Journal of Investigative Medicine:
EB Symposium Manuscripts
How Does High-Fat Diet Induce Adipose Tissue Fibrosis?
Pessin, Jeffrey E. PhD; Kwon, Hyokjoon PhD
From the Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY.
Received June 25, 2012.
Accepted for publication August 8, 2012.
Reprints: Hyokjoon Kwon, PhD, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA. E-mail: firstname.lastname@example.org.
Supported in part by a grant from the National Center for Research Resources (R13 RR023236).
Abstract: Obesity is one of the most serious pandemic health problems in modern society and the predisposing factor for the type 2 diabetes mellitus. Chronic low-grade inflammation mediates the pathogenesis of insulin resistance in obese humans and rodents, and white adipose tissue is one of major tissues to modulate inflammation. Obese humans and rodents show dynamic changes of immunocellular compositions in white adipose tissue to induce inflammatory responses. Innate and adaptive immune responses mainly mediated by macrophages and T cells contribute insulin resistance. Recently, it has been shown that adipose tissue fibrosis is also enhanced in obese humans and rodents along with inflammatory responses, and suppression of adipose tissue fibrosis shows improved insulin sensitivity in rodent models, suggesting that adipose tissue fibrosis is involved in insulin resistance.
INFLAMMATION AND INSULIN RESISTANCE
Obesity is the single predisposing factor for type 2 diabetes mellitus (T2DM) and is a major contributor to a variety of health issues including liver and cardiovascular diseases. In parallel, T2DM is a quickly growing global metabolic disease characterized by impaired insulin secretion and insulin resistance.1 Recent evidence has indicated that inflammation is one important contributing process for the development of insulin resistance in obese humans and rodents, and adipose tissue has been shown as a major site mediating the inflammatory response.2–4 White adipose tissue consists of a variety of cell types including adipocytes, macrophages, lymphocytes, preadipocytes, and endothelial cells. Innate immune response mainly mediated by macrophages is a key inflammatory process in adipose tissue resulting in insulin resistance. Macrophages are differentiated into 2 generally functional distinct populations, although there are numerous macrophage subtypes that seem to represent a continuum and interconversion with discrete functions. In a simplified version, the classically activated macrophages (M1, proinflammatory) induced by TH1 cytokines such as interferon gamma (IFN-γ) express nitric oxide synthase, whereas the alternatively activated macrophages (M2, anti-inflammatory) induced by TH2 cytokines such as IL-4 and IL-13 express arginase-1.5–9 F4/80+CD11c+ inflammatory M1 macrophages are increased in adipose tissue and secrete inflammatory cytokines such as tumor necrosis factor α (TNF-α), IL-6, and IL-1β. Tumor necrosis factor α levels are increased in obese diabetic humans and rodents, and neutralization of TNF-α improves insulin sensitivity in obese rodents.10 Tumor necrosis factor α induces serine phosphorylation of insulin receptor substrate 1 to inhibit signaling to downstream effectors of the insulin receptor resulting in insulin resistance.11 IL-1β is also elevated in circulation12 and in pancreatic islets of obese humans and rodents with T2DM and induces the loss of pancreatic β-cell mass resulting in hyperglycemia.13–15 IL-1β is mainly produced by monocytes and macrophages being synthesized as an IL-1β precursor in cytosol, and activation-induced NALP3 (cryopyrin) inflammasome activates caspase-1 to mediate active IL-1β secretion.16 IL-1β binds to IL-1 receptor type I (IL-1RI) and IL-1 receptor accessory protein17 and recruits MYD88, IRAK4, and TRAF6 to activate nuclear factor kappa B and mitogen-activated protein kinases.
