Metaflammation, NLRP3 Inflammasome Obesity and Metabolic Disease

Anna Meiliana, Andi Wijaya


BACKGROUND: Increasing prevalence of obesity gives rise to many problems associated with multiple morbidities, such as diabetes, hypertension, heart disease, sleep apnea and cancer. The mechanism of obesity is very complex, thus its link to various disease is poorly understood. This review highlights important concepts in our understanding of the pathogenesis of obesity and related complications.

CONTENT: Many studies have tried to explore the exciting and puzzling links between metabolic homeostasis and inflammatory responses. A form of subclinical, low-grade systemic inflammation is known to be associated with both obesity and chronic disease. This, later called as "metaflammation", refers to metabolically triggered inflammation. The nutrient-sensing pathway and the immune response coordination are facilitated by these molecular sites in order to maintain homeostasis under diverse metabolic and immune conditions. Recent studies have found that the NLRP3 inflammasome during metabolic stress forms a tie linking TXNIP, oxidative stress, and IL-1β production. This provides new opportunities for research and therapy for the disease often described as the next global pandemic: type 2 diabetes mellitus (T2DM).

SUMMARY: The crucial role of metaflammation in many complications of obesity shown by the unexpected overlap between inflammatory and metabolic sensors and their downstream tissue responses. Then great interest arose to explore the pathways that integrate nutrient and pathogen sensing, give more understanding in the mechanisms of insulin resistance type 2 diabetes, and other chronic metabolic pathologies. A family of intracellular sensors called NLR family is a critical component of the innate immune system. They can form multiprotein complexes, called inflammasome which is capable of responding to a wide range of stimuli including both microbial and self molecules by activating the cysteine protease caspase-1, leading to processing and secretion of the proinflammatory cytokines IL-1β and IL-18, which play crucial roles in host defense. Inflammasome dysregulation has been linked to some autoinflammatory and metabolic diseases. These provide opportunities to continue to improve our understanding of the nature of metaflammation in the hope of modifying it to prevent and treat diseasese.

KEYWORDS: Inflammation, metaflammation, inflammasome, metabolic disease, obesity

Full Text:



World Health Organization [homepage on the Internet]. Geneva: WHO; 2011. Obesity and overweight [updated Mar 2011, cited 2011 Apr 1]. Available from:

Finucane MM, Stevens GA, Cowan MJ, Danaei G, Lin JK, Paciorek CJ, et al. Global burden of metabolic risk factors of chronic diseases collaborating group (body mass index). National, regional, and global trends in bodymass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9.1 million participants. Lancet. 2011; 377: 557-67, CrossRef.

de Onis M, Blössner M, Borghi E. Global prevalence and trends of overweight and obesity among preschool children. Am J Clin Nutr. 2010; 92: 1257-64, CrossRef.

Wing RR. Changing diet and exercise behaviors in individuals at risk for weight gain. Obes Res. 1995; 3: S277-82, CrossRef.

Sacks FM, Bray GA, Carey VJ, Smith SR, Ryan DH, Anton SD, et al. Comparison of weight-loss diets with different compositions of fat, protein, and carbohydrates. N Engl J Med. 2009; 360: 859-73, CrossRef.

Malik VS, Popkin BM, Bray GA, Després JP, Hu FB. Sugarsweetened beverages, obesity, type 2 diabetes mellitus, and cardiovascular disease risk. Circulation. 2010; 121: 1356-64, CrossRef.

Gross LS, Li L, Ford ES, Liu S. Increased consumption of refined carbohydrates and the epidemic of type 2 diabetes in the United States: an ecologic assessment. Am J Clin Nutr. 2004; 79: 774-9, PMID.

Bray GA. Soft drink consumption and obesity: it is all about fructose. Curr Opin Lipidol. 2010; 21: 51-7, CrossRef.

Kestens Y, Daniel M. Social inequalities in food exposure around schools in an urban area. Am J Prev Med. 2010; 39: 33-40, CrossRef.

Berrington de Gonzalez A, Hartge P, Cerhan JR, Flint AJ, Hannan L, et al. Body-mass index and mortality among 1.46 million white adults. N Engl J Med. 2010; 363: 2211-9, CrossRef.

Flegal KM, Graubard BI, Williamson DF, Gail MH. Cause specific excess deaths associated with underweight, overweight, and obesity. JAMA. 2007; 298: 2028-37, CrossRef.

