The adaptive immune system as a fundamental regulator of adipose tissue inflammation and insulin resistance

Over the past decade, chronic inflammation in visceral adipose tissue (VAT) has gained acceptance as a lead promoter of insulin resistance in obesity. A great deal of evidence has pointed to the role of adipokines and innate immune cells, in particular, adipose tissue macrophages, in the regulation of fat inflammation and glucose homeostasis. However, more recently, cells of the adaptive immune system, specifically B and T lymphocytes, have emerged as unexpected promoters and controllers of insulin resistance. These adaptive immune cells infiltrate obesity expanded VAT and through cytokine secretion and macrophage modulation dictate the extent of the local inflammatory response, thereby directly impacting insulin resistance. The remarkable ability of our adaptive immune system to regulate insulin sensitivity and metabolism has unmasked a novel physiological function of this system, and promises new diagnostic and therapeutic strategies to manage the disease. This review highlights critical roles of adipose tissue lymphocytes in governing glucose homeostasis.

[1]  B. Lee,et al.  Deficiency for Costimulatory Receptor 4-1BB Protects Against Obesity-Induced Inflammation and Metabolic Disorders , 2011, Diabetes.

[2]  J. Stockman,et al.  Metabolic Syndrome and Altered Gut Microbiota in Mice Lacking Toll-Like Receptor 5 , 2012 .

[3]  Chih-Hao Lee,et al.  Adipocyte-derived Th2 cytokines and myeloid PPARdelta regulate macrophage polarization and insulin sensitivity. , 2008, Cell metabolism.

[4]  H. Spits,et al.  The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling , 2011, Nature Immunology.

[5]  E. Engleman,et al.  Obesity predisposes to Th17 bias , 2009, European journal of immunology.

[6]  Allan Vaag,et al.  Interleukin-1-receptor antagonist in type 2 diabetes mellitus. , 2007, The New England journal of medicine.

[7]  J. Pauli,et al.  Interleukin-10 is a protective factor against diet-induced insulin resistance in liver. , 2008, Journal of Hepatology.

[8]  C. Hupfeld,et al.  FTY720, a sphingosine‐1‐phosphate receptor modulator, reverses high‐fat diet–induced weight gain, insulin resistance and adipose tissue inflammation in C57BL/6 mice , 2008, Diabetes, obesity & metabolism.

[9]  P. Shah,et al.  Associations between autoantibodies against apolipoprotein B-100 peptides and vascular complications in patients with type 2 diabetes , 2009, Diabetologia.

[10]  C. Glass,et al.  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* , 2007, Journal of Biological Chemistry.

[11]  J. Olefsky,et al.  Targeting GPR120 and other fatty acid-sensing GPCRs ameliorates insulin resistance and inflammatory diseases. , 2011, Trends in pharmacological sciences.

[12]  S. Schinner,et al.  Adipocyte Death, Adipose Tissue Remodeling, and Obesity Complications , 2009 .

[13]  G. Núñez,et al.  The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis , 2009, Nature Immunology.

[14]  E. Ravussin,et al.  The NALP3/NLRP3 Inflammasome Instigates Obesity-Induced Autoinflammation and Insulin Resistance , 2010, Nature Medicine.

[15]  M. Desai,et al.  Obesity is associated with macrophage accumulation in adipose tissue. , 2003, The Journal of clinical investigation.

[16]  T. Young,et al.  Post-Streptococcal Auto-Antibodies Inhibit Protein Disulfide Isomerase and Are Associated with Insulin Resistance , 2010, PloS one.

[17]  E. Butcher,et al.  IL-17 Regulates Adipogenesis, Glucose Homeostasis, and Obesity , 2010, The Journal of Immunology.

[18]  A. Galinier,et al.  Adipose tissues as an ancestral immune organ: Site‐specific change in obesity , 2005, FEBS letters.

[19]  M. Fujimoto,et al.  A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses. , 2008, Immunity.

[20]  Vimal K. Narula,et al.  Visceral Adipose Inflammation in Obesity Is Associated with Critical Alterations in Tregulatory Cell Numbers , 2011, PloS one.

