Skip to main content
Top
Published in: Diabetologia 11/2013

01-11-2013 | Article

Obesity phenotype is related to NLRP3 inflammasome activity and immunological profile of visceral adipose tissue

Authors: Nathalie Esser, Laurent L’homme, Arnaud De Roover, Laurent Kohnen, André J. Scheen, Michel Moutschen, Jacques Piette, Sylvie Legrand-Poels, Nicolas Paquot

Published in: Diabetologia | Issue 11/2013

Login to get access

Abstract

Aims/hypothesis

Obesity is a heterogeneous condition comprising both individuals who remain metabolically healthy (MHO) and those who develop metabolic disorders (metabolically unhealthy, MUO). Adipose tissue is also heterogeneous in that its visceral component is more frequently associated with metabolic dysfunction than its subcutaneous component. The development of metabolic disorders is partly mediated by the NLR family pyrin domain containing-3 (NLRP3) inflammasome, which increases the secretion of inflammatory cytokines via activation of caspase-1. We compared the immunological profile and NLRP3 activity in adipose tissue between MUO and MHO individuals.

Methods

MHO and MUO phenotypes were defined, respectively, as the absence and the presence of the metabolic syndrome. Cellular composition and intrinsic inflammasome activity were investigated by flow cytometry, quantitative RT-PCR and tissue culture studies in subcutaneous and visceral adipose tissue from 23 MUO, 21 MHO and nine lean individuals.

Results

We found significant differences between the three study groups, including an increased secretion of IL-1β, increased expression of IL1B and NLRP3, increased number of adipose tissue macrophages and decreased number of regulatory T cells in the visceral adipose tissue of MUO patients compared with MHO and lean participants. In macrophages derived from visceral adipose tissue, both caspase-1 activity and IL-1β levels were higher in MUO patients than in MHO patients. Furthermore, caspase-1 activity was higher in CD11c+CD206+ adipose tissue macrophages than in CD11cCD206+ cells.

