In recent years, there has been an increasing incidence of metabolic syndrome, type 2 diabetes, and cardiovascular events related to insulin resistance. As one of the target organs for insulin, adipose tissue is essential for maintaining in vivo immune homeostasis and metabolic regulation. Currently, the specific adipose tissue mechanisms involved in insulin resistance remain incompletely understood. There is increasing evidence that the process of insulin resistance is mostly accompanied by a dramatic increase in the number and phenotypic changes of adipose tissue macrophages (ATMs). In this review, we discuss the origins and functions of ATMs, some regulatory factors of ATM phenotypes, and the mechanisms through which ATMs mediate insulin resistance. We explore how ATM phenotypes contribute to insulin resistance in adipose tissue. We expect that modulation of ATM phenotypes will provide a novel strategy for the treatment of diseases associated with insulin resistance.

Department of Endocrinology Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China

Zobrazit více v PubMed

Hill MA, Yang Y, Zhang L, Sun Z, Jia G, Parrish AR, Sowers JR. Insulin resistance, cardiovascular stiffening and cardiovascular disease. Metabolism. 2021;119:154766. doi: 10.1016/j.metabol.2021.154766. PubMed DOI

Jia G, Sowers JR. Hypertension in diabetes: an update of basic mechanisms and clinical disease. Hypertension. 2021;78:1197–1205. doi: 10.1161/HYPERTENSIONAHA.121.17981. PubMed DOI PMC

Lemieux I, Despres JP. Metabolic syndrome: past, present and future. Nutrients. 2020;12:3501. doi: 10.3390/nu12113501. PubMed DOI PMC

Guzik TJ, Skiba DS, Touyz RM, Harrison DG. The role of infiltrating immune cells in dysfunctional adipose tissue. Cardiovasc Res. 2017;113:1009–1023. doi: 10.1093/cvr/cvx108. PubMed DOI PMC

Lee YS, Olefsky J. Chronic tissue inflammation and metabolic disease. Genes Dev. 2021;35:307–328. doi: 10.1101/gad.346312.120. PubMed DOI PMC

Grant RW, Dixit VD. Adipose tissue as an immunological organ. Obesity (Silver Spring) 2015;23:512–518. doi: 10.1002/oby.21003. PubMed DOI PMC

Saklayen MG. The global epidemic of the metabolic syndrome. Curr Hypertens Rep. 2018;20:12. doi: 10.1007/s11906-018-0812-z. PubMed DOI PMC

Lee YS, Wollam J, Olefsky JM. An integrated view of immunometabolism. Cell. 2018;172:22–40. doi: 10.1016/j.cell.2017.12.025. PubMed DOI PMC

Russo L, Lumeng CN. Properties and functions of adipose tissue macrophages in obesity. Immunology. 2018;155:407–417. doi: 10.1111/imm.13002. PubMed DOI PMC

Viola A, Munari F, Sanchez-Rodriguez R, Scolaro T, Castegna A. The metabolic signature of macrophage responses. Front Immunol. 2019;10:1462. doi: 10.3389/fimmu.2019.01462. PubMed DOI PMC

Orliaguet L, Ejlalmanesh T, Alzaid F. Metabolic and molecular mechanisms of macrophage polarisation and adipose tissue insulin resistance. Int J Mol Sci. 2020;21:5731. doi: 10.3390/ijms21165731. PubMed DOI PMC

van Furth R, Cohn ZA, Hirsch JG, Humphrey JH, Spector WG, Langevoort HL. The mononuclear phagocyte system: a new classification of macrophages, monocytes, and their precursor cells. Bull World Health Organ. 1972;46:845–852. PubMed PMC

Mass E. Delineating the origins, developmental programs and homeostatic functions of tissue-resident macrophages. Int Immunol. 2018;30:493–501. doi: 10.1093/intimm/dxy044. PubMed DOI

Mass E, Ballesteros I, Farlik M, Halbritter F, Günther P, Crozet L, Jacome-Galarza CE, et al. Specification of tissue-resident macrophages during organogenesis. Science. 2016;353:aaf4238. doi: 10.1126/science.aaf4238. PubMed DOI PMC