Zheng W, McLerran DF, Rolland B, Zhang X, Inoue M, Matsuo K, et al. Association between body-mass index and risk of death in more than 1 million Asians. N Engl J Med. 2011; 364: 719-29, CrossRef.

Hevener AL, Febbraio MA, Stock Conference Working Group. The 2009 Stock Conference Report: Inflammation, obesity and metabolic disease. Obes Rev. 2010, 11: 635-44, CrossRef.

Spencer M, Yao-Borengasser A, Unal R, Rasouli N, Gurley CM, Zhu B, et al. Adipose tissue macrophages in insulinresistant subjects are associated with collagen VI and fibrosis and demonstrate alternative activation. Am J Physiol Metab. 2010; 299: E1016-27, CrossRef.

Lumeng CN, Saltiel AR. Inflammatory links between obesity and metabolic disease. J Clin Invest. 2011; 11: 2111-7, CrossRef.

Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006; 444: 860-7, CrossRef.

Schroder K, Tschopp J. The Inflammasomes. Cell. 2010; 140: 821-32, CrossRef.

Horng T, Hotamisligil GS. Linking the inflammasome to obesity-related disease. Nat Med. 2011; 17: 164-5, CrossRef.

Mori MA, Bezy O, Kahn CR. Metabolic syndrome: Is Nlrp3 inflammasome a trigger or a target of insulin resistance? Circ Res. 2011; 108: 1160-2, CrossRef.

Weiss R. Fat distribution and storage: how much, where, and How? Eur J Endocrinol. 2007; 157: S39-45, CrossRef.

Frayn KN. Adipose tissue as a buffer for daily lipid flux. Diabetologia. 2002; 45: 1201-10, CrossRef.

Wajchenberg BL. Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev. 2000; 21: 697-708, CrossRef.

Arner P. Introduction: the inflammation orchestra in adipose tissue. J Int Med. 2007; 262: 404-7, CrossRef.

Yang X, Smith U. Adipose tissue distribution and risk of metabolic disease: does thiazolidinedione-induced adipose tissue redistribution provide a clue to the answer? Diabetologia. 2007; 50: 1127-39, CrossRef.

Rocha VZ, Libby P. The multiple facets of the fat tissue. Thyroid. 2008; 18: 175-83, CrossRef.

Berg AH, Scherer PE. Adipose tissue, inflammation and cardiovascular disease. Circ Res. 2005; 96: 939-49, CrossRef.

Bergman RN, Kim SP, Catalano KJ, Hsu IR, Chiu JD, Kabir M, et al. Why visceral fat is bad: mechanisms of the metabolic syndrome. Obesity. 2006; 14 (Suppl 2): 16S-9S, CrossRef.

Hamdy O, Porramatikul S, Al-Ozairi E. Metabolic obesity: the paradox between visceral and subcutaneous fat. Curr Diab Rev. 2006; 2: 367-73, CrossRef.

Wiklund P, Toss F, Weinehall L, Hallmans G, Franks PW, Nordstrom A, et al. Abdominal and gynoid fat mass are associated with cardiovascular risk factors in men and women. J Clin Endocrinol Metab 2008; 93: 4360-6, CrossRef.

Karelis AD, St-Pierre DH, Conus F, Rabasa-Lhoret R, Poehlman ET. Metabolic and body composition factors in sub-groups of obesity: what do we know? J Clin Endocrinol Metab 2004; 89: 2569-75, CrossRef.

Cancello R, Tordjman J, Poitou C, Guilhem G, Bouillot JL, Hugol D, et al. Increased infiltration of macrophages in omental adipose tissue is associated with marked hepatic lesions in morbid human obesity. Diabetes. 2006; 55: 1554-61, CrossRef.

Goodarzi MT, Varmaziar L, Navidi AA, Parivar K. Study of oxidative stress in type 2 diabetic patients and its relationship with glycated hemoglobin. Saudi Med. J 2008; 29: 503-6, PMID.

Saltevo J, Laakso M, Jokelainen J, Keinanen-Kiukaanni S, Kumpusalo E, Vanhala M. Levels of adiponectin, C-reactive protein and interleukin-1 receptor antagonist are associated with insulin sensitivity: a population-based study. Diabetes Metab Res Rev. 2008; 24: 378-83, CrossRef.

Libby P. Inflammatory mechanisms: the molecular basis of inflammation and disease. Nutr Rev 2007; 65: S140-S146, CrossRef.

Hotamisligil GS, Shargill NS, Piegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 1993; 259: 87-91, CrossRef.