Conclusions/interpretation

The MUO phenotype seems to be associated with an increased activation of the NLPR3 inflammasome in macrophages infiltrating visceral adipose tissue, and a less favourable inflammatory profile compared with the MHO phenotype.
Appendix
Available only for authorised users
Literature
1.
go back to reference Alberti KG, Eckel RH, Grundy SM et al (2009) Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 120:1640–1645PubMedCrossRef Alberti KG, Eckel RH, Grundy SM et al (2009) Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 120:1640–1645PubMedCrossRef
2.
go back to reference Karelis AD, St-Pierre DH, Conus F, Rabasa-Lhoreth R, Poehlman ET (2004) Metabolic and body composition factors in subgroups of obesity: what do we know? J Clin Endocrinol Metab 89:2569–2575PubMedCrossRef Karelis AD, St-Pierre DH, Conus F, Rabasa-Lhoreth R, Poehlman ET (2004) Metabolic and body composition factors in subgroups of obesity: what do we know? J Clin Endocrinol Metab 89:2569–2575PubMedCrossRef
3.
go back to reference Wildman RP, Muntner P, Reynolds K et al (2008) The obese without cardiometabolic risk factor clustering and the normal weight with cardiometabolic risk factor clustering: prevalence and correlates of 2 phenotypes among the US population (NHANES 1999–2004). Arch Intern Med 168:1617–1624PubMedCrossRef Wildman RP, Muntner P, Reynolds K et al (2008) The obese without cardiometabolic risk factor clustering and the normal weight with cardiometabolic risk factor clustering: prevalence and correlates of 2 phenotypes among the US population (NHANES 1999–2004). Arch Intern Med 168:1617–1624PubMedCrossRef
4.
go back to reference Stefan N, Kantartzis K, Macham J et al (2008) Identification and characterization of metabolically benign obesity in humans. Arch Intern Med 168:1609–1616PubMedCrossRef Stefan N, Kantartzis K, Macham J et al (2008) Identification and characterization of metabolically benign obesity in humans. Arch Intern Med 168:1609–1616PubMedCrossRef
5.
go back to reference Bradshaw PT, Monda KL, Stevens J (2013) Metabolic syndrome in healthy obese, overweight, and normal weight individuals: the atherosclerosis risk in communities study. Obesity (Silver Spring) 21:203–209CrossRef Bradshaw PT, Monda KL, Stevens J (2013) Metabolic syndrome in healthy obese, overweight, and normal weight individuals: the atherosclerosis risk in communities study. Obesity (Silver Spring) 21:203–209CrossRef
6.
go back to reference Wajchenberg BL (2000) Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev 21:697–738PubMedCrossRef Wajchenberg BL (2000) Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev 21:697–738PubMedCrossRef
7.
go back to reference Tchernof A, Després JP (2013) Pathophysiology of human visceral obesity: an update. Physiol Rev 93:359–404PubMedCrossRef Tchernof A, Després JP (2013) Pathophysiology of human visceral obesity: an update. Physiol Rev 93:359–404PubMedCrossRef
8.
go back to reference Koster A, Stenholm S, Alley DE et al (2010) Body fat distribution and inflammation among obese older adults with and without metabolic syndrome. Obesity (Silver Spring) 18:2354–2361CrossRef Koster A, Stenholm S, Alley DE et al (2010) Body fat distribution and inflammation among obese older adults with and without metabolic syndrome. Obesity (Silver Spring) 18:2354–2361CrossRef
9.
go back to reference Fox CS, Massaro JM, Hoffmann U et al (2007) Abdominal visceral and subcutaneous adipose tissue compartments: association with metabolic risk factors in the Framingham Heart Study. Circulation 116:39–48PubMedCrossRef Fox CS, Massaro JM, Hoffmann U et al (2007) Abdominal visceral and subcutaneous adipose tissue compartments: association with metabolic risk factors in the Framingham Heart Study. Circulation 116:39–48PubMedCrossRef
10.
go back to reference Lundgren M, Svensson M, Lindmark S et al (2007) Fat cell enlargement is an independent marker of insulin resistance and ‘hyper-leptinaemia’. Diabetologia 50:625–633PubMedCrossRef Lundgren M, Svensson M, Lindmark S et al (2007) Fat cell enlargement is an independent marker of insulin resistance and ‘hyper-leptinaemia’. Diabetologia 50:625–633PubMedCrossRef
11.
go back to reference Weyer C, Foley JE, Bogardus C et al (2000) Enlarged subcutaneous abdominal adipocyte size but not obesity itself, predicts type II diabetes independent of insulin resistance. Diabetologia 43:1498–1506PubMedCrossRef Weyer C, Foley JE, Bogardus C et al (2000) Enlarged subcutaneous abdominal adipocyte size but not obesity itself, predicts type II diabetes independent of insulin resistance. Diabetologia 43:1498–1506PubMedCrossRef
12.
go back to reference Gossens GH (2008) The role of adipose tissue dysfunction in the pathogenesis of obesity-related insulin resistance. Physiol Behav 94:206–218CrossRef Gossens GH (2008) The role of adipose tissue dysfunction in the pathogenesis of obesity-related insulin resistance. Physiol Behav 94:206–218CrossRef
13.
15.
go back to reference Donath MT, Shoelson SE (2011) Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 11:98–107PubMedCrossRef Donath MT, Shoelson SE (2011) Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 11:98–107PubMedCrossRef
16.
