Inflammation, metaflammation and immunometabolic disorders


Proper regulation and management of energy, substrate diversity and quantity, as well as macromolecular synthesis and breakdown processes, are fundamental to cellular and organismal survival and are paramount to health. Cellular and multicellular organization are defended by the immune response, a robust and critical system through which self is distinguished from non-self, pathogenic signals are recognized and eliminated, and tissue homeostasis is safeguarded. Many layers of evolutionarily conserved interactions occur between immune response and metabolism. Proper maintenance of this delicate balance is crucial for health and has important implications for many pathological states such as obesity, diabetes, and other chronic non-communicable diseases.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Immunometabolic impact on health.
Figure 2: Evolutionary conservation of immune and metabolic pathway crosstalk.
Figure 3: Convergence of key signalling molecules on both metabolic and inflammatory pathways and functional outcomes.


  1. 1

    Hotamisligil, G. S. Inflammation and metabolic disorders. Nature 444, 860–867 (2006)

    ADS  CAS  PubMed  Google Scholar 

  2. 2

    Pearce, E. L. & Pearce, E. J. Metabolic pathways in immune cell activation and quiescence. Immunity 38, 633–643 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Kotas, M. E. & Medzhitov, R. Homeostasis, inflammation, and disease susceptibility. Cell 160, 816–827 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Agrawal, N. et al. The Drosophila TNF Eiger is an adipokine that acts on insulin-producing cells to mediate nutrient response. Cell Metab. 23, 675–684 (2016).An important study demonstrating the evolutionary conservation of the negative impact of TNF on insulin production, insulin action and glucose metabolism, and a demonstration of how cytokines can serve as metabolic hormones.

    CAS  PubMed  Google Scholar 

  5. 5

    Mabery, E. M. & Schneider, D. S. The Drosophila TNF ortholog Eiger is required in the fat body for a robust immune response. J. Innate Immun. 2, 371–378 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Wang, M. C., Bohmann, D. & Jasper, H. JNK extends life span and limits growth by antagonizing cellular and organism-wide responses to insulin signaling. Cell 121, 115–125 (2005)

    CAS  PubMed  Google Scholar 

  7. 7

    DiAngelo, J. R., Bland, M. L., Bambina, S., Cherry, S. & Birnbaum, M. J. The immune response attenuates growth and nutrient storage in Drosophila by reducing insulin signaling. Proc. Natl Acad. Sci. USA 106, 20853–20858 (2009)

    ADS  CAS  PubMed  Google Scholar 

  8. 8

    Hull-Thompson, J. et al. Control of metabolic homeostasis by stress signaling is mediated by the lipocalin NLaz. PLoS Genet. 5, e1000460 (2009)

    PubMed  PubMed Central  Google Scholar 

  9. 9

    Pasco, M. Y. & Léopold, P. High sugar-induced insulin resistance in Drosophila relies on the lipocalin Neural Lazarillo. PLoS One 7, e36583 (2012)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Morris, S. N. et al. Development of diet-induced insulin resistance in adult Drosophila melanogaster. Biochim. Biophys. Acta 1822, 1230–1237 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Pekala, P., Kawakami, M., Vine, W., Lane, M. D. & Cerami, A. Studies of insulin resistance in adipocytes induced by macrophage mediator. J. Exp. Med. 157, 1360–1365 (1983).This important paper demonstrates that macrophages activated by LPS secrete products that block insulin action in adipocytes.

