J Clin Invest 115(5): 1111-1119

Inflammation, stress, and diabetes

Department of Genetics & Complex Diseases, Harvard School of Public Health, Boston, Massachusetts, USA.

Address correspondence to: Gökhan S. Hotamisligil, Department of Genetics and Complex Diseases, Harvard School of Public Health, 665 Huntington Avenue, Boston, Massachusetts 02115, USA. Phone: (617) 432-1950; Fax: (617) 432-1941; E-mail: ude.dravrah.hpsh@simatohg.

Abstract

Over the last decade, an abundance of evidence has emerged demonstrating a close link between metabolism and immunity. It is now clear that obesity is associated with a state of chronic low-level inflammation. In this article, we discuss the molecular and cellular underpinnings of obesity-induced inflammation and the signaling pathways at the intersection of metabolism and inflammation that contribute to diabetes. We also consider mechanisms through which the inflammatory response may be initiated and discuss the reasons for the inflammatory response in obesity. We put forth for consideration some hypotheses regarding important unanswered questions in the field and suggest a model for the integration of inflammatory and metabolic pathways in metabolic disease.

Abstract

Click here to view.^{(52K, pdf)}

Acknowledgments

We are grateful to the members of the Hotamisligil laboratory for their contributions. Research in the Hotamisligil laboratory has been supported by the NIH, the American Diabetes Association, and the Pew and Sandler Foundations. We regret the omission of many important references by our colleagues in the field due to space limitations.

Note: References S1–S60 are available online with this article; doi:10.1172/JCI200525102DS1.

Acknowledgments

Footnotes

Nonstandard abbreviations used: AP-1, activator protein–1; DAG, diacylglycerol; FABP, fatty acid–binding protein; IκB, inhibitor of NF-κB; IKK, inhibitor of NF-κB kinase; IRS, insulin receptor substrate; JIP1, JNK-interacting protein–1; LXR, liver X receptor; TLR, Toll-like receptor; TZD, thiazolidinedione.

Conflict of interest: The authors have declared that no conflict of interest exists.