go back to reference Olefsky JM, Glass CK (2010) Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 72:219–246PubMedCrossRef Olefsky JM, Glass CK (2010) Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 72:219–246PubMedCrossRef
17.
go back to reference Chawla A, Nguyen KD, Goh YP (2011) Macrophage-mediated inflammation in metabolic disease. Nat Rev Immunol 11:738–749PubMedCrossRef Chawla A, Nguyen KD, Goh YP (2011) Macrophage-mediated inflammation in metabolic disease. Nat Rev Immunol 11:738–749PubMedCrossRef
18.
go back to reference Feve B, Bastard JP (2009) The role of interleukins in insulin resistance and type 2 diabetes mellitus. Nature Rev Endocrinol 5:305–311CrossRef Feve B, Bastard JP (2009) The role of interleukins in insulin resistance and type 2 diabetes mellitus. Nature Rev Endocrinol 5:305–311CrossRef
19.
go back to reference Osborn O, Olefsky JM (2012) The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med 18:363–374PubMedCrossRef Osborn O, Olefsky JM (2012) The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med 18:363–374PubMedCrossRef
20.
go back to reference Wentworth JM, Naselli G, Brown WA et al (2010) Pro-inflammatory CD11c+CD206+ adipose tissue macrophages are associated with insulin resistance in human obesity. Diabetes 59:1648–1656PubMedCrossRef Wentworth JM, Naselli G, Brown WA et al (2010) Pro-inflammatory CD11c+CD206+ adipose tissue macrophages are associated with insulin resistance in human obesity. Diabetes 59:1648–1656PubMedCrossRef
21.
go back to reference Fujisaka S, Usui I, Bukhari A et al (2009) Regulatory mechanisms for adipose tissue M1 and M2 macrophages in diet-induced obese mice. Diabetes 58:2574–2582PubMedCrossRef Fujisaka S, Usui I, Bukhari A et al (2009) Regulatory mechanisms for adipose tissue M1 and M2 macrophages in diet-induced obese mice. Diabetes 58:2574–2582PubMedCrossRef
22.
go back to reference Patsouris D, Li PP, Thapar D et al (2008) Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell Metab 8:301–309PubMedCrossRef Patsouris D, Li PP, Thapar D et al (2008) Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell Metab 8:301–309PubMedCrossRef
23.
go back to reference Feuerer M, Herrero L, Cipolletta D et al (2009) Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 15:930–939PubMedCrossRef Feuerer M, Herrero L, Cipolletta D et al (2009) Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 15:930–939PubMedCrossRef
24.
go back to reference Nishimura S, Manabe I, Nagasaki M et al (2009) CD8+ effector T cells contribute to macrophages recruitment and adipose tissue inflammation in obesity. Nat Med 15:914–920PubMedCrossRef Nishimura S, Manabe I, Nagasaki M et al (2009) CD8+ effector T cells contribute to macrophages recruitment and adipose tissue inflammation in obesity. Nat Med 15:914–920PubMedCrossRef
25.
go back to reference Winer S, Chan Y, Paltser G et al (2009) Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med 15:921–929PubMedCrossRef Winer S, Chan Y, Paltser G et al (2009) Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med 15:921–929PubMedCrossRef
26.
go back to reference Spranger J, Kroke A, Möhlig M et al (2003) 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 52:812–817PubMedCrossRef Spranger J, Kroke A, Möhlig M et al (2003) 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 52:812–817PubMedCrossRef
27.
go back to reference Thorand B, Kolb H, Baumert J et al (2005) Elevated levels of interleukin-18 predict the development of type 2 diabetes. Results from the MONICA/KORA Augsburg study, 1984–2002. Diabetes 54:2932–2938PubMedCrossRef Thorand B, Kolb H, Baumert J et al (2005) Elevated levels of interleukin-18 predict the development of type 2 diabetes. Results from the MONICA/KORA Augsburg study, 1984–2002. Diabetes 54:2932–2938PubMedCrossRef
29.
go back to reference Stienstra R, Tack CJ, Kanneganti TD, Joosten LAB, Netea MG (2012) The inflammasome puts obesity in the danger zone. Cell Metab 15:10–18PubMedCrossRef Stienstra R, Tack CJ, Kanneganti TD, Joosten LAB, Netea MG (2012) The inflammasome puts obesity in the danger zone. Cell Metab 15:10–18PubMedCrossRef
30.
go back to reference Vandanmagsar B, Youm YH, Ravussin A et al (2011) The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med 17:179–188PubMedCrossRef Vandanmagsar B, Youm YH, Ravussin A et al (2011) The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med 17:179–188PubMedCrossRef
31.
go back to reference Lee HM, Kim JJ, Kim HJ et al (2013) Upregulated NLRP3 inflammasome activation in patients with type 2 diabetes. Diabetes 62:194–204PubMedCrossRef Lee HM, Kim JJ, Kim HJ et al (2013) Upregulated NLRP3 inflammasome activation in patients with type 2 diabetes. Diabetes 62:194–204PubMedCrossRef
32.
go back to reference Koenen TB, Stienstra R, van Tits LJ et al (2011) The inflammasome and caspase-1 activation: a new mechanism underlying increased inflammatory activity in human visceral adipose tissue. Endocrinology 152:3769–3778PubMedCrossRef Koenen TB, Stienstra R, van Tits LJ et al (2011) The inflammasome and caspase-1 activation: a new mechanism underlying increased inflammatory activity in human visceral adipose tissue. Endocrinology 152:3769–3778PubMedCrossRef
33.
go back to reference Livak KJ, Schmitthen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25:402–408PubMedCrossRef Livak KJ, Schmitthen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25:402–408PubMedCrossRef