Egger G, Dixon J. Should obesity be the main game? Or do we need an environmental makeover to combat the inflammatory and chronic disease epidemics? Obes Rev. 2009; 10: 237-49, CrossRef.

Nathan C. Epidemic inflammation: pondering obesity. Mol Med. 2008; 14: 485-92, PMID.

Sun K, Scherer PE. Adipose tissue dysfunction: A multistep process. In: Christen Y, editor. Research and Perspectives in Endocrine Interactions. Berlin: Springer-Verlag Berlin Heidelberg; 2010. p.67-75. CrossRef.

Sun K, Kusminski CM, Scherer PE. Adipose tissue remodeling and obesity. J Clin Invest. 2011; 121: 2094-101, CrossRef.

Gordon S. The macrophage. Bioessays. 1995;17: 977-86, CrossRef.

Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E, et al. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res. 2005; 46: 2347-55, CrossRef.

Nishimura S, Manabe I, Nagasaki M, Hosoya Y, Yamashita H, Fujita H, et al. Adipogenesis in obesity requires close interplay between differentiating adipocytes, stromal cells, and blood vessels. Diabetes. 2007; 56: 1517-26, CrossRef.

Nishimura S, Manabe I, Nagasaki M, Seo K, Yamashita H, Hosoya Y, et al. In vivo imaging in mice reveals local cell dynamics and inflammation in obese adipose tissue. J Clin Invest. 2008;118: 710-21, CrossRef.

Strissel KJ, Stancheva Z, Miyoshi H, Perfield JW, DeFuria J, Jick Z, et al. Adipocyte death, adipose tissue remodeling, and obesity complications. Diabetes. 2007; 56: 2910-8, CrossRef.

Lumeng CN, Deyoung SM, Bodzin JL, Saltiel AR. Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity. Diabetes. 2007; 56: 16-23, CrossRef.

Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest. 2006; 116: 1494-505, CrossRef.

Weisberg SP, Hunter D, Huber R, Lemieux J, Slaymaker S, Vaddi K, et al. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest. 2006; 116: 115-24, CrossRef.

Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003; 112: 1821-30, CrossRef.

Nara N, Nakayama Y, Okamoto S, Tamura H, Kiyono M, Muraoka M, et al. Disruption of CXC motif chemokine ligand-14 in mice ameliorates obesity-induced insulin resistance. J Biol Chem. 2007; 282: 30794-803, CrossRef.

Trayhurn P, Wood IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr. 2004; 92: 347-55, CrossRef.

Halberg N, Khan T, Trujillo ME, Wernstedt-Asterholm I, Attie AD, Sherwani S, et al. Hypoxia-inducible factor 1 alpha induces fibrosis and insulin resistance in white adipose tissue. Mol Cell Biol. 2009; 29: 4467-83, CrossRef.

Hosogai N, Fukuhara A, Oshima K, Miyata Y, Tanaka S, Segawa K, et al. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes. 2007;56: 901-11, CrossRef.

Ye J, Gao Z, Yin J, He Q. Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am J Physiol Endocrinol Metab. 2007; 293: E1118-28, CrossRef.

Chen B, Lam KS, Wang Y, Wu D, Lam MC, Shen J, et al. Hypoxia dysregulates the production of adiponectin and plasminogen activator inhibitor-1 independent of reactive oxygen species in adipocytes. Biochem Biophys Res Commun. 2006; 341: 549-56, CrossRef.

Lolmede K, Durand de Saint Front V, Galitzky J, Lafontan M, Bouloumie A. Effects of hypoxia on the expression of proangiogenic factors in differentiated 3T3-F442A adipocytes. Int J Obes Relat Metab Disord. 2003; 27: 1187-95, CrossRef.

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: 3015-25, CrossRef.

Suganami T, Nishida J, Ogawa Y. A paracrine loop between adipocytes and macrophages aggravates inflammatory changes: role of free fatty acids and tumor necrosis factor alpha. Arterioscler Thromb Vasc Biol. 2005; 25: 2062-68, CrossRef.

Nguyen MT, Satoh H, Favelyukis S, Babendure JL, Imamura T, Sbodio JI, et al. JNK and tumor necrosis factor-alpha mediate free fatty acid-induced insulin resistance in 3T3-L1 adipocytes. J Biol Chem. 2005; 280: 35361-71, CrossRef.

Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest. 2007;117: 175-84, CrossRef.