Footnotes

References

1. Khovidhunkit W, et al Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host [review] J. Lipid Res.2004;45:1169–1196.[PubMed]
2. Chandra RKNutrition, immunity and infection: from basic knowledge of dietary manipulation of immune responses to practical application of ameliorating suffering and improving survival. Proc. Natl. Acad. Sci. U. S. A.1996;93:14304–14307.
3. Blackburn GLPasteur’s Quadrant and malnutrition. Nature.2001;409:397–401.[PubMed]
4. Cummings DE, Schwartz MWGenetics and pathophysiology of human obesity. Annu. Rev. Med.2003;54:453–471.[PubMed]
5. Hotamisligil, G.S. 2004. Inflammation, TNFalpha, and insulin resistance. In Diabetes mellitus: a fundamental and clinical text. D.T.S. LeRoith and J.M. Olefsky, editors. 3rd edition. Lippincott, Williams and Wilkins. New York, New York, USA. 953–962.
6. Hotamisligil GS, Shargill NS, Spiegelman BMAdipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science.1993;259:87–91.[PubMed]
7. Sethi JK, Hotamisligil GSThe role of TNF alpha in adipocyte metabolism. Semin. Cell Dev. Biol.1999;10:19–29.[PubMed]
8. Hotamisligil GS, et al Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J. Clin. Invest.1995;95:2409–2415.
9. Kern PA, et al. The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. J. Clin. Invest.1995;95:2111–2119.
10. Saghizadeh M, et al. The expression of TNF alpha by human muscle. Relationship to insulin resistance. J. Clin. Invest.1996;97:1111–1116.
11. Uysal KT, et al Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature.1997;389:610–614.[PubMed]
12. Pickup JCInflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care.2004;27:813–823.[PubMed]
13. Dandona P, Aljada A, Bandyopadhyay AInflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol.2004;25:4–7.[PubMed]
14. Miller C, et al Tumor necrosis factor-alpha levels in adipose tissue of lean and obese cats. J. Nutr.1998;128(Suppl. 12):2751S–2752S.[PubMed]
15. Soukas A, et al Leptin-specific patterns of gene expression in white adipose tissue. Genes Dev.2000;14:963–980.
16. Weisberg SP, et al Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest.2003;112:1796–1808. doi:10.1172/JCI200319246.
17. Xu H, et al Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest.2003;112:1821–1830. doi:10.1172/JCI200319451.
18. Fernandes G, et al. Immune response in the mutant diabetic C57BL/Ks-dt+ mouse. Discrepancies between in vitro and in vivo immunological assays. J. Clin. Invest.1978;61:243–250.
19. Farooqi IS, et al Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J. Clin. Invest.2002;110:1093–1103. doi:10.1172/JCI200215693.
20. Chandra RKCell-mediated immunity in genetically obese C57BL/6J ob/ob) mice. Am. J. Clin. Nutr.1980;33:13–16.[PubMed]
21. Lord GM, et al Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature.1998;394:897–901.[PubMed]
22. Berg AH, Combs TP, Scherer PEACRP30/adiponectin: an adipokine regulating glucose and lipid metabolism. Trends Endocrinol. Metab.2002;13:84–89.[PubMed]
23. Ouchi N, et al Obesity, adiponectin and vascular inflammatory disease. Curr. Opin. Lipidol.2003;14:561–566.[PubMed]
24. Steppan CM, Lazar MAThe current biology of resistin. J. Intern. Med.2004;255:439–447.[PubMed]
25. Lehrke M, et al An inflammatory cascade leading to hyperresistinemia in humans. PLoS Med.2004;1:e45. doi:10.1371/journal.pmed.0010045.
26. Fukuhara A, et al Visfatin: a protein secreted by visceral fat that mimics the effects of insulin. Science.2005;307:426–430.[PubMed]
27. Makowski L, et al Lack of macrophage fatty-acid-binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis. Nat. Med.2001;7:699–705.
28. Tontonoz P, et al PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell.1998;93:241–252.[PubMed]
29. Bouloumie A, et al Adipocyte produces matrix metalloproteinases 2 and 9: involvement in adipose differentiation. Diabetes.2001;50:2080–2086.[PubMed]
30. Cousin B, et al A role for preadipocytes as macrophage-like cells. FASEB J.1999;13:305–312.[PubMed]
