulation in fatty acid fluxes [32]. Necrosis of adipocytes is a prominent phagocytic stimulus that regulates ATMs infiltration. Macrophages aggregate around these dead adipocytes forming crown-like structures (CLSs) in advanced obesity [33–36]. Macrophages fuse to form multinucleated giant cells and to phagocyte the residual lipid droplet. They become increasingly activated in their attempt to clear the potentially cytotoxic remnant lipid droplet forming large lipid-laden multinucleated syncytia in the process, a commonly accepted hallmark of chronic inflammation [7, 33]. Macrophages aggregate to constitute a CLS surrounding dead adipocytes in advanced obesity [6, 34, 35]. Electron microscopic analysis also revealed lipid-laden phagolysosomes in macrophages within CLS [33]. It is shown that massive adipocyte death can indeed drive rapid accumulation of ATMs as an integral element in the remodeling of fat pads [37] by using a transgenic model of inducible lipoatrophy. The number of necrotic adipocytes positively correlates with average adipocyte size in obese mice and other mouse models of adipocyte hypertrophy [33, 36, 38]. It has been suggested that macrophage localization and infiltration are strongly linked to adipose cell death [9, 33]. It is shown that adipocyte death and/or the death receptor Fas signaling contribute to obesity-induced adipose tissue inflammation and systemic insulin resistance [39, 40]. TNF-alpha induces pro-apoptotic and/or death signals in a variety of cell types, it is therefore interesting to speculate that hypertrophied adipocytes, which are stimulated and thus dying by macrophage-derived TNF-alpha, can release saturated fatty acids as an endogenous danger signal that reports their diseased state to macrophages in obese adipose tissue [4]. CCL5 production by fibroblasts, platelets and monocytes/macrophages is a particular feature of inflammatory disorders such as atherosclerosis [41, 42]. It is shown that CCL5, through CCR1 and CCR5, contributes to transendothelial migration of monocytes and T cells in atherogenic lesions [43]. CCL5 provides anti-apoptotic signals via the Akt and Erk1/2 pathways, which could then favor the scavenging role of tissue macrophages [44]. Obese adipose tissue is shown to be poorly oxygenated [45, 46]. During the expansion of AT, hypoxic areas are created due to adipocyte hypertrophy [47] that leads to the upregulated secretion of macrophage migration inhibitory factor (MIF), the matrix metalloproteinases MMP-2 and MMP-9, IL-6, Angplt4, PAI-1, VEGF and leptin [46, 48–50] that all together lead to inflammation. Leptin and VEGF are hypoxia-associated genes that are directly regulated by HIF-1, a master regulator of hypoxia and oxygen homeostasis is HIF-1 [51, 52]. Sun et al., 2011, suggest that hypoxia-induced fibrosis that follows AT inflammation may be a key factor that ultimately stimulates the local inflammatory responses [2]. Free fatty acids are stored in AT in the form of triglycerides and can cause lipotoxic side effects when are present in high amounts in tissues. During adipocytes’ hypertrophy FFAs are released through lipolysis and cause inflammatory response. By increasing local extracellular lipid concentrations, FFAs lead to the accumulation of ATMs [53, 54]. FFAs may act as ligands for the TLR4 complex, like LPS [55]. Activation of TLR4 complex by saturated fatty acids may be involved in the regulation of metabolic homeostasis within the adipose tissue. FFAs contribute to the polarization of infiltrated macrophages toward M1 [4]. It is shown that M1 population of macrophages is dominant in the states of overnutrition and that inflammatory response is mediated by FFAs [7, 56].
4. The role of macrophages in tumors
The exact role of macrophages in tumor development and progression is still not fully examined, but it is shown that macrophages are associated with solid tumors. Studies performed with various tumors showed that tumor-associated macrophages (TAMs) have a lot of similarities with M2 type of macrophages with high expression of IL-10 and low expression of IL-12. The expression of CD163 is high in TAMs and is used as a reliable marker for TAMs [57, 58]. These are potential indicators that TAMs are M2 polarized macrophages [59] with potent immunosuppressive functions. It is shown that TAMs possess anti-inflammatory, pro-angiogenic and tumor-promoting properties [60] and are characteristic of the late stage of tumor progression. Adipose tissue may support breast and prostate cancer development and progression via secretion of pro-inflammatory cytokines. Studies performed with mammary gland-associated AT and periprostatic AT showed that secretion of pro-inflammatory cytokines is increased in surrounded AT [61].