Recently, adaptive immune responses have been shown to be a critical factor for high-fat diet (HFD)-induced inflammation and insulin resistance in humans and rodents (Fig. 1). Foxp3+CD4+ regulatory T cells (anti-inflammatory IL-10–producing cells), IL-4–producing TH2 CD4+ T cells, and eosinophils are decreased; whereas effector CD8+ T cells, IFN-γ–producing TH1 CD4+ T cells, and autoantibody-producing B cells are increased in obese mice.18–21 Interestingly, adoptive transfer of CD4+ cells, which produce IL-4 and IL-13, rescues HFD-induced obesity and insulin resistance in Rag1-deficient mice,18 suggesting that TH2 cytokines such as IL-4 and IL-13 suppress HFD-induced inflammation to improve insulin sensitivity. In addition, IL-13 and IL-4 mediate TH2 immune responses to activate eosinophils, basophils, and B cells resulting in the clearance of extracellular parasites.6 IL-13 is a 4-helix bundle short-chain and TH2 CD4+ T-cell–derived cytokine that is also involved in allergic inflammation, asthma, tissue remodeling and, in this context, fibrosis.22,23 IL-13 is a ligand for IL-13Rα1 and IL-13Rα2 receptors.24–27 IL-13Rα1 is a low-affinity receptor by itself but forms a high-affinity receptor with IL-4Rα to generate an IL-4Rα and IL-13Rα1 heterodimer, termed the type II IL-4 receptor (IL-4RII).28,29 As IL-4RII shares IL-4Rα and IL-13Rα1, IL-13 activates JAK1, Tyk2, and STAT6; and although IL-13 and IL-4 are functionally related, conventional IL-13–deficient mice demonstrate a unique role of IL-13 in TH2 immune responses.30
IMMUNE RESPONSES IN TISSUE FIBROSIS
Fibrosis is a common pathological consequence of many inflammatory diseases such as idiopathic pulmonary fibrosis, liver cirrhosis, systemic sclerosis, and progressive kidney disease.22,23 Therefore, fibrotic disorders are a critical problem of morbidity and mortality worldwide and cause approximately 45% of deaths in the United States.31 Intensive studies to understand the molecular mechanisms of fibrosis have shown that IL-13 and transforming growth factor-β1 (TGF-β1) are key regulators,32–35 and activated fibroblasts produce extracellular matrix (ECM) including collagens, elastins, and proteoglycans22,31 resulting in the pathogenesis of fibrosis. Damaged epithelial and endothelial cells secrete inflammatory mediators to initiate blood clotting and epithelial/endothelial cells, and platelets produce chemokines and growth factors such as TGF-β and platelet-derived growth factor to recruit neutrophils and macrophages. Furthermore, T cells, B cells, and eosinophils are recruited to generate profibrotic cytokines such as IL-13 and TGF-β1. Fibroblasts are also accumulated in injured region from epithelial-mesenchymal transition (EMT) and bone marrow–derived fibrocytes. Fibroblasts are activated by IL-13 and TGF-β1 and then differentiate into α-smooth muscle actin expressing myofibroblasts to produce ECM. Myofibroblasts, macrophages, and epithelial/endothelial cells also produce matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases for ECM regulation. Therefore, the balance between ECM formation and degradation is a critical process for normal tissue repair. Tissue repair process becomes pathogenic fibrosis if the balance between ECM formation and degradation is not tightly regulated, resulting in the distortion of normal tissue architecture and function.