    CAS  PubMed  Google Scholar 

  12. 12

    Hotamisligil, G. S., Shargill, N. S. & Spiegelman, B. M. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259, 87–91 (1993)

    ADS  CAS  PubMed  Google Scholar 

  13. 13

    Uysal, K. T., Wiesbrock, S. M., Marino, M. W. & Hotamisligil, G. S. Protection from obesity-induced insulin resistance in mice lacking TNF-α function. Nature 389, 610–614 (1997)

    ADS  CAS  PubMed  Google Scholar 

  14. 14

    Xu, H. et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 112, 1821–1830 (2003)

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Weisberg, S. P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 (2003).Published simultaneously, these two important studies (refs 14 and 15 ) demonstrated macrophage infiltration into adipose tissue and relate this to metabolic deterioration.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Hausberger, F. X. Pathological changes in adipose tissue of obese mice. Anat. Rec. 154, 651–660 (1966)

    CAS  PubMed  Google Scholar 

  17. 17

    Hellman, B. Studies in obese-hyperglycemic mice. Ann. NY Acad. Sci. 131, 541–558 (1965)

    ADS  CAS  PubMed  Google Scholar 

  18. 18

    Lumeng, C. N., Bodzin, J. L. & Saltiel, A. R. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J. Clin. Invest. 117, 175–184 (2007)

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Nguyen, M. T. 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. J. Biol. Chem. 282, 35279–35292 (2007)

    CAS  PubMed  Google Scholar 

  20. 20

    Hevener, A. L. et al. Macrophage PPARg is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones. J. Clin. Invest. 117, 1658–1669 (2007)

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Fan, R. et al. Loss of the co-repressor GPS2 sensitizes macrophage activation upon metabolic stress induced by obesity and type 2 diabetes. Nat. Med. 22, 780–791 (2016)

    ADS  CAS  PubMed  Google Scholar 

  22. 22

    Li, P. et al. Hematopoietic-derived Galectin-3 causes cellular and systemic insulin resistance. Cell 167, 973–984.e12 (2016)

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Wen, H. et al. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat. Immunol. 12, 408–415 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Stienstra, R. et al. The inflammasome-mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity. Cell Metab. 12, 593–605 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Herder, C., Dalmas, E., Böni-Schnetzler, M. & Donath, M. Y. The IL-1 pathway in type 2 diabetes and cardiovascular complications. Trends Endocrinol. Metab. 26, 551–563 (2015)

    CAS  PubMed  Google Scholar 

  26. 26

    Larsen, C. M. et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med. 356, 1517–1526 (2007).A critical study demonstrating the benefits of blocking inflammation in humans with type 2 diabetes.

    CAS  PubMed  Google Scholar 

  27. 27

    Song, F. et al. RAGE regulates the metabolic and inflammatory response to high-fat feeding in mice. Diabetes 63, 1948–1965 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Montes, V. N. et al. Anti-HMGB1 antibody reduces weight gain in mice fed a high-fat diet. Nutr. Diabetes 5, e161 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Lu, B. et al. Novel role of PKR in inflammasome activation and HMGB1 release. Nature 488, 670–674 (2012)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    He, Y., Franchi, L. & Núñez, G. The protein kinase PKR is critical for LPS-induced iNOS production but dispensable for inflammasome activation in macrophages. Eur. J. Immunol. 43, 1147–1152 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Boriushkin, E., Wang, J. J., Li, J., Bhatta, M. & Zhang, S. X. p58IPK suppresses NLRP3 inflammasome activation and IL-1β production via inhibition of PKR in macrophages. Sci. Rep. 6, 25013 (2016)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Li, W., Li, J., Sama, A. E. & Wang, H. Carbenoxolone blocks endotoxin-induced protein kinase R (PKR) activation and high mobility group Box 1 (HMGB1) release. Mol. Med. 19, 203–211 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Hett, E. C. et al. Chemical genetics reveals a kinase-independent role for protein kinase R in pyroptosis. Nat. Chem. Biol. 9, 398–405 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Xie, M. et al. PKM2-dependent glycolysis promotes NLRP3 and AIM2 inflammasome activation. Nat. Commun. 7, 13280 (2016).This study demonstrates the importance of PKR in inflammasome activation, and how cellular metabolism influences this activity.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Youssef, O. A. et al. Potential role for snoRNAs in PKR activation during metabolic stress. Proc. Natl Acad. Sci. USA 112, 5023–5028 (2015)