Palis J, Robertson S, Kennedy M, Wall C, Keller G. Development of erythroid and myeloid progenitors in the yolk sac and embryo proper of the mouse. Development. 1999;126:5073–5084. doi: 10.1242/dev.126.22.5073. PubMed DOI

Perdiguero EG, Geissmann F. The development and maintenance of resident macrophages. Nat Immunol. 2016;17:2–8. doi: 10.1038/ni.3341. PubMed DOI PMC

Amano SU, Cohen JL, Vangala P, Tencerova M, Nicoloro SM, Yawe JC, Shen Y, Czech MP, Aouadi M. Local proliferation of macrophages contributes to obesity-associated adipose tissue inflammation. Cell Metab. 2014;19:162–171. doi: 10.1016/j.cmet.2013.11.017. PubMed DOI PMC

Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature. 2013;496:445–455. doi: 10.1038/nature12034. PubMed DOI PMC

Hirayama D, Iida T, Nakase H. The phagocytic function of macrophage-enforcing innate immunity and tissue homeostasis. Int J Mol Sci. 2017;19:92. doi: 10.3390/ijms19010092. PubMed DOI PMC

Rosales C, Uribe-Querol E. Phagocytosis: a fundamental process in immunity. Biomed Res Int. 2017;2017:9042851. doi: 10.1155/2017/9042851. PubMed DOI PMC

Spalding KL, Arner E, Westermark PO, Bernard S, Buchholz BA, Bergmann O, Blomqvist L, et al. Dynamics of fat cell turnover in humans. Nature. 2008;453:783–787. doi: 10.1038/nature06902. PubMed DOI

Strissel KJ, Stancheva Z, Miyoshi H, Perfield JW, 2nd, DeFuria J, Jick Z, Greenberg AS, Obin MS. Adipocyte death, adipose tissue remodeling, and obesity complications. Diabetes. 2007;56:2910–2918. doi: 10.2337/db07-0767. PubMed DOI

Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E, Wang S, et al. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res. 2005;46:2347–2355. doi: 10.1194/jlr.M500294-JLR200. PubMed DOI

Bigornia SJ, Farb MG, Mott MM, Hess DT, Carmine B, Fiscale A, Joseph L, Apovian CM, Gokce N. Relation of depot-specific adipose inflammation to insulin resistance in human obesity. Nutr Diabetes. 2012;2:e30. doi: 10.1038/nutd.2012.3. PubMed DOI PMC

Ruytinx P, Proost P, Van Damme J, Struyf S. Chemokine-induced macrophage polarization in inflammatory conditions. Front Immunol. 2018;9:1930. doi: 10.3389/fimmu.2018.01930. PubMed DOI PMC

Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012;122:787–795. doi: 10.1172/JCI59643. PubMed DOI PMC

Liu YC, Zou XB, Chai YF, Yao YM. Macrophage polarization in inflammatory diseases. Int J Biol Sci. 2014;10:520–529. doi: 10.7150/ijbs.8879. PubMed DOI PMC

Bashir S, Sharma Y, Elahi A, Khan F. Macrophage polarization: the link between inflammation and related diseases. Inflamm Res. 2016;65:1–11. doi: 10.1007/s00011-015-0874-1. PubMed DOI

Saha S, Shalova IN, Biswas SK. Metabolic regulation of macrophage phenotype and function. Immunol Rev. 2017;280:102–111. doi: 10.1111/imr.12603. PubMed DOI

Ferrante CJ, Leibovich SJ. Regulation of macrophage polarization and wound healing. Adv Wound Care (New Rochelle) 2012;1:10–16. doi: 10.1089/wound.2011.0307. PubMed DOI PMC

Roszer T. Understanding the mysterious M2 macrophage through activation markers and effector mechanisms. Mediators Inflamm. 2015;2015:816460. doi: 10.1155/2015/816460. PubMed DOI PMC

Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004;25:677–686. doi: 10.1016/j.it.2004.09.015. PubMed DOI

Martinez FO, Sica A, Mantovani A, Locati M. Macrophage activation and polarization. Front Biosci. 2008;13:453–461. doi: 10.2741/2692. PubMed DOI

Colin S, Chinetti-Gbaguidi G, Staels B. Macrophage phenotypes in atherosclerosis. Immunol Rev. 2014;262:153–166. doi: 10.1111/imr.12218. PubMed DOI