5. Conclusions and future perspectives
Further investigations are needed to understand the molecular mechanisms by which ATMs participate in the development of various disorders, which would open the door to the findings and development of new molecular target therapies. Dalmas et al., 2015 [62], suggested that inhibition of interferon regulatory factor 5 (IRF5), transcription factor implicated in polarization of macrophages towards M1, could be a potential strategy to control pathological AT expansion in obesity and insulin resistance. Repolarization of ATMs could also be one of the possible ways of treatment, but further investigation in this direction is needed.
Acknowledgments
This work is a part of the project III 41017 funded by the Ministry of Education, Science and Technological development of the Republic of Serbia.
References
- 1.
Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol 2005; 5(12): 953–964. - 2.
Sun K, Kusminski CM, Scherer PE. Adipose tissue remodeling and obesity. J Clin Invest 2011; 121(6): 2094–2101. - 3.
Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003; 112(12): 1796–1808. - 4.
Suganami T, Ogawa Y. Adipose tissue macrophages: their role in adipose tissue remodeling. J Leukoc Biol 2010; 88: 33–39. - 5.
Nguyen MT, Favelyukis S, Nguyen AK, Reichart D, Scott PA, Jenn A, Liu-Bryan R, Glass CK, Neels JG, Olefsky JM. 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 2007; 282(48): 35279–35292. - 6.
Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 2007; 117(1): 175–184. - 7.
Lumeng CN, Deyoung SM, Bodzin JL, Saltiel AR. Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity. Diabetes 2007; 56(1): 16–23. - 8.
Gordon S. Alternative activation of macrophages. Nat Rev Immunol. 2003; 3(1): 23–35. - 9.
Stienstra R, Duval C, Keshtkar S, van der Laak J, Kersten S, Müller M. Peroxisome proliferator-activated receptor gamma activation promotes infiltration of alternatively activated macrophages into adipose tissue. J Biol Chem 2008; 283(33): 22620–22627. - 10.
Satriano J. Arginine pathways and the inflammatory response: interregulation of nitric oxide and polyamines: review article. Amino Acids 2004; 26(4): 321–329. - 11.
Schenk S, Saberi M, Olefsky JM. Insulin sensitivity: modulation by nutrients and inflammation. J Clin Invest 2008; 118(9): 2992–3002. - 12.
Hotamisligil GS. Inflammation and metabolic disorders. Nature 2006; 444(7121): 860–867. - 13.
Berg AH, Scherer PE. Adipose tissue, inflammation, and cardiovascular disease. Circ Res 2005; 96(9): 939–949. - 14.
Rocha VZ, Libby P. Obesity, inflammation, and atherosclerosis. Nat Rev Cardiol 2009; 6(6): 399–409. - 15.
Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003; 112(12): 1821–1830. - 16.
Matsuzawa Y, Funahashi T, Nakamura T. Molecular mechanism of metabolic syndrome X: contribution of adipocytokines adipocyte-derived bioactive substances. Ann N Y Acad Sci 1999; 892: 146-54. - 17.
Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest 2006; 116(7): 1784–1792. - 18.
Berg AH, Lin Y, Lisanti MP, Scherer PE. Adipocyte differentiation induces dynamic changes in NF-kB expression and activity. Am J Physiol Endocrinol Metab 2004; 287(6): E1178–E1188. - 19.
Trujillo ME, Scherer PE. Adipose Tissue-Derived Factors: Impact on Health and Disease. Endocr Rev 2006; 27(7): 762–778. - 20.
Lumeng CN, DelProposto JB, Westcott DJ, Saltiel AR. Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes. Diabetes 2008; 57(2): 3239–3246. - 21.