    ADS  CAS  PubMed  Google Scholar 

  36. 36

    Michel, C. I. et al. Small nucleolar RNAs U32a, U33, and U35a are critical mediators of metabolic stress. Cell Metab. 14, 33–44 (2011).A paper demonstrating the critical role of small nucleolar RNAs in mediating the detrimental effects of metabolic stress, particularly in response to lipids.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Fu, S., Watkins, S. M. & Hotamisligil, G. S. The role of endoplasmic reticulum in hepatic lipid homeostasis and stress signaling. Cell Metab. 15, 623–634 (2012)

    CAS  PubMed  Google Scholar 

  38. 38

    Lancaster, G. I. et al. PKR is not obligatory for high-fat diet-induced obesity and its associated metabolic and inflammatory complications. Nat. Commun. 7, 10626 (2016)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Hage Hassan, R. et al. Sustained action of ceramide on the insulin signaling pathway in muscle cells: implication of the double-stranded RNA-activated protein kinase. J. Biol. Chem. 291, 3019–3029 (2016)

    PubMed  Google Scholar 

  40. 40

    Chen, S. S. et al. Activation of double-stranded RNA-dependent protein kinase inhibits proliferation of pancreatic β-cells. Biochem. Biophys. Res. Commun. 443, 814–820 (2014)

    CAS  PubMed  Google Scholar 

  41. 41

    Song, Y. et al. Activated PKR inhibits pancreatic β-cell proliferation through sumoylation-dependent stabilization of P53. Mol. Immunol. 68 (2 Pt A), 341–349 (2015)

    CAS  PubMed  Google Scholar 

  42. 42

    Yang, H. 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. J. Immunol. 185, 1836–1845 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Feuerer, M. et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat. Med. 15, 930–939 (2009)

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Winer, S. et al. Normalization of obesity-associated insulin resistance through immunotherapy. Nat. Med. 15, 921–929 (2009)

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Ilan, Y. et al. Induction of regulatory T cells decreases adipose inflammation and alleviates insulin resistance in ob/ob mice. Proc. Natl Acad. Sci. USA 107, 9765–9770 (2010)

    ADS  CAS  PubMed  Google Scholar 

  46. 46

    Bapat, S. P. et al. Depletion of fat-resident Treg cells prevents age-associated insulin resistance. Nature 528, 137–141 (2015)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Cipolletta, D. et al. PPAR-γ is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature 486, 549–553 (2012).This paper demonstrates that an established anti-diabetic agent produces its anti-inflammatory and anti-diabetic effects through PPARγ n T reg cells.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Winer, D. A. et al. B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat. Med. 17, 610–617 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    DeFuria, J. et al. B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile. Proc. Natl Acad. Sci. USA 110, 5133–5138 (2013)

    ADS  CAS  PubMed  Google Scholar 

  50. 50

    Nishimura, S. et al. Adipose natural regulatory B cells negatively control adipose tissue inflammation. Cell Metab. 18, 759–766 (2013)

    CAS  PubMed  Google Scholar 

  51. 51

    Ji, Y. et al. Activation of natural killer T cells promotes M2 macrophage polarization in adipose tissue and improves systemic glucose tolerance via interleukin-4 (IL-4)/STAT6 protein signaling axis in obesity. J. Biol. Chem. 287, 13561–13571 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Lynch, L. Adipose invariant natural killer T cells. Immunology 142, 337–346 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Kwon, H. et al. Adipocyte-specific IKKβ signaling suppresses adipose tissue inflammation through an IL-13-dependent paracrine feedback pathway. Cell Reports 9, 1574–1583 (2014).This important paper demonstrates the anti-inflammatory activity of the IKK pathway, and shows that IKK activation is not equivalent to inflammation owing to its impact on resolution in the adipose tissue.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Zhang, X. et al. Hypothalamic IKKβ/NF-κB and ER stress link overnutrition to energy imbalance and obesity. Cell 135, 61–73 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Goldfine, A. B. et al. Salicylate (salsalate) in patients with type 2 diabetes: a randomized trial. Ann. Intern. Med. 159, 1–12 (2013)