Kosteli A, Sugaru E, Haemmerle G, Martin JF, Lei J, Zechner R, et al. Weight loss and lipolysis promote a dynamic immune response in murine adipose tissue. J Clin Invest. 2010; 120: 3466-79, CrossRef.

Shoelson SE. Banking on ATM as a new target in metabolic syndrome. Cell Metab. 2006; 4: 337-8, CrossRef.

Conde J, Gomez R, Scotece M, Bianco G, Lago F, Gualillo O. Adipocytes and macrophages: two engines powering inflammation in obesity and its complications. Obes Metabolism. 2010; 6: 5-9, article.

Suganami T, Ogawa Y. Adipose tissue macrophages: their role in adipose tissue remodeling. J Leukoc Biol 2010; 88: 33-9, CrossRef.

Mantovani A, Allavena P, Sica A, Balkwill F. Cancer related inflammation. Nature 2008; 454: 436-44, CrossRef.

Medzhitov R. Origin and physiological roles of inflammation. Nature. 2008; 454: 428-35, CrossRef.

Egger G, Dixon J. Obesity and chronic disease: always offender or often just accomplice? Br J Nutr. 2009; 102: 1238-42, CrossRef.

Hajer GR, van Haeften TW, Visseren FLJ Adipose tissue dysfunction in obesity, diabetes, and vascular diseases. Eur Heart J. 2008; 9, 2959-71, CrossRef.

O’Keefe JH, Bybee KA, Lavie CJ Alcohol and cardiovascular health: the razor-sharp double-edged sword. J Am Coll Cardiol. 2007; 50: 1009-14, CrossRef.

Solinas G, Vilcu C, Neels JG, Bandyopadhyay GK, Luo JL, Naugler W, et al. JNK1 in hematopoietically derived cells contributes to diet-induced inflammation and insulin resistance without affecting obesity. Cell Metab. 2007; 6: 386-97, CrossRef.

Esmaillzadeh A, Kimiagar M, Mehrabi Y, Azadbakht L, Hu FB, Willett WC. Dietary patterns and markers of systemic inflammation among Iranian women. J Nutr. 2007; 137: 992-8, PMID.

Haversen L, Danielsson KN, Fogelstrand L, Wiklund O. Induction of proinflammatory cytokines by long-chain saturated fatty acids in human macrophages. Atherosclerosis. 2009; 202: 382-93, CrossRef.

Harvey KA, Arnold T, Rasool T, Antalis C, Miller SJ, Siddiqui RA. Trans-fatty acids induce pro-inflammatory responses and endothelial cell dysfunction. Br J Nutr. 2008; 99: 723-31, CrossRef.

Rayssiguier Y, Gueux E, Nowacki W, Rock E, Mazur A. High fructose consumption combined with low dietary magnesium intake may increase the incidence of the metabolic syndrome by inducing inflammation. Magnes Res. 2006; 19: 237-43, PMID.

Dickinson S, Hancock DP, Petocz P, Ceriello A, Brand-Miller J. High-glycemic index carbohydrate increases nuclear factorkappaB activation in mononuclear cells of young, lean healthy subjects. Am J Clin Nutr. 2008; 87: 1188-93, PMID.

Simpson N, Dinges DF. Sleep and inflammation. Nutr Rev 2007; 65: S244-52, CrossRef.

Thorley AJ, Tetley TD. Pulmonary epithelium, cigarette smoke, and chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2007; 2: 409-28, PMID.

Kulmatycki KM, Jamali F. Drug disease interactions: role of inflammatory mediators in depression and variability in antidepressant drug response. J Pharm Pharm Sci. 2006; 9: 292-306, PMID.

Hickling S, Hung J, Knuiman M, Divitini M, Beilby J. Are the associations between diet and C-reactive protein independent of obesity? Prev Med. 2008; 47: 71-6, CrossRef.

Watt MJ. Storing up trouble: does accumulation of intramyocellular triglyceride protect skeletal muscle from insulin resistance? Clin Exp Pharmacol Physiol. 2009; 36: 5-11, CrossRef.

Hamburg NM, McMackin CJ, Huang AL, Shenouda SM, Widlansky ME, Schulz E, et al. Physical inactivity rapidly induces insulin resistance and microvascular dysfunction in healthy volunteers. Arterioscler Thromb Vasc Biol. 2007; 27: 2650-6, CrossRef.