Odegaard JI, Ricardo-Gonzalez RR, Red Eagle A, Vats D, Morel CR, Goforth MH, Subramanian V, Mukundan L, Ferrante AW, Chawla A. Alternative (M2) activation of Kupffer cells by PPARδ ameliorates obesity-induced insulin resistance. Cell Metab 2008; 7(6): 496–507. - 22.
Odegaard JI, Ricardo-Gonzalez RR, Goforth MH, Morel CR, Subramanian V, Mukundan L, Red Eagle A, Vats D, Brombacher F, Ferrante AW, Chawla A. Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature 2007; 447(7148): 1116–1120. - 23.
Kang K, Reilly SM, Karabacak V, Gangl MR, Fitzgerald K, Hatano B, Lee CH. Adipocyte-derived Th2 cytokines and myeloid PPARdelta regulate macrophage polarization and insulin sensitivity. Cell Metab 2008; 7(6):485–495. - 24.
Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, Kitazawa S, Miyachi H, Maeda S, Egashira K, Kasuga M. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 2006; 116(6): 1494–1505. - 25.
Kamei N, Tobe K, Suzuki R, Ohsugi M, Watanabe T, Kubota N, Ohtsuka-Kowatari N, Kumagai K, Sakamoto K, Kobayashi M, Yamauchi T, Ueki K, Oishi Y, Nishimura S, Manabe I, Hashimoto H, Ohnishi Y, Ogata H, Tokuyama K, Tsunoda M, Ide T, Murakami K, Nagai R, Kadowaki T. Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance. J Biol Chem 2006; 281(36): 26602–26614. - 26.
Nara N, Nakayama Y, Okamoto S, Tamura H, Kiyono M, Muraoka M, Tanaka K, Taya C, Shitara H, Ishii R, Yonekawa H, Minokoshi Y, Hara T. Disruption of CXC motif chemokine ligand-14 in mice ameliorates obesity-induced insulin resistance. J Biol Chem. 2007; 282(42): 30794–30803. - 27.
Ito A, Suganami T, Yamauchi A, Degawa-Yamauchi M, Tanaka M, Kouyama R, Kobayashi Y, Nitta N, Yasuda K, Hirata Y, Kuziel WA, Takeya M, Kanegasaki S, Kamei Y, Ogawa Y. Role of CC chemokine receptor 2 in bone marrow cells in the recruitment of macrophages into obese adipose tissue. J Biol Chem 2008; 283(51): 35715–35723. - 28.
Nomiyama T, Perez-Tilve D, Ogawa D, Gizard F, Zhao Y, Heywood EB, Jones KL, Kawamori R, Cassis LA, Tschöp MH, Bruemmer D. Osteopontin mediates obesity-induced adipose tissue macrophage infiltration and insulin resistance in mice. J Clin Invest 2007; 117(10): 2877–2888. - 29.
Tabata M, Kadomatsu T, Fukuhara S, Miyata K, Ito Y, Endo M, Urano T, Zhu HJ, Tsukano H, Tazume H, Kaikita K, Miyashita K, Iwawaki T, Shimabukuro M, Sakaguchi K, Ito T, Nakagata N, Yamada T, Katagiri H, Kasuga M, Ando Y, Ogawa H, Mochizuki N, Itoh H, Suda T, Oike Y. Angiopoietin-like protein 2 promotes chronic adipose tissue inflammation and obesity-related systemic insulin resistance. Cell Metab 2009; 10(3): 178–188. - 30.
Ito A, Suganami T, Miyamoto Y, Yoshimasa Y, Takeya M, Kamei Y, Ogawa Y. Role of MAPK phosphatase-1 in the induction of monocyte chemoattractant protein-1 during the course of adipocyte hypertrophy. J Biol Chem 2007; 282(35): 25445–25452. - 31.
Oh DY, Morinaga H, Talukdar S, Bae EJ, Olefsky JM. Increased Macrophage Migration Into Adipose Tissue in Obese Mice. Diabetes 2012; 61(2): 346–354. - 32.