    PubMed  PubMed Central  Google Scholar 

  56. 56

    Hundal, R. S. et al. Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes. J. Clin. Invest. 109, 1321–1326 (2002)

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Gehart, H., Kumpf, S., Ittner, A. & Ricci, R. MAPK signalling in cellular metabolism: stress or wellness? EMBO Rep. 11, 834–840 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    González-Terán, B. et al. p38γ and p38δ reprogram liver metabolism by modulating neutrophil infiltration. EMBO J. 35, 536–552 (2016)

    PubMed  PubMed Central  Google Scholar 

  59. 59

    Hirosumi, J. et al. A central role for JNK in obesity and insulin resistance. Nature 420, 333–336 (2002)

    ADS  CAS  PubMed  Google Scholar 

  60. 60

    Tuncman, G. et al. Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance. Proc. Natl Acad. Sci. USA 103, 10741–10746 (2006)

    ADS  CAS  PubMed  Google Scholar 

  61. 61

    Sabio, G. et al. A stress signaling pathway in adipose tissue regulates hepatic insulin resistance. Science 322, 1539–1543 (2008).This manuscript shows the pathological role of JNK activity in adipose tissue and demonstrates how this inflammatory input disrupts liver insulin action and glucose metabolism. This paper also addresses the role of JNK1 in macrophages.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Tsaousidou, E. et al. Distinct roles for JNK and IKK activation in Agouti-related peptide neurons in the development of obesity and insulin resistance. Cell Reports 9, 1495–1506 (2014)

    CAS  PubMed  Google Scholar 

  63. 63

    Hotamisligil, G. S. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 140, 900–917 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Zhang, K. & Kaufman, R. J. From endoplasmic-reticulum stress to the inflammatory response. Nature 454, 455–462 (2008)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Keestra-Gounder, A. M. et al. NOD1 and NOD2 signalling links ER stress with inflammation. Nature 532, 394–397 (2016)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Oslowski, C. M. et al. Thioredoxin-interacting protein mediates ER stress-induced β cell death through initiation of the inflammasome. Cell Metab. 16, 265–273 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Bettigole, S. E. & Glimcher, L. H. Endoplasmic reticulum stress in immunity. Annu. Rev. Immunol. 33, 107–138 (2015)

    CAS  PubMed  Google Scholar 

  68. 68

    Yang, L. et al. S-Nitrosylation links obesity-associated inflammation to endoplasmic reticulum dysfunction. Science 349, 500–506 (2015)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Jurczak, M. J. et al. Dissociation of inositol-requiring enzyme (IRE1α)-mediated c-Jun N-terminal kinase activation from hepatic insulin resistance in conditional X-box-binding protein-1 (XBP1) knock-out mice. J. Biol. Chem. 287, 2558–2567 (2012)

    CAS  PubMed  Google Scholar 

  70. 70

    Turner, N. & Heilbronn, L. K. Is mitochondrial dysfunction a cause of insulin resistance? Trends Endocrinol. Metab. 19, 324–330 (2008)

    CAS  PubMed  Google Scholar 

  71. 71

    Morino, K., Petersen, K. F. & Shulman, G. I. Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes 55 (Suppl 2), S9–S15 (2006)

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Freemerman, A. J. et al. Metabolic reprogramming of macrophages: glucose transporter 1 (GLUT1)-mediated glucose metabolism drives a proinflammatory phenotype. J. Biol. Chem. 289, 7884–7896 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Miao, H. et al. Macrophage CGI-58 deficiency activates ROS-inflammasome pathway to promote insulin resistance in mice. Cell Reports 7, 223–235 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Bogacka, I., Xie, H., Bray, G. A. & Smith, S. R. Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo. Diabetes 54, 1392–1399 (2005)