Duluc D, Delneste Y, Tan F, Moles M-P, Grimaud L, Lenoir J, Preisser L, et al. Tumor-associated leukemia inhibitory factor and IL-6 skew monocyte differentiation into tumor-associated macrophage-like cells. Blood. 2007;110:4319–4330. doi: 10.1182/blood-2007-02-072587. PubMed DOI

Wang Q, Ni H, Lan L, Wei X, Xiang R, Wang Y. Fra-1 protooncogene regulates IL-6 expression in macrophages and promotes the generation of M2d macrophages. Cell Res. 2010;20:701–712. doi: 10.1038/cr.2010.52. PubMed DOI

Xue J, Schmidt SV, Sander J, Draffehn A, Krebs W, Quester I, De Nardo D, et al. Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity. 2014;40:274–288. doi: 10.1016/j.immuni.2014.01.006. PubMed DOI PMC

Dey A, Allen J, Hankey-Giblin PA. Ontogeny and polarization of macrophages in inflammation: blood monocytes versus tissue macrophages. Front Immunol. 2014;5:683. doi: 10.3389/fimmu.2014.00683. PubMed DOI PMC

Kratz M, Coats BR, Hisert KB, Hagman D, Mutskov V, Peris E, Schoenfelt KQ, et al. Metabolic dysfunction drives a mechanistically distinct proinflammatory phenotype in adipose tissue macrophages. Cell Metab. 2014;20:614–625. doi: 10.1016/j.cmet.2014.08.010. PubMed DOI PMC

Puschel GP, Klauder J, Henkel J. Macrophages, low-grade inflammation, insulin resistance and hyperinsulinemia: a mutual ambiguous relationship in the development of metabolic diseases. J Clin Med. 2022;11:4358. doi: 10.3390/jcm11154358. PubMed DOI PMC

Okabe Y, Medzhitov R. Tissue-specific signals control reversible program of localization and functional polarization of macrophages. Cell. 2014;157:832–844. doi: 10.1016/j.cell.2014.04.016. PubMed DOI PMC

Vijay K. Toll-like receptors in immunity and inflammatory diseases: Past, present, and future. Int Immunopharmacol. 2018;59:391–412. doi: 10.1016/j.intimp.2018.03.002. PubMed DOI PMC

Brennan JJ, Gilmore TD. Evolutionary origins of toll-like receptor signaling. Mol Biol Evol. 2018;35:1576–1587. doi: 10.1093/molbev/msy050. PubMed DOI

Vidya MK, Kumar VG, Sejian V, Bagath M, Krishnan G, Bhatta R. Toll-like receptors: significance, ligands, signaling pathways, and functions in mammals. Int Rev Immunol. 2018;37:20–36. doi: 10.1080/08830185.2017.1380200. PubMed DOI

Catalán V, Gómez-Ambrosi J, Rodríguez A, Ramírez B, Rotellar F, Valentí V, Silva C, et al. Increased tenascin C and Toll-like receptor 4 levels in visceral adipose tissue as a link between inflammation and extracellular matrix remodeling in obesity. J Clin Endocrinol Metab. 2012;97:E1880–E1889. doi: 10.1210/jc.2012-1670. PubMed DOI PMC

Beutler B. Tlr4: central component of the sole mammalian LPS sensor. Curr Opin Immunol. 2000;12:20–26. doi: 10.1016/S0952-7915(99)00046-1. PubMed DOI

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;116:3015–3025. doi: 10.1172/JCI28898. PubMed DOI PMC

Kawanishi N, Yano H, Yokogawa Y, Suzuki K. Exercise training inhibits inflammation in adipose tissue via both suppression of macrophage infiltration and acceleration of phenotypic switching from M1 to M2 macrophages in high-fat-diet-induced obese mice. Exerc Immunol Rev. 2010;16:105–118. PubMed

Shan B, Shao M, Zhang Q, Hepler C, Paschoal VA, Barnes SD, Vishvanath L, et al. Perivascular mesenchymal cells control adipose-tissue macrophage accrual in obesity. Nat Metab. 2020;2:1332–1349. doi: 10.1038/s42255-020-00301-7. PubMed DOI PMC