34.
go back to reference Arend WP, Palmer G, Gabay C (2008) IL-1, IL-18, and IL-33 families of cytokines. Immunol Rev 223:20–38PubMedCrossRef Arend WP, Palmer G, Gabay C (2008) IL-1, IL-18, and IL-33 families of cytokines. Immunol Rev 223:20–38PubMedCrossRef
35.
go back to reference Schertzer JD, Klip A (2011) Give a NOD to insulin resistance. Am J Physiol Endocrinol Metab 301:E585–E586PubMedCrossRef Schertzer JD, Klip A (2011) Give a NOD to insulin resistance. Am J Physiol Endocrinol Metab 301:E585–E586PubMedCrossRef
36.
go back to reference Kim MS, Choi M-S, Han SN (2011) High fat diet-induced obesity leads to proinflammatory response associated with higher expression of NOD2 protein. Nutr Res Pract 5:219–223PubMedCrossRef Kim MS, Choi M-S, Han SN (2011) High fat diet-induced obesity leads to proinflammatory response associated with higher expression of NOD2 protein. Nutr Res Pract 5:219–223PubMedCrossRef
37.
go back to reference Deiuliis J, Shah Z, Shah N et al (2011) Visceral adipose inflammation in obesity is associated with critical alterations in T regulatory cell numbers. PLoS One 6:e16376PubMedCrossRef Deiuliis J, Shah Z, Shah N et al (2011) Visceral adipose inflammation in obesity is associated with critical alterations in T regulatory cell numbers. PLoS One 6:e16376PubMedCrossRef
38.
go back to reference Greenberg AS, Obin MS (2006) Obesity and the role of adipose tissue in inflammation and metabolism. Am J Clin Nutr 83:461S–465SPubMed Greenberg AS, Obin MS (2006) Obesity and the role of adipose tissue in inflammation and metabolism. Am J Clin Nutr 83:461S–465SPubMed
39.
go back to reference Fried SK, Bunkin DA, Greenberg AS (1998) Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid. J Clin Endocrinol Metab 83:847–850PubMedCrossRef Fried SK, Bunkin DA, Greenberg AS (1998) Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid. J Clin Endocrinol Metab 83:847–850PubMedCrossRef
40.
go back to reference Membrez M, Ammon-Zufferay C, Philippe D et al (2008) Interleukin-18 protein level is upregulated in adipose tissue of obese mice. Obesity (Silver Spring) 17:393–395CrossRef Membrez M, Ammon-Zufferay C, Philippe D et al (2008) Interleukin-18 protein level is upregulated in adipose tissue of obese mice. Obesity (Silver Spring) 17:393–395CrossRef
41.
go back to reference Skurk T, Kolb H, Muller-Scholze S et al (2005) The proatherogenic cytokine interleukin-18 is secreted by human adipocytes. Eur J Endocrinol 152:863–868PubMedCrossRef Skurk T, Kolb H, Muller-Scholze S et al (2005) The proatherogenic cytokine interleukin-18 is secreted by human adipocytes. Eur J Endocrinol 152:863–868PubMedCrossRef
42.
go back to reference Poulain-Godefroy O, Lecoeur C, Pattou F et al (2008) Inflammation is associated with a decrease of lipogenic factors in omental fat in women. Am J Physiol Regul Integr Comp Physiol 295:R1–R7PubMedCrossRef Poulain-Godefroy O, Lecoeur C, Pattou F et al (2008) Inflammation is associated with a decrease of lipogenic factors in omental fat in women. Am J Physiol Regul Integr Comp Physiol 295:R1–R7PubMedCrossRef
43.
go back to reference Lemieux I, Poirier P, Bergeron J et al (2007) Hypertriglyceridemic waist: a useful screening phenotype in preventive cardiology? Can J Cardiol 23(suppl B):23B–31BPubMedCrossRef Lemieux I, Poirier P, Bergeron J et al (2007) Hypertriglyceridemic waist: a useful screening phenotype in preventive cardiology? Can J Cardiol 23(suppl B):23B–31BPubMedCrossRef
44.
go back to reference Shi H, Kokoeva M, Inouye K et al (2006) TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 116:3015–3025PubMedCrossRef Shi H, Kokoeva M, Inouye K et al (2006) TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 116:3015–3025PubMedCrossRef
45.
go back to reference Wen H, Gris D, Lei Y et al (2011) Fatty acid-induced NLRP3-ASC inflammasomes activation interferes with insulin signaling. Nat Immunol 12:408–415PubMedCrossRef Wen H, Gris D, Lei Y et al (2011) Fatty acid-induced NLRP3-ASC inflammasomes activation interferes with insulin signaling. Nat Immunol 12:408–415PubMedCrossRef
46.
go back to reference Oh DY, Talukdar S, Baz EJ et al (2010) GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin –sensitizing effects. Cell 142:687–698PubMedCrossRef Oh DY, Talukdar S, Baz EJ et al (2010) GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin –sensitizing effects. Cell 142:687–698PubMedCrossRef
47.
go back to reference Chatzigeorgiou A, Karalis KP, Bornstein SR, Chavakis T (2012) Lymphocytes in obesity-related adipose tissues inflammation. Diabetologia 55:2583–2592PubMedCrossRef Chatzigeorgiou A, Karalis KP, Bornstein SR, Chavakis T (2012) Lymphocytes in obesity-related adipose tissues inflammation. Diabetologia 55:2583–2592PubMedCrossRef
Metadata
Title
Obesity phenotype is related to NLRP3 inflammasome activity and immunological profile of visceral adipose tissue
Authors
Nathalie Esser
Laurent L’homme
Arnaud De Roover
Laurent Kohnen
André J. Scheen
Michel Moutschen
Jacques Piette
Sylvie Legrand-Poels
Nicolas Paquot
Publication date
01-11-2013
Publisher
Springer Berlin Heidelberg
Published in
Diabetologia / Issue 11/2013
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-013-3023-9

Other articles of this Issue 11/2013

Diabetologia 11/2013 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.