    CAS  PubMed  Google Scholar 

  75. 75

    Kelley, D. E., He, J., Menshikova, E. V. & Ritov, V. B. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 51, 2944–2950 (2002)

    CAS  PubMed  Google Scholar 

  76. 76

    Arruda, A. P. et al. Chronic enrichment of hepatic endoplasmic reticulum-mitochondria contact leads to mitochondrial dysfunction in obesity. Nat. Med. 20, 1427–1435 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Fujita, H. et al. The E3 ligase synoviolin controls body weight and mitochondrial biogenesis through negative regulation of PGC-1β. EMBO J. 34, 1042–1055 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Arruda, A. P. & Hotamisligil, G. S. Calcium homeostasis and organelle function in the pathogenesis of obesity and diabetes. Cell Metab. 22, 381–397 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Randle, P. J., Garland, P. B., Hales, C. N. & Newsholme, E. A. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 281, 785–789 (1963)

    Google Scholar 

  80. 80

    McGarry, J. D. Glucose-fatty acid interactions in health and disease. Am. J. Clin. Nutr. 67 (Suppl), 500S–504S (1998)

    CAS  PubMed  Google Scholar 

  81. 81

    Glass, C. K. & Olefsky, J. M. Inflammation and lipid signaling in the etiology of insulin resistance. Cell Metab. 15, 635–645 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Nguyen, M. T. et al. JNK and tumor necrosis factor-a mediate free fatty acid-induced insulin resistance in 3T3-L1 adipocytes. J. Biol. Chem. 280, 35361–35371 (2005). This paper demonstrates that FFAs induce insulin resistance in cells by activating inflammatory cascades involving JNK and IKK.

    CAS  PubMed  Google Scholar 

  83. 83

    Tynan, G. A. et al. Endogenous oils derived from human adipocytes are potent adjuvants that promote IL-1α-dependent inflammation. Diabetes 63, 2037–2050 (2014)

    CAS  PubMed  Google Scholar 

  84. 84

    Yu, C. et al. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J. Biol. Chem. 277, 50230–50236 (2002)

    CAS  PubMed  Google Scholar 

  85. 85

    Lee, J. Y. et al. Reciprocal modulation of Toll-like receptor-4 signaling pathways involving MyD88 and phosphatidylinositol 3-kinase/AKT by saturated and polyunsaturated fatty acids. J. Biol. Chem. 278, 37041–37051 (2003)

    CAS  PubMed  Google Scholar 

  86. 86

    Huang, S. et al. Saturated fatty acids activate TLR-mediated proinflammatory signaling pathways. J. Lipid Res. 53, 2002–2013 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Davis, J. E., Gabler, N. K., Walker-Daniels, J. & Spurlock, M. E. Tlr-4 deficiency selectively protects against obesity induced by diets high in saturated fat. Obesity (Silver Spring) 16, 1248–1255 (2008)

    CAS  Google Scholar 

  88. 88

    Jin, C., Henao-Mejia, J. & Flavell, R. A. Innate immune receptors: key regulators of metabolic disease progression. Cell Metab. 17, 873–882 (2013)

    CAS  PubMed  Google Scholar 

  89. 89

    Kleinridders, A. et al. MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity. Cell Metab. 10, 249–259 (2009)

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Sampey, B. P. et al. Metabolomic profiling reveals mitochondrial-derived lipid biomarkers that drive obesity-associated inflammation. PLoS One 7, e38812 (2012)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Lim, J. et al. Diet-induced obesity, adipose inflammation, and metabolic dysfunction correlating with PAR2 expression are attenuated by PAR2 antagonism. FASEB J. 27, 4757–4767 (2013)

    ADS  CAS  PubMed  Google Scholar 

  92. 92

    Bikman, B. T. & Summers, S. A. Ceramides as modulators of cellular and whole-body metabolism. J. Clin. Invest. 121, 4222–4230 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Griffin, M. E. et al. Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. Diabetes 48, 1270–1274 (1999)

    CAS  PubMed  Google Scholar 

  94. 94

    Szendroedi, J. et al. Role of diacylglycerol activation of PKCθ in lipid-induced muscle insulin resistance in humans. Proc. Natl Acad. Sci. USA 111, 9597–9602 (2014).This study shows that in human subjects lipid-induced insulin resistance in muscle is associated with DAG–PKC activation.