Orr JS, Puglisi MJ, Ellacott KL, Lumeng CN, Wasserman DH, Hasty AH. Toll-like receptor 4 deficiency promotes the alternative activation of adipose tissue macrophages. Diabetes. 2012;61:2718–2727. doi: 10.2337/db11-1595. PubMed DOI PMC

Griffin C, Eter L, Lanzetta N, Abrishami S, Varghese M, McKernan K, Muir L, et al. TLR4, TRIF, and MyD88 are essential for myelopoiesis and CD11c(+) adipose tissue macrophage production in obese mice. J Biol Chem. 2018;293:8775–8786. doi: 10.1074/jbc.RA117.001526. PubMed DOI PMC

Rendra E, Riabov V, Mossel DM, Sevastyanova T, Harmsen MC, Kzhyshkowska J. Reactive oxygen species (ROS) in macrophage activation and function in diabetes. Immunobiology. 2019;224:242–253. doi: 10.1016/j.imbio.2018.11.010. PubMed DOI

Xia W, Lu Z, Chen W, Zhou J, Zhao Y. Excess fatty acids induce pancreatic acinar cell pyroptosis through macrophage M1 polarization. BMC Gastroenterol. 2022;22:72. doi: 10.1186/s12876-022-02146-8. PubMed DOI PMC

Yuan Y, Chen Y, Peng T, Li L, Zhu W, Liu F, Liu S, et al. Mitochondrial ROS-induced lysosomal dysfunction impairs autophagic flux and contributes to M1 macrophage polarization in a diabetic condition. Clin Sci (Lond) 2019;133:1759–1777. doi: 10.1042/CS20190672. PubMed DOI

Acín-Pérez R, Iborra S, Martí-Mateos Y, Cook ECL, Conde-Garrosa R, Petcherski A, Del Mar Muñoz M, et al. Fgr kinase is required for proinflammatory macrophage activation during diet-induced obesity. Nat Metab. 2020;2:974–988. doi: 10.1038/s42255-020-00273-8. PubMed DOI PMC

Li W, Zeng H, Xu M, Huang C, Tao L, Li J, Zhang T, et al. Oleanolic acid improves obesity-related inflammation and insulin resistance by regulating macrophages activation. Front Pharmacol. 2021;12:697483. doi: 10.3389/fphar.2021.697483. PubMed DOI PMC

Wang Y, Tang B, Long L, Luo P, Xiang W, Li X, Wang H, et al. Improvement of obesity-associated disorders by a small-molecule drug targeting mitochondria of adipose tissue macrophages. Nat Commun. 2021;12:102. doi: 10.1038/s41467-020-20315-9. PubMed DOI PMC

Holmstrom KM, Finkel T. Cellular mechanisms and physiological consequences of redox-dependent signalling. Nat Rev Mol Cell Biol. 2014;15:411–421. doi: 10.1038/nrm3801. PubMed DOI

Kausar S, Wang F, Cui H. The role of mitochondria in reactive oxygen species generation and its implications for neurodegenerative diseases. Cells. 2018;7:274. doi: 10.3390/cells7120274. PubMed DOI PMC

Yang Z, Min Z, Yu B. Reactive oxygen species and immune regulation. Int Rev Immunol. 2020;39:292–298. doi: 10.1080/08830185.2020.1768251. PubMed DOI

Appari M, Channon KM, McNeill E. Metabolic regulation of adipose tissue macrophage function in obesity and diabetes. Antioxid Redox Signal. 2018;29:297–312. doi: 10.1089/ars.2017.7060. PubMed DOI PMC

Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest. 2007;117:175–184. doi: 10.1172/JCI29881. PubMed DOI PMC

Shin KC, Hwang I, Choe SS, Park J, Ji Y, Kim JI, Lee GY, et al. Macrophage VLDLR mediates obesity-induced insulin resistance with adipose tissue inflammation. Nat Commun. 2017;8:1087. doi: 10.1038/s41467-017-01232-w. PubMed DOI PMC

Shields JM, Christy RJ, Yang VW. Identification and characterization of a gene encoding a gut-enriched Kruppel-like factor expressed during growth arrest. J Biol Chem. 1996;271:20009–20017. doi: 10.1074/jbc.271.33.20009. PubMed DOI PMC

McConnell BB, Yang VW. Mammalian Kruppel-like factors in health and diseases. Physiol Rev. 2010;90:1337–1381. doi: 10.1152/physrev.00058.2009. PubMed DOI PMC