31. Charriere G, et al. Preadipocyte conversion to macrophage. Evidence of plasticity. J. Biol. Chem.2003;278:9850–9855.[PubMed]
32. White MFThe insulin signalling system and the IRS proteins. Diabetologia.1997;40(Suppl. 2):S2–S17.[PubMed]
33. Saltiel AR, Pessin JEInsulin signaling pathways in time and space. Trends Cell Biol.2002;12:65–71.[PubMed]
34. Yin MJ, Yamamoto Y, Gaynor RBThe anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature.1998;396:77–80.[PubMed]
35. Hotamisligil GS, 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.[PubMed]
36. Aguirre V, et al The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307) J. Biol. Chem.2000;275:9047–9054.[PubMed]
37. Aguirre V, et al Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action. J. Biol. Chem.2002;277:1531–1537.[PubMed]
38. Paz K, et al. A molecular basis for insulin resistance. Elevated serine/threonine phosphorylation of IRS-1 and IRS-2 inhibits their binding to the juxtamembrane region of the insulin receptor and impairs their ability to undergo insulin-induced tyrosine phosphorylation. J. Biol. Chem.1997;272:29911–29918.[PubMed]
39. Ozcan U, et al Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science.2004;306:457–461.[PubMed]
40. Nakatani Y, et al Involvement of endoplasmic reticulum stress in insulin resistance and diabetes. J. Biol. Chem.2005;280:847–851.[PubMed]
41. Ozawa K, et al The endoplasmic reticulum chaperone improves insulin resistance in type 2 diabetes. Diabetes.2005;54:657–663.[PubMed]
42. Lin Y, et al The hyperglycemia-induced inflammatory response in adipocytes: the role of reactive oxygen species. J. Biol. Chem.2005;280:4617–4626.[PubMed]
43. Furukawa S, et al Increased oxidative stress in obesity and its impact on metabolic syndrome. J. Clin. Invest.2004;114:1752–1761. doi:10.1172/JCI200421625.
44. Zick YRole of Ser/Thr kinases in the uncoupling of insulin signaling. Int. J. Obes. Relat. Metab. Disord.2003;27(Suppl. 3):S56–S60.[PubMed]
45. Medzhitov RToll-like receptors and innate immunity. Nat. Rev. Immunol.2001;1:135–145.[PubMed]
46. Davis RJSignal transduction by the JNK group of MAP kinases. Cell.2000;103:239–252.[PubMed]
47. Hirosumi J, et al A central role for JNK in obesity and insulin resistance. Nature.2002;420:333–336.[PubMed]
48. Gao Z, et al Inhibition of insulin sensitivity by free fatty acids requires activation of multiple serine kinases in 3T3-L1 adipocytes. Mol. Endocrinol.2004;18:2024–2034.[PubMed]
49. Nakatani Y, et al Modulation of the JNK pathway in liver affects insulin resistance status. J. Biol. Chem.2004;279:45803–45809.[PubMed]
50. Waeber G, et al The gene MAPK8IP1, encoding islet-brain-1, is a candidate for type 2 diabetes. Nat. Genet.2000;24:291–295.[PubMed]
51. Jaeschke A, Czech MP, Davis RJAn essential role of the JIP1 scaffold protein for JNK activation in adipose tissue. Genes Dev.2004;18:1976–1980.
52. Ricci R, et al Requirement of JNK2 for scavenger receptor A-mediated foam cell formation in atherogenesis. Science.2004;306:1558–1561.[PubMed]
53. Kaneto H, et al Possible novel therapy for diabetes with cell-permeable JNK-inhibitory peptide. Nat. Med.2004;10:1128–1132.[PubMed]
54. 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.2002;277:50230–50236.[PubMed]
55. Perseghin G, Petersen K, Shulman GICellular mechanism of insulin resistance: potential links with inflammation. Int. J. Obes. Relat. Metab. Disord.2003;27(Suppl. 3):S6–S11.[PubMed]
56. Schmitz-Peiffer CProtein kinase C and lipid-induced insulin resistance in skeletal muscle. Ann. N. Y. Acad. Sci.2002;967:146–157.[PubMed]
57. Gao Z, et al Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex. J. Biol. Chem.2002;277:48115–48121.[PubMed]
58. Shoelson SE, Lee J, Yuan MInflammation and the IKK beta/I kappa B/NF-kappa B axis in obesity- and diet-induced insulin resistance. Int. J. Obes. Relat. Metab. Disord.2003;27(Suppl. 3):S49–S52.[PubMed]