Fibrosis is closely linked with TH2 immune responses, and especially IL-13, produced by TH2 CD4+ T cells, is the major cytokine to mediate tissue fibrosis.31,36,37 The expression of IL-13 is increased in tissues and bronchoalveolar lavage fluid in idiopathic pulmonary fibrosis, sarcoidosis, and liver fibrosis. However, molecular mechanisms to mediate IL-13–induced tissue fibrosis are complicated. The profibrotic effects of IL-13 are dependent on TGF-β1 in lung fibrosis.34,35 Three isotypes of TGF-β (TGF-β1, TGF-β2, and TGF-β3) have been found in mammals, and TGF-β1, mainly produced by monocytes and macrophages, is the major isotype to mediate tissue fibrosis. IL-13 induces matrix metalloproteinase-9 and activates cathepsin-based proteolytic pathways to cleave latency-associated protein (LAP) for the generation of active TGF-β1 resulting in the stimulation of myofibroblasts to produce ECM. In contrast, IL-13–induced liver fibrosis in schistosomiasis is TGF-β1 independent.38 Schistosoma mansoni–infected IL-13–deficient mice showed improved liver fibrosis although TGF-β production is not diminished. Furthermore, the treatment of neutralizing TGF-β antibody, TGF-βR-Fc, and Smad3-deficient mice do not modulate development of liver fibrosis and production of IL-13 in schistosomiasis, suggesting that S. mansoni–induced liver fibrosis is mediated by IL-13 but TGF-β1 independent. Therefore, IL-13 and TGF-β1 seem to be critical cytokines mediating tissue fibrosis. However, the specific pathways and mechanisms dictating the independent and cooperative interaction of IL-13 and TGF-β1 in the pathogenesis of specific tissue fibrosis remain enigmatic.
UNIQUE MICROENVIRONMENT IN ADIPOSE TISSUE FIBROSIS
Adipose tissue stores excess nutrition and also releases fatty acids to compensate nutrition deprivation. Thus, adipose tissue maintains whole body energy homeostasis through hyperplasia and hypertrophy. Excess nutrition initiates adipocyte expansion along with triglyceride accumulation, adipocyte cell death, adipokine/cytokine production, endoplasmic reticulum stress and adipose tissue hypoxia resulting in the immune cell infiltration, low-grade chronic inflammation and adipose tissue fibrosis in both humans and rodents.3,39–43 Collagen type VI is a dominant ECM in mice, and collagen VI–deficient ob/ob and HFD-fed mice have reduced adipose tissue fibrosis with improved insulin sensitivity, suggesting that adipose tissue fibrosis may be an important determinant of insulin sensitivity.41 Adipocyte hypertrophy induces the expression of hypoxia-inducible factor 1α (HIF-1α), and increased lysyl oxidase one of target genes of HIF-1α mediates cross-linking of collagens for adipose tissue fibrosis.42 In parallel, obesity in humans is recently shown to be associated with adipose tissue fibrosis. White adipose tissues of obese humans have more collagen deposition than lean subjects.40 Adipose tissue fibrosis may induce rigid extracellular environment, which restrains adipocyte expansion and then triggers adipocyte cell death and inflammatory responses by increased mechanical stress.
Obese humans and rodents show accumulated diverse inflammatory immune cells in adipose tissue,18–21 and interactions between macrophages and preadipocytes are involved in ECM production,43 suggesting that immune cells such as macrophages and T cells are involved in adipose tissue fibrosis. However, molecular mechanisms of HFD-induced adipose tissue fibrosis are not clear. IL-13 is the critical mediator in liver and lung fibrosis, and TH2 CD4+ T cells are major source of IL-13 to produce ECM. However, the expression of IL-4 is significantly diminished,21 whereas IL-13 levels are increased in adipose tissue of HFD-induced obese rodents (unpublished results). Because TH2 CD4+ T cells and eosinophils are decreased after HFD feeding, it is likely that non-CD4+ T cells are responsible for the production of IL-13 in adipose tissue (Fig. 2). In addition, IFN-γ produced by TH1 CD4+ T cells suppresses the differentiation of alternatively activated M2 macrophages and TH2 CD4+ T cells, resulting in the abrogation of tissue fibrosis in the liver.44,45 In contrast, IFN-γ producing CD4+ T cells are increased in adipose tissue of HFD-fed or genetically modified obese mice although adipose tissue fibrosis is enhanced. Thus, in contrast to the liver, adipose tissue has unique molecular mechanisms driving fibrosis in vivo. We suggest that HFD induces the expression of IL-13 from non-TH2 CD4+ T cells and may mediate the deposition of collagen to induced adipose tissue fibrosis although IFN-γ expression is enhanced owing to increased TH1 CD4+ T cells. To elucidate molecular mechanisms of HFD-induced adipose fibrosis, one important goal is to identify the source of IL-13 in adipose tissue and signaling pathway mediating the expression of IL-13 in adipose tissue.