Neubauer O, Koenig D. Wagner KH. Recovery after an Ironman triathlon: sustained inflammatory responses and muscular stress. Eur J Appl Physiol 2008; 104: 417-26, CrossRef.

Fabbrini E, Magkos F, Mohammed BS, Pietka T, Abumrad NA, Patterson BW, et al. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc Natl Acad Sci U S A. 2009;106: 15430-5, CrossRef.

Li Z, Soloski MJ, Diehl AM. Dietary factors alter hepatic innate immune system in mice with non-alcoholic fatty liver disease. Hepatology. 2005; 42: 880-5, CrossRef.

Kremer M, Hines IN, Mil ton RJ, Wheeler MD. Favored T helper 1 response in a mouse model of hepatosteatosis is associated with enhanced T cell- mediated hepatitis. Hepatology. 2006; 44: 216-27, CrossRef.

Baffy G. Kupffer cells in non-alcoholic fatty liver disease: the emerging view. J Hepatol. 2009; 51: 212-23, CrossRef.

Odegaard JI, Ricardo-Gonzalez RR, Red Eagle A, Vats D, Morel CR, Goforth MH, et al. Alternative M2 activation of Kupffer cells by PPARdelta ameliorates obesity-induced insulin resistance. Cell Metab. 2008; 7: 496-507, CrossRef.

Kang K, Reilly SM, Karabacak V, Gangl MR, Fitzgerald K, Hatano B, et al. Adipocyte-derived Th2 cytokines and myeloid PPARdelta regulate macrophage polarization and insulin sensitivity. Cell Metab. 2008;7: 485-95, CrossRef.

Obstfeld AE, Sugaru E, Thearle M, Francisco AM, Gayet C, Ginsberg HN, et al. C-C chemokine receptor 2 (CCR2) regulates the hepatic recruitment of myeloid cells that promote obesity-induced hepatic steatosis. Diabetes. 2010;59: 916-25, CrossRef.

Ehses JA, Boni-Schnetzler M, Faulenbach M, Donath MY. Macrophages, cytokines and beta-cell death in Type 2 diabetes. Biochem Soc Trans. 2008; 36: 340-2, CrossRef.

Donath MY, Boni-Schnetzler M, Ellingsgaard H, Halban PA, Ehses JA. Cytokine production by islets in health and diabetes: cellular origin, regulation and function. Trends Endocrinol Metab. 2010; 21: 261-7, CrossRef.

Maedler K, Sergeev P, Ris F, Oberholzer J, Joller-Jemelka HI, Spinas GA, et al. Glucose-induced beta cell production of IL-1 beta contributes to glucotoxicity in human pancreatic islets. J Clin Invest. 2002; 110: 851-60, CrossRef.

Mathis K, Shoelson SE. Immunometabolism: an emerging frontier. Nat Rev Immunol. 2011; 11: 81-3, CrossRef.

Demas GE, Chefer V, Talan MI, Nelson RJ. Metabolic costs of mounting an antigen-stimulated immune response in adult and aged C57BL/56J mice. Am J Physiol. 1997; 273: R1631-7, PMID.

Marti A, Marcos A, Martinez JA. Obesity and immune function relationships. Obes Rev. 2001; 2: 131-40, CrossRef.

Hotamisligil GS, Erbay E. Nutrient sensing and inflammation in metabolic diseases. Nat Rev Immunol. 2008; 8: 923-34, CrossRef.

Ozcan, U, Ozcan L, Yilmaz E, Düvel K, Sahin M, Manning BD, et al. Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosis. Mol Cell. 2008; 29: 541-51, CrossRef.

Egger G, Dixon J. Inflammatory effects of nutritrional stimuli: further support for the need for a big picture approach to tackling obesity and chronic disease. Obes Rev. 2010; 11: 137-49, CrossRef.

Matzinger, P. Tolerance, danger, and the extended family. Annu Rev Immunol. 1994; 12: 991-1045, CrossRef.

Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. 2010; 140: 805-20, CrossRef.

Martinon F, Tschopp J. Inflammatory caspases and inflammasomes: master switches of inflammation. Cell Death Differ. 2007; 14: 10-22, CrossRef.

Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell. 2002; 10: 417-26, CrossRef.

Zhou R, Tardivel A, Thorens B, Choi I, Tschopp J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat Immunol. 2010; 11: 136-40, CrossRef.

Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006; 440: 237-41, CrossRef.

Catania C, Binder E, Cota D. mTORC1 signaling in energy balance and metabolic disease. Int J Obes 2011; 35: 751-61, CrossRef.