[21]  Christophe Benoist,et al.  Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters , 2009, Nature Medicine.

[22]  S. Hori Regulatory T cell plasticity: beyond the controversies. , 2011, Trends in immunology.

[23]  K. Clément,et al.  Deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice , 2009, Nature Medicine.

[24]  S. Weisberg,et al.  Obesity in C57BL/6J mice is characterized by adipose tissue hypoxia and cytotoxic T-cell infiltration , 2008, International Journal of Obesity.

[25]  ChristianWeber,et al.  CD40L Deficiency Ameliorates Adipose Tissue Inflammation and Metabolic Manifestations of Obesity in Mice , 2011 .

[26]  C. Nathan,et al.  Identification of interferon-gamma as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity , 1983, The Journal of experimental medicine.

[27]  M. Lafontan,et al.  Unexpected trafficking of immune cells within the adipose tissue during the onset of obesity. , 2009, Biochemical and biophysical research communications.

[28]  Y. Kamei,et al.  Activating Transcription Factor 3 Constitutes a Negative Feedback Mechanism That Attenuates Saturated Fatty Acid/Toll-Like Receptor 4 Signaling and Macrophage Activation in Obese Adipose Tissue , 2009, Circulation research.

[29]  T. Willson,et al.  Interleukin-4-dependent production of PPAR-gamma ligands in macrophages by 12/15-lipoxygenase. , 1999, Nature.

[30]  F. Atzeni,et al.  Clinical and laboratory aspects of Ro/SSA-52 autoantibodies. , 2011, Autoimmunity reviews.

[31]  Michael N. Alonso,et al.  B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies , 2011, Nature Medicine.

[32]  A. Bhan,et al.  A Case for Regulatory B Cells1 , 2006, The Journal of Immunology.

[33]  M. White,et al.  SOCS-1 and SOCS-3 Block Insulin Signaling by Ubiquitin-mediated Degradation of IRS1 and IRS2* , 2002, The Journal of Biological Chemistry.

[34]  F. Greenway,et al.  Obesity Increases the Production of Proinflammatory Mediators from Adipose Tissue T Cells and Compromises TCR Repertoire Diversity: Implications for Systemic Inflammation and Insulin Resistance , 2010, The Journal of Immunology.

[35]  M. Matsuda,et al.  Adipose Tissue Hypoxia in Obesity and Its Impact on Adipocytokine Dysregulation , 2007, Diabetes.

[36]  P. Allavena,et al.  Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. , 2002, Trends in immunology.

[37]  A. Saltiel,et al.  Obesity induces a phenotypic switch in adipose tissue macrophage polarization. , 2007, The Journal of clinical investigation.

[38]  Frank Brombacher,et al.  Macrophage-specific PPARγ controls alternative activation and improves insulin resistance , 2007, Nature.

[39]  A. Chervonsky,et al.  Deletion of Fas in adipocytes relieves adipose tissue inflammation and hepatic manifestations of obesity in mice. , 2010, The Journal of clinical investigation.

[40]  Denis Gris,et al.  Fatty acid–induced NLRP3-ASC inflammasome activation interferes with insulin signaling , 2011, Nature Immunology.

[41]  Ludwig Kappos,et al.  A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. , 2010, The New England journal of medicine.

[42]  茂呂 和世 Innate production of T[H]2 cytokines by adipose tissue-associated c-Kit[+]Sca-1[+] lymphoid cells , 2010 .

[43]  M. Ruth Normalization of obesity-associated insulin resistance through immunotherapy , 2010 .

[44]  R. Locksley,et al.  Eosinophils Sustain Adipose Alternatively Activated Macrophages Associated with Glucose Homeostasis , 2011, Science.

[45]  Egil Lien,et al.  NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals , 2010, Nature.

[46]  E. Van Obberghen,et al.  SOCS-3 Inhibits Insulin Signaling and Is Up-regulated in Response to Tumor Necrosis Factor-α in the Adipose Tissue of Obese Mice* , 2001, The Journal of Biological Chemistry.

[47]  A. Lindén,et al.  Interleukin-17 family members and inflammation. , 2004, Immunity.