Feinberg MW, Cao Z, Wara AK, Lebedeva MA, Senbanerjee S, Jain MK. Kruppel-like factor 4 is a mediator of proinflammatory signaling in macrophages. J Biol Chem. 2005;280:38247–38258. doi: 10.1074/jbc.M509378200. PubMed DOI

Liao X, Sharma N, Kapadia F, Zhou G, Lu Y, Hong H, Paruchuri K, et al. Kruppel-like factor 4 regulates macrophage polarization. J Clin Invest. 2011;121:2736–2749. doi: 10.1172/JCI45444. PubMed DOI PMC

Pan Y, Hui X, Hoo RLC, Ye D, Cheung Chan CY, Feng T, Wang Y, Ling Lam KS, Xu A. Adipocyte-secreted exosomal microRNA-34a inhibits M2 macrophage polarization to promote obesity-induced adipose inflammation. J Clin Invest. 2019;129:834–849. doi: 10.1172/JCI123069. PubMed DOI PMC

Qiu Y, Xu J, Yang L, Zhao G, Ding J, Chen Q, Zhang N, et al. MiR-375 silencing attenuates pro-inflammatory macrophage response and foam cell formation by targeting KLF4. Exp Cell Res. 2021;400:112507. doi: 10.1016/j.yexcr.2021.112507. PubMed DOI

Luan B, Yoon YS, Le Lay J, Kaestner KH, Hedrick S, Montminy M. CREB pathway links PGE2 signaling with macrophage polarization. Proc Natl Acad Sci U S A. 2015;112:15642–15647. doi: 10.1073/pnas.1519644112. PubMed DOI PMC

Nanjan MJ, Mohammed M, Prashantha Kumar BR, Chandrasekar MJN. Thiazolidinediones as antidiabetic agents: A critical review. Bioorg Chem. 2018;77:548–567. doi: 10.1016/j.bioorg.2018.02.009. PubMed DOI

Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature. 1998;391:79–82. doi: 10.1038/34178. PubMed DOI

Chawla A. Control of macrophage activation and function by PPARs. Circ Res. 2010;106:1559–1569. doi: 10.1161/CIRCRESAHA.110.216523. PubMed DOI PMC

Lawrence T, Natoli G. Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat Rev Immunol. 2011;11:750–761. doi: 10.1038/nri3088. PubMed DOI

Odegaard JI, Ricardo-Gonzalez RR, Goforth MH, Morel CR, Subramanian V, Mukundan L, Red Eagle A, et al. Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature. 2007;447:1116–1120. doi: 10.1038/nature05894. PubMed DOI PMC

Kiran S, Rakib A, Kodidela S, Kumar S, Singh UP. High-fat diet-induced dysregulation of immune cells correlates with macrophage phenotypes and chronic inflammation in adipose tissue. Cells. 2022;11:1327. doi: 10.3390/cells11081327. PubMed DOI PMC

Li C, Ying W, Huang Z, Brehm T, Morin A, Vella AT, Zhou B. IRF6 regulates alternative activation by suppressing PPARgamma in male murine macrophages. Endocrinology. 2017;158:2837–2847. doi: 10.1210/en.2017-00053. PubMed DOI PMC

Xu J, Dong J, Ding H, Wang B, Wang Y, Qiu Z, Yao F. Ginsenoside compound K inhibits obesity-induced insulin resistance by regulation of macrophage recruitment and polarization via activating PPARgamma. Food Funct. 2022;13:3561–3571. doi: 10.1039/D1FO04273D. PubMed DOI

Saltiel AR. Insulin signaling in health and disease. J Clin Invest. 2021;131:e142241. doi: 10.1172/JCI142241. PubMed DOI PMC

Rahman MS, Hossain KS, Das S, Kundu S, Adegoke EO, Rahman MA, Hannan MA, Uddin MJ, Pang M-G. Role of insulin in health and disease: an update. Int J Mol Sci. 2021;22:6403. doi: 10.3390/ijms22126403. PubMed DOI PMC

Haeusler RA, McGraw TE, Accili D. Biochemical and cellular properties of insulin receptor signalling. Nat Rev Mol Cell Biol. 2018;19:31–44. doi: 10.1038/nrm.2017.89. PubMed DOI PMC