    ADS  CAS  PubMed  Google Scholar 

  95. 95

    Kim, J. K. et al. PKC-θ knockout mice are protected from fat-induced insulin resistance. J. Clin. Invest. 114, 823–827 (2004)

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Serra, C. et al. Transgenic mice with dominant negative PKC-theta in skeletal muscle: a new model of insulin resistance and obesity. J. Cell. Physiol. 196, 89–97 (2003)

    CAS  PubMed  Google Scholar 

  97. 97

    Kewalramani, G., Fink, L. N., Asadi, F. & Klip, A. Palmitate-activated macrophages confer insulin resistance to muscle cells by a mechanism involving protein kinase C θ and ε. PLoS One 6, e26947 (2011)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Yilmaz, M., Claiborn, K. C. & Hotamisligil, G. S. De novo lipogenesis products and endogenous lipokines. Diabetes 65, 1800–1807 (2016)

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Fox, M. J., Kuzma, J. F. & Washam, W. T. Transitory diabetic syndrome associated with meningococcic meningitis. Arch. Intern. Med. (Chic.) 79, 614–621 (1947)

    CAS  Google Scholar 

  100. 100

    Dimas, A. S. et al. Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity. Diabetes 63, 2158–2171 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    McCarthy, M. I. Genomics, type 2 diabetes, and obesity. N. Engl. J. Med. 363, 2339–2350 (2010)

    CAS  PubMed  Google Scholar 

  102. 102

    Florez, J. C. Newly identified loci highlight beta cell dysfunction as a key cause of type 2 diabetes: where are the insulin resistance genes? Diabetologia 51, 1100–1110 (2008)

    CAS  PubMed  Google Scholar 

  103. 103

    Jain, P. et al. Systems biology approach reveals genome to phenome correlation in type 2 diabetes. PLoS One 8, e53522 (2013)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Manning, A. K. et al. A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance. Nat. Genet. 44, 659–669 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    Kooner, J. S. et al. Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci. Nat. Genet. 43, 984–989 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106

    Cho, Y. S. et al. Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians. Nat. Genet. 44, 67–72 (2011)

    PubMed  PubMed Central  Google Scholar 

  107. 107

    Waeber, G. et al. The gene MAPK8IP1, encoding islet-brain-1, is a candidate for type 2 diabetes. Nat. Genet. 24, 291–295 (2000).This paper identifies a mutation in MAPK81P1 which causes constitutive JNK activation in humans leading to a Mendelian form of diabetes.

    CAS  PubMed  Google Scholar 

  108. 108

    Ichimura, A. et al. Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human. Nature 483, 350–354 (2012).This paper examines the role of GPR120, which was previously demonstrated by the Olefsky laboratory to be a lipid sensor critical for immunometabolism and diabetes, in human genetic studies.

    ADS  CAS  PubMed  Google Scholar 

  109. 109

    Locke, A. E. et al. Genetic studies of body mass index yield new insights for obesity biology. Nature 518, 197–206 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    Shungin, D. et al. New genetic loci link adipose and insulin biology to body fat distribution. Nature 518, 187–196 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111

    Brown, A. E. et al. p38 MAPK activation upregulates proinflammatory pathways in skeletal muscle cells from insulin-resistant type 2 diabetic patients. Am. J. Physiol. Endocrinol. Metab. 308, E63–E70 (2015)