59. Yuan M, et al Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science.2001;293:1673–1677.[PubMed]
60. Kim JK, et al Prevention of fat-induced insulin resistance by salicylate. J. Clin. Invest.2001;108:437–446. doi:10.1172/JCI200111559.
61. Hundal RS, et al Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes. J. Clin. Invest.2002;109:1321–1326. doi:10.1172/JCI200214955.
62. Cai D, et al Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat. Med.2005;11:183–190.
63. Arkan MC, et al IKK-beta links inflammation to obesity-induced insulin resistance. Nat. Med.2005;11:191–198.[PubMed]
64. Rohl M, et al Conditional disruption of IkappaB kinase 2 fails to prevent obesity-induced insulin resistance. J. Clin. Invest.2004;113:474–481. doi:10.1172/JCI200418712.
65. Rui L, et al SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. J. Biol. Chem.2002;277:42394–42398.[PubMed]
66. Mooney RA, et al. Suppressors of cytokine signaling-1 and -6 associate with and inhibit the insulin receptor. A potential mechanism for cytokine-mediated insulin resistance. J. Biol. Chem.2001;276:25889–25893.[PubMed]
67. Emanuelli B, et al SOCS-3 inhibits insulin signaling and is up-regulated in response to tumor necrosis factor-alpha in the adipose tissue of obese mice. J. Biol. Chem.2001;276:47944–47949.[PubMed]
68. Ueki K, Kondo T, Kahn CRSuppressor 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.
69. Mori H, et al Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. Nat. Med.2004;10:739–743.[PubMed]
70. Howard JK, et al Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3. Nat. Med.2004;10:734–738.[PubMed]
71. Shimabukuro M, et al Role of nitric oxide in obesity-induced beta cell disease. J. Clin. Invest.1997;100:290–295.
72. Perreault M, Marette ATargeted disruption of inducible nitric oxide synthase protects against obesity-linked insulin resistance in muscle. Nat. Med.2001;7:1138–1143.[PubMed]
73. Seo JB, et al Activated liver X receptors stimulate adipocyte differentiation through induction of peroxisome proliferator-activated receptor gamma expression. Mol. Cell. Biol.2004;24:3430–3444.
74. Moller DE, Berger JPRole of PPARs in the regulation of obesity-related insulin sensitivity and inflammation. Int. J. Obes. Relat. Metab. Disord.2003;27(Suppl. 3):S17–S21.[PubMed]
75. Joseph SB, et al Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. Nat. Med.2003;9:213–219.[PubMed]
76. Jiang C, Ting AT, Seed BPPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature.1998;391:82–86.[PubMed]
77. Chawla A, et al PPAR-gamma dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation. Nat. Med.2001;7:48–52.[PubMed]
78. Chawla A, et al A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol. Cell.2001;7:161–171.[PubMed]
79. Daynes RA, Jones DCEmerging roles of PPARs in inflammation and immunity. Nat. Rev. Immunol.2002;2:748–759.[PubMed]
80. Castrillo A, et al Crosstalk between LXR and toll-like receptor signaling mediates bacterial and viral antagonism of cholesterol metabolism. Mol. Cell.2003;12:805–816.[PubMed]
81. Bjorkbacka H, et al Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways. Nat. Med.2004;10:416–421.[PubMed]
82. Joseph SB, et al LXR-dependent gene expression is important for macrophage survival and the innate immune response. Cell.2004;119:299–309.[PubMed]
83. Lee CH, et al Transcriptional repression of atherogenic inflammation: modulation by PPARdelta. Science.2003;302:453–457.[PubMed]
84. Maeda K, et al Adipocyte/macrophage fatty acid binding proteins control integrated metabolic responses in obesity and diabetes. Cell Metabolism.2005;1:107–119.[PubMed]
85. Spiegelman BMPPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes.1998;47:507–514.[PubMed]
86. Makowski L, Hotamisligil GSFatty acid binding proteins — the evolutionary crossroads of inflammatory and metabolic responses. J. Nutr.2004;134:2464S–2468S.
87. Lee CH, Olson P, Evans RMMinireview: lipid metabolism, metabolic diseases, and peroxisome proliferator-activated receptors. Endocrinology.2003;144:2201–2207.[PubMed]