1. Ogden CL, Carroll MD, Curtin LR, et al.. Prevalence of overweight and obesity in the United States, 1999–2004. JAMA
. 2006; 295: 1549–1555.
2. Hotamisligil GS. Inflammation and metabolic disorders. Nature
. 2006; 444: 860–867.
3. Schenk S, Saberi M, Olefsky JM. Insulin sensitivity: modulation by nutrients and inflammation. J Clin Invest
. 2008; 118: 2992–3002.
4. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest
. 2006; 116: 1793–1801.
5. Mantovani A, Sica A, Sozzani S, et al.. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol
. 2004; 25: 677–686.
6. Martinez FO, Helming L, Gordon S. Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol
. 2009; 27: 451–483.
7. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol
. 2008; 8: 958–969.
8. Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest
. 2007; 117: 175–184.
9. Lumeng CN, Deyoung SM, Bodzin JL, et al.. Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity. Diabetes
. 2007; 56: 16–23.
10. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science
. 1993; 259: 87–91.
11. Hotamisligil GS, Peraldi P, Budavari A, et al.. IRS-1–mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha– and obesity-induced insulin resistance. Science
. 1996; 271: 665–668.
12. Spranger J, Kroke A, Mohlig M, et al.. Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Diabetes
. 2003; 52: 812–817.
13. Donath MY, Gross DJ, Cerasi E, et al.. Hyperglycemia-induced beta-cell apoptosis in pancreatic islets of Psammomys obesus during development of diabetes. Diabetes
. 1999; 48: 738–744.
14. Ehses JA, Lacraz G, Giroix MH, et al.. IL-1 antagonism reduces hyperglycemia and tissue inflammation in the type 2 diabetic GK rat. Proc Natl Acad Sci U S A
. 2009; 106: 13998–14003.
15. Sauter NS, Schulthess FT, Galasso R, et al.. The anti-inflammatory cytokine interleukin-1 receptor antagonist protects from high-fat diet-induced hyperglycemia. Endocrinology
. 2008; 149: 2208–2218.
16. Dinarello CA. Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol
. 2009; 27: 519–550.
17. Sims JE, Smith DE. The IL-1 family: regulators of immunity. Nat Rev Immunol
. 2010; 10: 89–102.
18. Winer S, Chan Y, Paltser G, et al.. Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med
. 2009; 15: 921–929.
19. Nishimura S, Manabe I, Nagasaki M, et al.. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med
. 2009; 15: 914–920.
20. Feuerer M, Herrero L, Cipolletta D, et al.. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med
. 2009; 15: 930–939.
21. Wu D, Molofsky AB, Liang HE, et al.. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science
. 2011; 332: 243–247.
22. Meneghin A, Hogaboam CM. Infectious disease, the innate immune response, and fibrosis. J Clin Invest
. 2007; 117: 530–538.
23. Wynn TA. IL-13 effector functions. Annu Rev Immunol
. 2003; 21: 425–456.
24. Donaldson DD, Whitters MJ, Fitz LJ, et al.. The murine IL-13 receptor alpha 2: molecular cloning, characterization, and comparison with murine IL-13 receptor alpha 1. J Immunol
. 1998; 161: 2317–2324.
25. Hilton DJ, Zhang JG, Metcalf D, et al.. Cloning and characterization of a binding subunit of the interleukin 13 receptor that is also a component of the interleukin 4 receptor. Proc Natl Acad Sci U S A
. 1996; 93: 497–501.
26. Caput D, Laurent P, Kaghad M, et al.. Cloning and characterization of a specific interleukin (IL)-13 binding protein structurally related to the IL-5 receptor alpha chain. J Biol Chem
. 1996; 271: 16921–16926.