Rachdi L, Balcazar N, Osorio-Duque F, Elghazi L, Weiss A, Gould A, et al. Disruption of Tsc2 in pancreatic beta cells induces beta cell mass expansion and improved glucose tolerance in a TORC1-dependent manner. Proc Natl Acad Sci USA. 2008; 105: 9250-55, CrossRef.

Fu A, Ng AC, Depatie C, Wijesekara N, He Y, Wang GS, et al. Loss of Lkb1 in adult beta cells increases beta cell mass and enhances glucose tolerance in mice. Cell Metab. 2009; 10: 285-95, CrossRef.

Hamada S, Hara K, Hamada T, Yasuda H, Moriyama H, Nakayama R, et al. Upregulation of the mammalian target of rapamycin complex 1 pathway by Ras homolog enriched in brain in pancreatic beta-cells leads to increased beta-cell mass and prevention of hyperglycemia. Diabetes. 2009; 58: 1321-32, CrossRef.

Schroder K, Zhou R, Tschopp J. The NLRP3 inflammasome: A sensor for metabolic danger? Science 2010; 327: 296-9, CrossRef.

Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med. 2011;17:179-88, CrossRef.

Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2011; 469: 221-5, CrossRef.

Masters SL, Dunne A, Subramanian SL, Hull RL, Tannahill GM, Sharp FA,et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1beta in type 2 diabetes. Nat Immunol. 2010; 11: 897-904, CrossRef.

Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010 ;464: 1357-61, CrossRef.

Wassel CL, Lange LA, Keating BJ, Taylor KC, Johnson AD, Palmer C, et al. Association of genomic loci from a cardiovascular gene SNP array with fibrinogen levels in European Americans and African-Americans from six cohort studies: the Candidate Gene Association Resource (CARe). Blood. 2011; 117: 268-75, CrossRef.

Dehghan A, Dupuis J, Barbalic M, Bis JC, Eiriksdottir G, Lu C, et al. Meta-analysis of genome-wide association studies in 80,000 subjects identifies multiple Loci for C-reactive protein levels. Cirulation. 2011; 123: 731-8, CrossRef.

Denoble AE, Huffman KM, Stabler TV, Kelly SJ, Hershfield MS, McDaniel GE, et al. Uric acid is a danger signal of increasing risk for osteoarthritis through inflammasome activation. Proc Natl Acad Sci USA. 2011; 108: 2088-93, CrossRef.

Vilaysane A, Chun J, Seamone ME, Wang W, Chin R, Hirota S, et al. The NLRP3 inflammasome promotes renal inflammation and contributes to CKD. J Am Soc Nephrol. 2010; 21: 1732-44, CrossRef.

Satirapoj B. Review on pathophysiology and treatment of diabetic kidney disease. J Med Assoc Thai. 2010; 93 (Suppl 6): S228-41, PMID.

Boden G. Free fatty acids, insulin resistance, and type 2 diabetes mellitus. Proc Assoc Am Phys. 1999; 111: 241-8, CrossRef.

Newgard CB, An J, Bain JR, Muehlbauer MJ, Stevens RD, Lien LF, et al. A branched-chain amino acid- related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab. 2009; 9: 311-26, CrossRef.

Lowell BB, Shulman GI. Mitochondrial dysfunction and type 2 diabetes. Science. 2005; 307: 384-7, CrossRef.

Houstis N, Rosen ED, Lander ES. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature. 2006; 440: 944-8, CrossRef.

Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 2004; 306: 457- 61, CrossRef.

Ouchi N, Kihara S, Funahashi T, Matsuzawa Y, Walsh, K. Obesity, adiponectin and vascular inflammatory disease. Curr Opin Lipidol. 2003; 14: 561-6, CrossRef.

Berg AH, Scherer PE. Adipose tissue, inflammation, and cardiovascular disease. Circ Res. 2005; 96: 939-49, CrossRef.

Samaras K, Botelh NK, Chisholm DJ, Lord RV. Subcutaneous and visceral adipose tissue gene expression of serum adipokines that predict type 2 diabetes. Obesity. 2010; 18: 884-9, CrossRef.

Fried SK, Bunkin DA, Greenberg AS. Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid. J Clin Endocrinol Metab. 1998; 83: 847-50, CrossRef.