[48]  M. Reilly,et al.  Interferon γ Attenuates Insulin Signaling, Lipid Storage, and Differentiation in Human Adipocytes via Activation of the JAK/STAT Pathway* , 2009, Journal of Biological Chemistry.

[49]  I. Verma,et al.  Hematopoietic cell-specific deletion of toll-like receptor 4 ameliorates hepatic and adipose tissue insulin resistance in high-fat-fed mice. , 2009, Cell metabolism.

[50]  Y. Wan,et al.  An essential role of the transcription factor GATA-3 for the function of regulatory T cells. , 2011, Immunity.

[51]  W. Scherbaum,et al.  Immunohistochemical and ultrastructural localization of leptin and leptin receptor in human white adipose tissue and differentiating human adipose cells in primary culture. , 2000, Diabetes.

[52]  Ludwig Kappos,et al.  Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. , 2010, The New England journal of medicine.

[53]  J. Zieleński,et al.  Normalization of Obesity-Associated Insulin Resistance through Immunotherapy: CD4+ T Cells Control Glucose Homeostasis , 2009, Nature Medicine.

[54]  S. Msika,et al.  The inflammatory receptor CD40 is expressed on human adipocytes: contribution to crosstalk between lymphocytes and adipocytes , 2009, Diabetologia.

[55]  J. Huber,et al.  Inflammation Correlates With Markers of T‐Cell Subsets Including Regulatory T Cells in Adipose Tissue From Obese Patients , 2011, Obesity.

[56]  Tom Britton,et al.  Dynamics of fat cell turnover in humans , 2008, Nature.

[57]  K. Haas,et al.  B-1a and B-1b cells exhibit distinct developmental requirements and have unique functional roles in innate and adaptive immunity to S. pneumoniae. , 2005, Immunity.

[58]  Alberto Mantovani,et al.  Macrophage activation and polarization. , 2008, Frontiers in bioscience : a journal and virtual library.

[59]  R. Ley,et al.  Metabolic Syndrome and Altered Gut Microbiota in Mice Lacking Toll-Like Receptor 5 , 2010, Science.

[60]  S. Rhee,et al.  Saturated Fatty Acids, but Not Unsaturated Fatty Acids, Induce the Expression of Cyclooxygenase-2 Mediated through Toll-like Receptor 4* , 2001, The Journal of Biological Chemistry.

[61]  R. Locksley,et al.  IL-4/STAT6 immune axis regulates peripheral nutrient metabolism and insulin sensitivity , 2010, Proceedings of the National Academy of Sciences.

[62]  K. Strissel,et al.  T‐Cell Recruitment and Th1 Polarization in Adipose Tissue During Diet‐Induced Obesity in C57BL/6 Mice , 2010, Obesity.

[63]  T. Kadowaki,et al.  CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity , 2009, Nature Medicine.

[64]  Masayuki Orimo,et al.  A crucial role for adipose tissue p53 in the regulation of insulin resistance , 2009, Nature Medicine.

[65]  E. S. St. Clair,et al.  Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells. , 2011, Blood.

[66]  D. Rubin,et al.  Toll-like receptors regulate B cell cytokine production in patients with diabetes , 2010, Diabetologia.

[67]  R. Kunze,et al.  Sera from Patients with Type 2 Diabetes Contain Agonistic Autoantibodies Against G Protein‐Coupled Receptors , 2009, Scandinavian journal of immunology.

[68]  D. Becker,et al.  Autoimmune islet destruction in spontaneous type 1 diabetes is not β-cell exclusive , 2003, Nature Medicine.

[69]  S. Pillai,et al.  Peripheral B cell subsets. , 2008, Current opinion in immunology.

[70]  X. Yang,et al.  Mice Lacking NKT Cells but with a Complete Complement of CD8+ T-Cells Are Not Protected against the Metabolic Abnormalities of Diet-Induced Obesity , 2011, PloS one.

[71]  C. Glass,et al.  Macrophages, inflammation, and insulin resistance. , 2010, Annual review of physiology.

[72]  G. Semenza,et al.  Control of TH17/Treg Balance by Hypoxia-Inducible Factor 1 , 2011, Cell.