Sun K, Scherer PE. Adipose Tissue Dysfunction: A Multistep Process. In: Novel Insights into Adipose Cell Functions. Christen Y, Clement K, Spiegelman BM (eds.), Springer-Verlag, Berlin Heidelberg; 2010:67–75. - 33.
Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E, Wang S, Fortier M, Greenberg AS, Obin MS. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res 2005; 46(11): 2347–2355. - 34.
Nishimura S, Manabe I, Nagasaki M, Hosoya Y, Yamashita H, Fujita H, Ohsugi M, Tobe K, Kadowaki T, Nagai R, Sugiura S. Adipogenesis in obesity requires close interplay between differentiating adipocytes, stromal cells, and blood vessels. Diabetes 2007; 56(6): 1517–1526. - 35.
Nishimura S, Manabe I, Nagasaki M, Seo K, Yamashita H, Hosoya Y, Ohsugi M, Tobe K, Kadowaki T, Nagai R, Sugiura S. In vivo imaging in mice reveals local cell dynamics and inflammation in obese adipose tissue. J Clin Invest 2008; 118(2): 710–721. - 36.
Strissel KJ, Stancheva Z, Miyoshi H, Perfield JW, DeFuria J, Jick Z, Greenberg AS, Obin MS. Adipocyte death, adipose tissue remodeling, and obesity complications. Diabetes 2007; 56(12): 2910–2918. - 37.
Pajvani UB, Trujillo ME, Combs TP, Iyengar P, Jelicks L, Roth KA, Kitsis RN, Scherer PE. Fat apoptosis through targeted activation of caspase 8: a new mouse model of inducible and reversible lipoatrophy. Nat Med 2005; 11(7): 797–803. - 38.
Khan T, Muise ES, Iyengar P, Wang ZV, Chandalia M, Abate N, Zhang BB, Bonaldo P, Chua S, Scherer PE. Metabolic Dysregulation and Adipose Tissue Fibrosis: Role of Collagen VI. Mol Cell Biol 2009; 29(6): 1575–1591. - 39.
Alkhouri N, Gornicka A, Berk MP, Thapaliya S, Dixon LJ, Kashyap S, Schauer PR, Feldstein AE. Adipocyte apoptosis, a link between obesity, insulin resistance, and hepatic steatosis. J Biol Chem 2010; 285(5): 3428–3438. - 40.
Wueest S, Rapold RA, Schumann DM, Rytka JM, Schildknecht A, Nov O, Chervonsky AV, Rudich A, Schoenle EJ, Donath MY, Konrad D. Deletion of Fas in adipocytes relieves adipose tissue inflammation and hepatic manifestations of obesity in mice. J Clin Invest 2010; 120(1): 191–202. - 41.
Eriksson EE. Mechanisms of leukocyte recruitment to atherosclerotic lesions: future prospects. Curr Opin Lipidol 2004; 15(5): 553–558. - 42.
Keophiphath M, Rouault C, Divoux A, Clément K, Lacasa D. CCL5 Promotes Macrophage Recruitment and Survival in Human Adipose Tissue. Arterioscler Thromb Vasc Biol 2010; 30(1): 39–45. - 43.
Zernecke A, Shagdarsuren E, Weber C. Chemokines in atherosclerosis: an update. Arterioscler Thromb Vasc Biol 2008; 28(11): 1897–1908. - 44.
Tyner JW, Uchida O, Kajiwara N, Kim EY, Patel AC, O'Sullivan MP, Walter MJ, Schwendener RA, Cook DN, Danoff TM, Holtzman MJ. CCL5-CCR5 interaction provides antiapoptotic signals for macrophage survival during viral infection. Nat Med 2005; 11(11): 1180 –1187. - 45.
Virtanen KA, Lönnroth P, Parkkola R, Peltoniemi P, Asola M, Viljanen T, Tolvanen T, Knuuti J, Rönnemaa T, Huupponen R, Nuutila P. Glucose uptake and perfusion in subcutaneous and visceral adipose tissue during insulin stimulation in nonobese and obese humans. J Clin Endocrinol Metab 2002; 87(8): 3902–3910. - 46.