Chatterjee TK, Stoll LL, Denning GM, Harrelson A, Blomkalns AL, Idelman G, et al. Proinflammatory phenotype of perivascular adipocytes: influence of high-fat feeding. Circ Res. 2009; 104: 541-9, CrossRef.

Takaoka M, Nagata D, Kihara S, Shimomura I, Kimura Y, Tabata Y, et al. Periadventitial adipose tissue plays a critical role in vascular remodeling. Circ Res. 2009; 105: 906-11, CrossRef.

Ouchi N, Parker JL, Lugus JJ, Walsh K. Adipokines in inflammation and metabolic disease. Nat Rev Immunol. 2011; 11: 85-97, CrossRef.

Ouchi N, Higuchi A, Ohashi K, Oshima Y, Gokce N, Shibata R, et al. Sfrp5 is an anti-inflammatory adipokine that modulates metabolic dysfunction in obesity. Science. 2010; 329: 454-7, CrossRef.

Hummasti S, Hotamisligil GS. Endoplasmic reticulum stress and inflammation in obesity and diabetes. Circ Res. 2010; 107: 579-91, CrossRef.

Hotamisligil GS. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell. 2010; 140: 900-17, CrossRef.

Yang L, Li P, Fu S, Calay ES., Hotamisligil, GS. Defective hepatic autophagy in obesity causes insulin resistance. Cell Metab. 2010; 6: 467-78, CrossRef.

Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell. 2008; 132: 27-42, CrossRef.

Zitvogel L, Kepp O, Kroemer G. Decoding cell death signals in inflammation and immunity. Cell. 2010; 140: 798-804, CrossRef.

Lewis JR, Mohanty SR. Nonalcoholic fatty liver disease: a review and update. Dig Dis Sci. 2010; 55: 560-78, CrossRef.

Lazo M, Clark JM. The epidemiology of nonalcoholic fatty liver disease: a global perspective. Semin Liver Dis. 2008; 28: 339-50, CrossRef.

Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology. 2003; 37: 1202-19, CrossRef.

Ferre P, Foufelle F. Hepatic steatosis: a role for the novo lipogenesis and the transcription factor SREBP-1C. Diabet Obes Metabolism. 2010; 12 (Suppl 2): 83-92, CrossRef.

Mollica MP, Lionetti L, Putti R, Cavaliere G, Gaita M, Barletta A. From chronic overfeeding to hepatic injury: Role of endoplasmic reticulum stress and inflammation. Nut Metabolism Cardiovasc Dis 2011; 21: 222-30, CrossRef.

Robertson RP, Harmon J, Tran PO, Poitout V. β-cell glucose toxicity, lipotoxicity, and chronic oxidative stress in type 2 diabetes. Diabetes. 2004; 53: S119-24, CrossRef.

Weir GC, Bonner-Weir, S. Five stages of evolving β-cell dysfunction during progression to diabetes. Diabetes. 2004; 53: S16-21, CrossRef.

Prentki M, Nolan CJ. Islet β cell failure in type 2 diabetes. J Clin Invest. 2006; 116: 1802-12, CrossRef.

Hull RL, Westermark GT, Westermark P, Kahn SE. Islet amyloid: a critical entity in the pathogenesis of type 2 diabetes. J Clin Endocrinol Metab. 2004; 89: 3629-43, CrossRef.

Harding HP, Ron D. Endoplasmic reticulum stress and the development of diabetes: a review. Diabetes 2002; 51: S455-61, CrossRef.

Donath MY, Storling J, Maedler, K. & Mandrup-Poulsen, T. Inflammatory mediators and islet β-cell failure: a link between type 1 and type 2 diabetes. J Mol Med. 2003; 81: 455-70, CrossRef.

Ehses JA, Ellingsgaard H, Boni-Schnetzler M, Donath MY. Pancreatic islet inflammation in type 2 diabetes: from α and β cell compensation to dysfunction. Arch Physiol Biochem. 2009; 115: 240-7, CrossRef.

Donath MY, Schumann DM, Faulenbach M, Ellingsgaard H, Perren A, Ehses JA. Islet inflammation in type 2 diabetes: from metabolic stress to therapy. Diabetes Care. 2008; 31: S161-4, CrossRef.

Masters SL, Dunne A, Subramanian SL, Hull RL, Tannahill GM, Sharp FA, et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes. Nature Immunol. 2010; 11: 897-904, CrossRef.

Pickup JC, Mattock MB, Chusney GD, Burt D. NIDDM as a disease of the innate immune system: association of acutephase reactants and interleukin-6 with metabolic syndrome X. Diabetologia. 1997; 40: 1286-92, CrossRef.