88. Laffitte BA, et al Activation of liver X receptor improves glucose tolerance through coordinate regulation of glucose metabolism in liver and adipose tissue. Proc. Natl. Acad. Sci. U. S. A.2003;100:5419–5424.
89. Wellen KE, et al Interaction of tumor necrosis factor-alpha- and thiazolidinedione-regulated pathways in obesity. Endocrinology.2004;145:2214–2220.[PubMed]
90. Peraldi P, Xu M, Spiegelman BMThiazolidinediones block tumor necrosis factor-alpha-induced inhibition of insulin signaling. J. Clin. Invest.1997;100:1863–1869.
91. Ruan H, Pownall HJ, Lodish HFTroglitazone antagonizes tumor necrosis factor-alpha-induced reprogramming of adipocyte gene expression by inhibiting the transcriptional regulatory functions of NF-kappaB. J. Biol. Chem.2003;278:28181–28192.[PubMed]
92. Miles PD, et al TNF-alpha-induced insulin resistance in vivo and its prevention by troglitazone. Diabetes.1997;46:1678–1683.[PubMed]
93. Lehmann JM, et al An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma) J. Biol. Chem.1995;270:12953–12956.[PubMed]
94. Staels B, et al Activation of human aortic smooth-muscle cells is inhibited by PPARalpha but not by PPARgamma activators. Nature.1998;393:790–793.[PubMed]
95. Knobler H, et al Tumor necrosis factor-alpha-induced insulin resistance may mediate the hepatitis C virus-diabetes association. Am. J. Gastroenterol.2003;98:2751–2756.[PubMed]
96. Bahtiyar G, et al Association of diabetes and hepatitis C infection: epidemiologic evidence and pathophysiologic insights. Curr. Diab. Rep.2004;4:194–198.[PubMed]
97. Iribarren C, Tolstykh IV, Eisner MDAre patients with asthma at increased risk of coronary heart disease? Int. J. Epidemiol.2004;33:743–748.[PubMed]
98. Rana JS, et al Chronic obstructive pulmonary disease, asthma, and risk of type 2 diabetes in women. Diabetes Care.2004;27:2478–2484.[PubMed]
99. Sattar N, et al Explaining how “high-grade” systemic inflammation accelerates vascular risk in rheumatoid arthritis. Circulation.2003;108:2957–2963.[PubMed]
100. Hung JH, et al Endoplasmic reticulum stress stimulates the expression of cyclooxygenase-2 through activation of NF-kappaB and pp38 mitogen-activated protein kinase. J. Biol. Chem.2004;279:46384–46392.[PubMed]
101. Brownlee MBiochemistry and molecular cell biology of diabetic complications. Nature.2001;414:813–820.[PubMed]
102. Hatada EN, Krappmann D, Scheidereit CNF-kappaB and the innate immune response. Curr. Opin. Immunol.2000;12:52–58.[PubMed]
103. Bluher M, et al Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance. Dev. Cell.2002;3:25–38.[PubMed]
104. Xu H, et al Exclusive action of transmembrane TNF alpha in adipose tissue leads to reduced adipose mass and local but not systemic insulin resistance. Endocrinology.2002;143:1502–1511.[PubMed]
105. Lowell BB, Shulman GIMitochondrial dysfunction and type 2 diabetes. Science.2005;307:384–387.[PubMed]
106. Vozarova B, et al The interleukin-6 (-174) G/C promoter polymorphism is associated with type-2 diabetes mellitus in Native Americans and Caucasians. Hum. Genet.2003;112:409–413.[PubMed]
107. Dalziel B, et al Association of the TNF-alpha -308 G/A promoter polymorphism with insulin resistance in obesity. Obes. Res.2002;10:401–407.[PubMed]
108. Costa A, et al Lower rate of tumor necrosis factor-alpha -863A allele and higher concentration of tumor necrosis factor-alpha receptor 2 in first-degree relatives of subjects with type 2 diabetes. Metabolism.2003;52:1068–1071.[PubMed]
109. Furuta M, et al Relationship of the tumor necrosis factor-alpha -308 A/G promoter polymorphism with insulin sensitivity and abdominal fat distribution in Japanese patients with type 2 diabetes mellitus. Diabetes Res. Clin. Pract.2002;56:141–145.[PubMed]
110. Florez JC, Hirschhorn J, Altshuler DThe inherited basis of diabetes mellitus: implications for the genetic analysis of complex traits. Annu. Rev. Genomics Hum. Genet.2003;4:257–291.[PubMed]