[73]  J. Stephens,et al.  Interferon-γ-induced Regulation of Peroxisome Proliferator-activated Receptor γ and STATs in Adipocytes* , 2001, The Journal of Biological Chemistry.

[74]  Shupei Wang,et al.  Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans Published, JLR Papers in Press, September 8, 2005. DOI 10.1194/jlr.M500294-JLR200 , 2005, Journal of Lipid Research.

[75]  J. Flier,et al.  TLR4 links innate immunity and fatty acid-induced insulin resistance. , 2006, The Journal of clinical investigation.

[76]  G. Hotamisligil,et al.  Endoplasmic Reticulum Stress and the Inflammatory Basis of Metabolic Disease , 2010, Cell.

[77]  Hyunjin Shin,et al.  State of the union between metabolism and the immune system in type 2 diabetes , 2011, Genes and Immunity.

[78]  J. Sowers,et al.  Bariatric Surgery Reduces Visceral Adipose Inflammation and Improves Endothelial Function in Type 2 Diabetic Mice , 2011, Arteriosclerosis, thrombosis, and vascular biology.

[79]  Leif E. Peterson,et al.  T-Cell Accumulation and Regulated on Activation, Normal T Cell Expressed and Secreted Upregulation in Adipose Tissue in Obesity , 2007, Circulation.

[80]  C. Roberts,et al.  Depot-specific differences in inflammatory mediators and a role for NK cells and IFN-γ in inflammation in human adipose tissue , 2009, International Journal of Obesity.

[81]  P. Libby,et al.  Interferon- (cid:1) , a Th1 Cytokine, Regulates Fat Inflammation A Role for Adaptive Immunity in Obesity , 2022 .

[82]  K. Jablonski,et al.  The Effects of Salsalate on Glycemic Control in Patients With Type 2 Diabetes , 2010, Annals of Internal Medicine.

[83]  T. Willson,et al.  Interleukin-4-dependent production of PPAR-γ ligands in macrophages by 12/15-lipoxygenase , 1999, Nature.

[84]  H. Tsutsui,et al.  Natural Killer T Cells Are Involved in Adipose Tissues Inflammation and Glucose Intolerance in Diet-Induced Obese Mice , 2010, Arteriosclerosis, thrombosis, and vascular biology.

[85]  C. Apovian,et al.  Elevated Proinflammatory Cytokine Production by a Skewed T Cell Compartment Requires Monocytes and Promotes Inflammation in Type 2 Diabetes , 2011, The Journal of Immunology.

[86]  A. Attie,et al.  Hypoxia-Inducible Factor 1α Induces Fibrosis and Insulin Resistance in White Adipose Tissue , 2009, Molecular and Cellular Biology.

[87]  J. Tschopp,et al.  Thioredoxin-interacting protein links oxidative stress to inflammasome activation , 2010, Nature Immunology.

[88]  Yaron Ilan,et al.  Induction of regulatory T cells decreases adipose inflammation and alleviates insulin resistance in ob/ob mice , 2010, Proceedings of the National Academy of Sciences.

[89]  J. Dudenhausen,et al.  Childhood obesity, other cardiovascular risk factors, and premature death. , 2010, The New England journal of medicine.

[90]  S. Rodriguez-Segade,et al.  Autoantibodies to glial fibrillary acid protein and S100β in diabetic patients , 2010, Diabetic medicine : a journal of the British Diabetic Association.

[91]  HiroyukiTsutsui,et al.  Natural Killer T Cells Are Involved in Adipose Tissues Inflammation and Glucose Intolerance in Diet-Induced Obese Mice , 2010 .

[92]  L. Tartaglia,et al.  Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. , 2003, The Journal of clinical investigation.

[93]  L. Joosten,et al.  Inflammasome is a central player in the induction of obesity and insulin resistance , 2011, Proceedings of the National Academy of Sciences.

[94]  P. Schauer,et al.  Adipocyte Apoptosis, a Link between Obesity, Insulin Resistance, and Hepatic Steatosis* , 2009, The Journal of Biological Chemistry.