Jaldin-Fincati JR, Pavarotti M, Frendo-Cumbo S, Bilan PJ, Klip A. Update on GLUT4 vesicle traffic: a cornerstone of insulin action. Trends Endocrinol Metab. 2017;28:597–611. doi: 10.1016/j.tem.2017.05.002. PubMed DOI

Lee SH, Park SY, Choi CS. Insulin resistance: from mechanisms to therapeutic strategies. Diabetes Metab J. 2022;46:15–37. doi: 10.4093/dmj.2021.0280. PubMed DOI PMC

Chattopadhyay D, Das S, Guria S, Basu S, Mukherjee S. Fetuin-A regulates adipose tissue macrophage content and activation in insulin resistant mice through MCP-1 and iNOS: involvement of IFNgamma-JAK2-STAT1 pathway. Biochem J. 2021;478:4027–4043. doi: 10.1042/BCJ20210442. PubMed DOI

Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol. 2010;72:219–246. doi: 10.1146/annurev-physiol-021909-135846. PubMed DOI

Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab. 2001;280:E745–E751. doi: 10.1152/ajpendo.2001.280.5.E745. PubMed DOI

Akash MSH, Rehman K, Liaqat A. Tumor necrosis factor-alpha: role in development of insulin resistance and pathogenesis of type 2 diabetes mellitus. J Cell Biochem. 2018;119:105–110. doi: 10.1002/jcb.26174. PubMed DOI

Bruun JM, Lihn AS, Verdich C, Pedersen SB, Toubro ST, Astrup A, Richelsen B. Regulation of adiponectin by adipose tissue-derived cytokines: in vivo and in vitro investigations in humans. Am J Physiol Endocrinol Metab. 2003;285:E527–E533. doi: 10.1152/ajpendo.00110.2003. PubMed DOI

Kita S, Maeda N, Shimomura I. Interorgan communication by exosomes, adipose tissue, and adiponectin in metabolic syndrome. J Clin Invest. 2019;129:4041–4049. doi: 10.1172/JCI129193. PubMed DOI PMC

Yaribeygi H, Farrokhi FR, Butler AE, Sahebkar A. Insulin resistance: Review of the underlying molecular mechanisms. J Cell Physiol. 2019;234:8152–8161. doi: 10.1002/jcp.27603. PubMed DOI

Akbari M, Hassan-Zadeh V. IL-6 signalling pathways and the development of type 2 diabetes. Inflammopharmacology. 2018;26:685–698. doi: 10.1007/s10787-018-0458-0. PubMed DOI

Ueki K, Kondo T, Kahn CR. Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms. Mol Cell Biol. 2004;24:5434–5446. doi: 10.1128/MCB.24.12.5434-5446.2004. PubMed DOI PMC

Rotter V, Nagaev I, Smith U. Interleukin-6 (IL-6) induces insulin resistance in 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-alpha, overexpressed in human fat cells from insulin-resistant subjects. J Biol Chem. 2003;278:45777–45784. doi: 10.1074/jbc.M301977200. PubMed DOI

Lira FS, Rosa JC, Dos Santos RV, Venancio DP, Carnier J, de Lima Sanches P, do Nascimento CMO, et al. Visceral fat decreased by long-term interdisciplinary lifestyle therapy correlated positively with interleukin-6 and tumor necrosis factor-alpha and negatively with adiponectin levels in obese adolescents. Metabolism. 2011;60:359–365. doi: 10.1016/j.metabol.2010.02.017. PubMed DOI

Stanford KI, Middelbeek RJ, Townsend KL, An D, Nygaard EB, Hitchcox KM, Markan KR, et al. Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. J Clin Invest. 2013;123:215–223. doi: 10.1172/JCI62308. PubMed DOI PMC

Li G, Klein RL, Matheny M, King MA, Meyer EM, Scarpace PJ. Induction of uncoupling protein 1 by central interleukin-6 gene delivery is dependent on sympathetic innervation of brown adipose tissue and underlies one mechanism of body weight reduction in rats. Neuroscience. 2002;115:879–889. doi: 10.1016/S0306-4522(02)00447-5. PubMed DOI

Type 2 Diabetes, Obesity and Their Relation to the Risks of Thyroid Cancer