Spranger J, Kroke A, Mölig M, Hoffmann K, Bergmann MM, Ristow 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: 812-7, CrossRef.

Herder C, Illig T, Rathmann W, Martin S, Haastert B, Müller-Scholze S, et al. Inflammation and type 2 diabetes: results from KORA Augsburg. Gesundheitswesen 2005; 67: S115-21, CrossRef.

Herder C, Brunner EJ, Rathmann W, Strassburger K, Tabák AG, Schloot NC, et al. Elevated levels of the anti-inflammatory interleukin-1 receptor antagonist precede the onset of type 2 diabetes: the Whitehall II study. Diabetes Care. 2009; 32: 421-3, CrossRef.

Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA. 2001; 286: 327-34, CrossRef.

Carstensen, M., Herder C, Kivimäki M, Jokela M, Roden M, Shipley MJ, et al. Accelerated increase in serum interleukin-1 receptor antagonist starts 6 years before diagnosis of type 2 diabetes: Whitehall II prospective cohort study. Diabetes. 2010; 59: 1222-7, CrossRef.

Marculescu R, Endler G, Schillinger M, Iordanova N, Exner M, Hayden E, et al. Interleukin-1 receptor antagonist genotype is associated with coronary atherosclerosis in patients with type 2 diabetes. Diabetes. 2002; 51: 3582-5, CrossRef.

Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol. 2011; 11: 98-107, CrossRef.

Ehses JA, Meier DT, Wueest S, Rytka J, Boller S, Wielinga PY, et al. Toll-like receptor 2-deficient mice are protected from insulin resistance and β cell dysfunction induced by a highfat diet. Diabetologia. 2010; 53: 1795-806, CrossRef.

Haversen L, Danielsson KN, Fogelstrand L, Wiklund O. Induction of proinflammatory cytokines by long-chain saturated fatty acids in human macrophages. Atherosclerosis. 2009; 202: 382-93, CrossRef.

Lee JY, Sohn KH, Rhee SH, Hwang D. Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4. J Biol Chem. 2001; 276: 16683-9, CrossRef.

Lee JY, Zhao L, Youn HS, Weatherill AR, Tapping R, Feng L, et al. Saturated fatty acid activates but polyunsaturated fatty acid inhibits Toll-like receptor 2 dimerized with Toll-like receptor 6 or 1. J Biol. Chem. 2004; 279: 16971-9, CrossRef.

van de Veerdonk FL, Smeekens SP, Joosten LA, Kullberg BJ, Dinarello CA, van der Meer JW, et al. Reactive oxygen species-independent activation of the IL-1β inflammasome in cells from patients with chronic granulomatous disease. Proc Natl Acad Sci USA. 2010; 107: 3030-3, CrossRef.

Meissner F, Seger RA, Moshous D, Fischer A, Reichenbach J, Zychlinsky A. Inflammasome activation in NADPH oxidase defective mononuclear phagocytes from patients with chronic granulomatous disease. Blood. 2010; 116: 1570-3, CrossRef.

Dinarello CA. The role of the interleukin-1-receptor antagonist in blocking inflammation mediated by interleukin-1. N Engl J Med. 2000; 343: 732-4, CrossRef.

Dinarello CA. Biologic basis for interleukin-1 in disease. Blood. 1996; 87: 2095-147, PMID.

Ehses JA, Lacraz G, Giroix MH, Schmidlin F, Coulaud J, Kassis N, et al. IL-1 antagonism reduces hyperglycemia and tissue inflammation in the type 2 diabetic GK rat. Proc Natl Acad Sci USA. 2009; 106: 13998-4003, CrossRef.

Böni-Schnetzler M, Thorne J, Parnaud G, Marselli L, Ehses JA, Kerr-Conte, et al. Increased interleukin (IL)-1β messenger ribonucleic acid expression in β-cells of individuals with type 2 diabetes and regulation of IL-1β in human islets by glucose and autostimulation. J Clin Endocrinol Metab. 2008; 93: 4065-74, CrossRef.

Böi-Schnetzler M, Boller S, Debray S, Bouzakri K, Meier DT, Prazak R, et al. Free fatty acids induce a proinflammatory response in islets via the abundantly expressed interleukin-1 receptor I. Endocrinology. 2009; 150: 5218-29, CrossRef.


Indexed by:






The Prodia Education and Research Institute