    CAS  PubMed  Google Scholar 

  112. 112

    Toubal, A., Treuter, E., Clément, K. & Venteclef, N. Genomic and epigenomic regulation of adipose tissue inflammation in obesity. Trends Endocrinol. Metab. 24, 625–634 (2013)

    CAS  PubMed  Google Scholar 

  113. 113

    Burska, A. N., Sakthiswary, R. & Sattar, N. Effects of tumour necrosis factor antagonists on insulin sensitivity/resistance in rheumatoid arthritis: a systematic review and meta-analysis. PLoS One 10, e0128889 (2015)

    PubMed  PubMed Central  Google Scholar 

  114. 114

    Solomon, D. H. et al. Association between disease-modifying antirheumatic drugs and diabetes risk in patients with rheumatoid arthritis and psoriasis. J. Am. Med. Assoc. 305, 2525–2531 (2011)

    CAS  Google Scholar 

  115. 115

    Donath, M. Y. Targeting inflammation in the treatment of type 2 diabetes: time to start. Nat. Rev. Drug Discov. 13, 465–476 (2014)

    CAS  PubMed  Google Scholar 

  116. 116

    Schork, N. J. Personalized medicine: time for one-person trials. Nature 520, 609–611 (2015)

    ADS  CAS  PubMed  Google Scholar 

  117. 117

    Cerami, A. TNF and EPO: major players in the innate immune response: their discovery. Ann. Rheum. Dis. 71 (Suppl 2), i55–i59 (2012)

    CAS  PubMed  Google Scholar 

  118. 118

    Collino, M. et al. A non-erythropoietic peptide derivative of erythropoietin decreases susceptibility to diet-induced insulin resistance in mice. Br. J. Pharmacol. 171, 5802–5815 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

    Brines, M. et al. ARA 290, a nonerythropoietic peptide engineered from erythropoietin, improves metabolic control and neuropathic symptoms in patients with type 2 diabetes. Mol. Med. 20, 658–666 (2015)

    PubMed  PubMed Central  Google Scholar 

  120. 120

    Kothari, V., Galdo, J. A. & Mathews, S. T. Hypoglycemic agents and potential anti-inflammatory activity. J. Inflamm. Res. 9, 27–38 (2016)

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Scheen, A. J., Esser, N. & Paquot, N. Antidiabetic agents: potential anti-inflammatory activity beyond glucose control. Diabetes Metab. 41, 183–194 (2015)

    CAS  PubMed  Google Scholar 

  122. 122

    Lancaster, G. I. & Febbraio, M. A. The immunomodulating role of exercise in metabolic disease. Trends Immunol. 35, 262–269 (2014)

    CAS  PubMed  Google Scholar 

  123. 123

    Coward, W. R., Marei, A., Yang, A., Vasa-Nicotera, M. M. & Chow, S. C. Statin-induced proinflammatory response in mitogen-activated peripheral blood mononuclear cells through the activation of caspase-1 and IL-18 secretion in monocytes. J. Immunol. 176, 5284–5292 (2006)

    CAS  PubMed  Google Scholar 

  124. 124

    Henriksbo, B. D. et al. Fluvastatin causes NLRP3 inflammasome-mediated adipose insulin resistance. Diabetes 63, 3742–3747 (2014).This study demonstrates a direct link between a statin and inflammasome activation, showing a mechanism by which statins may act as pro-inflammatory agents.

    CAS  PubMed  Google Scholar 

  125. 125

    Nishimoto, S. et al. Obesity-induced DNA released from adipocytes stimulates chronic adipose tissue inflammation and insulin resistance. Sci. Adv. 2, e1501332 (2016)

    ADS  PubMed  PubMed Central  Google Scholar 

  126. 126

    Lefere, S. et al. Hypoxia-regulated mechanisms in the pathogenesis of obesity and non-alcoholic fatty liver disease. Cell. Mol. Life Sci. 73, 3419–3431 (2016)