Hosogai N, Fukuhara A, Oshima K, Miyata Y, Tanaka S, Segawa K, Furukawa S, Tochino Y, Komuro R, Matsuda M, Shimomura I. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes 2007; 56(4): 901–911. - 47.
Trayhurn P, Wood IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr 2004; 92(3): 347–355. - 48.
Ye J, Gao Z, Yin J, He Q. 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 2007; 293(4): E1118–E1128. - 49.
Chen B, Lam KS, Wang Y, Wu D, Lam MC, Shen J, Wong L, Hoo RL, Zhang J, Xu A. Hypoxia dysregulates the production of adiponectin and plasminogen activator inhibitor-1 independent of reactive oxygen species in adipocytes. Biochem Biophys Res Commun 2006; 341(2): 549–556. - 50.
Lolmede K, Durand de Saint Front V, Galitzky J, Lafontan M, Bouloumie A. Effects of hypoxia on the expression of proangiogenic factors in differentiated 3T3-F442A adipocytes. Int J Obes Relat Metab Disord 2003; 27(10): 1187–1195. - 51.
Brahimi-Horn MC, Chiche J, Pouyssegur J. Hypoxia and cancer. J Mol Med 2007; 85(12): 1301–1307. - 52.
Brahimi-Horn MC, Pouyssegur J. Oxygen, a source of life and stress. FEBS Lett 2007; 581(19): 3582–3591. - 53.
Suganami T, Nishida J, Ogawa Y. A paracrine loop between adipocytes and macrophages aggravates inflammatory changes: role of free fatty acids and tumor necrosis factor alpha. Arterioscler Thromb Vasc Biol 2005; 25(10): 2062–2068. - 54.
Nguyen MT, Satoh H, Favelyukis S, Babendure JL, Imamura T, Sbodio JI, Zalevsky J, Dahiyat BI, Chi NW, Olefsky JM. JNK and tumor necrosis factor- alpha mediate free fatty acid-induced insulin resistance in 3T3-L1 adipocytes. J Biol Chem 2005; 280(42): 35361–35371. - 55.
Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 2006; 116(11): 3015–3025. - 56.
Shoelson SE. Banking on ATM as a new target in metabolic syndrome. Cell Metab 2006; 4(5): 337–338. - 57.
Lau SK, Chu PG, Weiss LM. CD163: A specific marker of macrophages in paraffin-embedded tissue samples. Am J Clin Pathol 2004; 122(5): 794-801. - 58.
Pettersen JS, Fuentes-Duculan J, Suárez-Fariñas M, Pierson KC, Pitts-Kiefer A, Fan L, Belkin DA, Wang CQ, Bhuvanendran S, Johnson-Huang LM, Bluth MJ,Krueger JG, Lowes MA, Carucci JA. Tumor associated macrophages in the cutaneous SSC microenvironment are herterogeneously activated. J Invest Dermatol 2011; 131(6): 1322- 1330. - 59.
Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 2002; 23(11): 549–555. - 60.
Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol 2010; 11: 889–896. - 61.
Chaldakov GN, Tunçel N, Beltowski J, Fiore M, Rančić G, Tonchev A, Panayotov P, Evtimov N, Hinev A, Anakievski D, Ghenev P, Aloe L. Adipoparacrinology: an Emerging Field in Biomedical Research. Balkan Med J 2012; 29: 2–9. - 62.
Dalmas E, Toubal A, Alzaid F, Blazek K, Eames HL, Lebozec K, Pini M, Hainault I, Montastier E, Denis RG, Ancel P, Lacombe A, Ling Y, Allatif O, Cruciani-Guglielmacci C, André S, Viguerie N, Poitou C, Stich V, Torcivia A, Foufelle F, Luquet S, Aron-Wisnewsky J, Langin D, Clément K, Udalova IA, Venteclef N. Irf5 deficiency in macrophages promotes beneficial adipose tissue expansion and insulin sensitivity during obesity. Nat Med 2015; 21(6): 610–618.