27. Aman MJ, Tayebi N, Obiri NI, et al.. cDNA cloning and characterization of the human interleukin 13 receptor alpha chain. J Biol Chem
. 1996; 271: 29265–29270.
28. Wills-Karp M, Finkelman FD. Untangling the complex web of IL-4- and IL-13-mediated signaling pathways. Sci Signal
. 2008; 1 (51): pe55.
29. McKenzie AN, Culpepper JA, de Waal Malefyt R, et al.. Interleukin 13, a T-cell–derived cytokine that regulates human monocyte and B-cell function. Proc Natl Acad Sci U S A
. 1993; 90: 3735–3739.
30. McKenzie GJ, Emson CL, Bell SE, et al.. Impaired development of TH
2 cells in IL-13–deficient mice. Immunity
. 1998; 9: 423–432.
31. Wynn TA. Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat Rev Immunol
. 2004; 4: 583–594.
32. Aliprantis AO, Wang J, Fathman JW, et al.. Transcription factor T-bet regulates skin sclerosis through its function in innate immunity and via IL-13. Proc Natl Acad Sci U S A
. 2007; 104: 2827–2830.
33. Blease K, Jakubzick C, Westwick J, et al.. Therapeutic effect of IL-13 immunoneutralization during chronic experimental fungal asthma. J Immunol
. 2001; 166: 5219–5224.
34. Fichtner-Feigl S, Strober W, Kawakami K, et al.. IL-13 signaling through the IL-13alpha2 receptor is involved in induction of TGF-beta1 production and fibrosis. Nat Med
. 2006; 12: 99–106.
35. Lee CG, Homer RJ, Zhu Z, et al.. Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor beta(1). J Exp Med
. 2001; 194: 809–821.
36. Chiaramonte MG, Donaldson DD, Cheever AW, et al.. An IL-13 inhibitor blocks the development of hepatic fibrosis during a T-helper type 2-dominated inflammatory response. J Clin Invest
. 1999; 104: 777–785.
37. Zhu Z, Homer RJ, Wang Z, et al.. Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J Clin Invest
. 1999; 103: 779–788.
38. Kaviratne M, Hesse M, Leusink M, et al.. IL-13 activates a mechanism of tissue fibrosis that is completely TGF-beta independent. J Immunol
. 2004; 173: 4020–4029.
39. Sun K, Kusminski CM, Scherer PE. Adipose tissue remodeling and obesity. J Clin Invest
. 2011; 121: 2094–2101.
40. Divoux A, Tordjman J, Lacasa D, et al.. Fibrosis in human adipose tissue: composition, distribution, and link with lipid metabolism and fat mass loss. Diabetes
. 2010; 59: 2817–2825.
41. Khan T, Muise ES, Iyengar P, et al.. Metabolic dysregulation and adipose tissue fibrosis: role of collagen VI. Mol Cell Biol
. 2009; 29: 1575–1591.
42. Halberg N, Khan T, Trujillo ME, et al.. Hypoxia-inducible factor 1 alpha induces fibrosis and insulin resistance in white adipose tissue. Mol Cell Biol
. 2009; 29: 4467–4483.
43. Keophiphath M, Achard V, Henegar C, et al.. Macrophage-secreted factors promote a profibrotic phenotype in human preadipocytes. Mol Endocrinol
. 2009; 23: 11–24.
44. Hoffmann KF, Cheever AW, Wynn TA. IL-10 and the dangers of immune polarization: excessive type 1 and type 2 cytokine responses induce distinct forms of lethal immunopathology in murine schistosomiasis. J Immunol
. 2000; 164: 6406–6416.
45. Gurujeyalakshmi G, Giri SN. Molecular mechanisms of antifibrotic effect of interferon gamma in bleomycin-mouse model of lung fibrosis: downregulation of TGF-beta and procollagen I and III gene expression. Exp Lung Res
. 1995; 21: 791–808.
adipose tissue; inflammation; fibrosis; obesity
© 2012 American Federation for Medical Research
Highlight selected keywords in the article text.