    CAS  PubMed  Google Scholar 

  127. 127

    Minamino, T. et al. A crucial role for adipose tissue p53 in the regulation of insulin resistance. Nat. Med. 15, 1082–1087 (2009)

    CAS  PubMed  Google Scholar 

  128. 128

    Thaler, J. P. et al. Obesity is associated with hypothalamic injury in rodents and humans. J. Clin. Invest. 122, 153–162 (2012)

    CAS  PubMed  Google Scholar 

  129. 129

    Wernstedt Asterholm, I. et al. Adipocyte inflammation is essential for healthy adipose tissue expansion and remodeling. Cell Metab. 20, 103–118 (2014)

    CAS  PubMed  Google Scholar 

  130. 130

    Vereecke, L. et al. A20 controls intestinal homeostasis through cell-specific activities. Nat. Commun. 5, 5103 (2014)

    ADS  CAS  PubMed  Google Scholar 

  131. 131

    Yi, Z., Stunz, L. L. & Bishop, G. A. CD40-mediated maintenance of immune homeostasis in the adipose tissue microenvironment. Diabetes 63, 2751–2760 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132

    Li, Y. et al. A functional genomics approach to understand variation in cytokine production in humans. Cell 167, 1099–1110.e14 (2016)

    CAS  PubMed  Google Scholar 

  133. 133

    ter Horst, R. et al. Host and environmental factors influencing individual human cytokine responses. Cell 167, 1111–1124.e13 (2016)

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134

    Schirmer, M. et al. Linking the human gut microbiome to inflammatory cytokine production capacity. Cell 167, 1125–1136.e8 (2016)

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135

    Bogue, M. A., Churchill, G. A. & Chesler, E. J. Collaborative cross and diversity outbred data resources in the Mouse Phenome Database. Mamm. Genome 26, 511–520 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136

    Kebede, M. A. & Attie, A. D. Insights into obesity and diabetes at the intersection of mouse and human genetics. Trends Endocrinol. Metab. 25, 493–501 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    Ouchi, N. et al. Sfrp5 is an anti-inflammatory adipokine that modulates metabolic dysfunction in obesity. Science 329, 454–457 (2010)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  138. 138

    Fuster, J. J. et al. Non-canonical Wnt signaling promotes obesity-induced adipose tissue inflammation and metabolic dysfunction independent of adipose tissue expansion. Diabetes 64, 1235–1248 (2015)

    CAS  PubMed  Google Scholar 

  139. 139

    Suzuki, K., Kumanogoh, A. & Kikutani, H. Semaphorins and their receptors in immune cell interactions. Nat. Immunol. 9, 17–23 (2008)

    CAS  PubMed  Google Scholar 

  140. 140

    Shimizu, I. et al. Semaphorin3E-induced inflammation contributes to insulin resistance in dietary obesity. Cell Metab. 18, 491–504 (2013).This study illustrates a new mechanism that couples adipocytes and immune cells and impairs systemic insulin action and glucose metabolism through TNF-mediated inflammatory signals.

    CAS  PubMed  Google Scholar 

Download references


I am grateful to all members of the Hotamisligil laboratory for helpful discussions, and especially G. Parlakgül for the initial preparation of figures, and K. Claiborn for discussions and invaluable editorial assistance. Work in the Hotamisligil laboratory is supported by grants from the National Institutes of Health (DK052539, HL125753, AI116901), the JDRF (2SRA-2016-147-Q-R), and sponsored research agreements from Union Chemique Belge and Servier.

Author information



Corresponding author

Correspondence to Gökhan S. Hotamisligil.

Ethics declarations

Competing interests

The author declares no competing financial interests.

Additional information

Reviewer Information Nature thanks M. Febbraio and R. Kahn for their contribution to the peer review of this work.

Supplementary information

Supplementary Information

This file contains a Supplementary Table and Supplementary Figure 1. (PDF 1339 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Hotamisligil, G. Inflammation, metaflammation and immunometabolic disorders. Nature 542, 177–185 (2017).

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing