Obesity and its comorbidities are closely related to the inflammatory environment created by expanded adipose tissue. Several mechanisms trigger inflammation in adipose tissue, including excess fatty acids, hypoxia, and activation of the inflammasome. Inflammation is characterized by the abundance of immune cells, particularly M1 macrophages and T lymphocytes, which have increased secretion of proinflammatory cytokines that act to perpetuate systemic inflammation and induce insulin resistance. The gut microbiota is also involved in obesity-induced inflammation via LPS-related endotoxemia that induces cytokine secretion and insulin resistance. Innate lymphoid type 2 cells, regulatory T cells, and interleukine (IL)-10 counteract the inflammation and insulin resistance, establishing classical or metabolically healthy obesity.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
de Heredia FP, Gomez-Martinez S, Marcos A. Obesity, inflammation and the immune system. Proc Nutr Soc. 2012;71:332–8.
Ouchi N, Parker JL, Lugus JJ, Walsh K. Adipokines in inflammation and metabolic disease. Nat Rev Immunol. 2011;11:85–97.
Fain, J.N. Release of inflammatory mediators by human adipose tissue is enhanced in obesity and primarily by the nonfat cells: a review. Mediators Inflamm 2010, 513948.
van Greevenbroek MM, Schalkwijk CG, Stehouwer CD. Obesity-associated low-grade inflammation in type 2 diabetes mellitus: causes and consequences. Neth J Med. 2013;71:174–87.
Bigornia SJ, Farb MG, Mott MM, Hess DT, Carmine B, Fiscale A, et al. Relation of depot-specific adipose inflammation to insulin resistance in human obesity. Nutr Diabetes. 2012;2:e30.
Despres JP, Lemieux I, Bergeron J, Pibarot P, Mathieu P, Larose E, et al. Abdominal obesity and the metabolic syndrome: contribution to global cardiometabolic risk. Arterioscler Thromb Vasc Biol. 2008;28:1039–49.
Marinou K, Tousoulis D, Antonopoulos AS, Stefanadi E, Stefanadis C. Obesity and cardiovascular disease: from pathophysiology to risk stratification. Int J Cardiol. 2010;138:3–8.
Primeau V, Coderre L, Karelis AD, Brochu M, Lavoie ME, Messier V, et al. Characterizing the profile of obese patients who are metabolically healthy. Int J Obes (Lond). 2011;35:971–81.
Zeyda M, Stulnig TM. Obesity, inflammation, and insulin resistance–a mini-review. Gerontology. 2009;55:379–86.
Girard J, Lafontan M. Impact of visceral adipose tissue on liver metabolism and insulin resistance. Part II: Visceral adipose tissue production and liver metabolism. Diabetes Metab. 2008;34:439–45.
Coelho M, Oliveira T, Fernandes R. Biochemistry of adipose tissue: an endocrine organ. Arch Med Sci. 2013;9:191–200.
Li ZY, Wang P, Miao CY. Adipokines in inflammation, insulin resistance and cardiovascular disease. Clin Exp Pharmacol Physiol. 2011;38:888–96.
Lemoine AY, Ledoux S, Larger E. Adipose tissue angiogenesis in obesity. Thromb Haemost. 2013;110.
Gualillo O, Gonzalez-Juanatey JR, Lago F. The emerging role of adipokines as mediators of cardiovascular function: physiologic and clinical perspectives. Trends Cardiovasc Med. 2007;17:275–83.
Pujanek M, Bronisz A, Malecki P, Junik R. Pathomechanisms of the development of obesity in some endocrinopathies - an overview. Endokrynol Pol. 2013;64:150–5.
Leal Vde O, Mafra D. Adipokines in obesity. Clin Chim Acta. 2013;419:87–94.
Jung CH, Kim MS. Molecular mechanisms of central leptin resistance in obesity. Arch Pharm Res. 2013;36:201–7.
D’Ippolito S, Tersigni C, Scambia G, Di Simone N. Adipokines, an adipose tissue and placental product with biological functions during pregnancy. Biofactors. 2012;38:14–23.
Ye J, McGuinness OP. Inflammation during obesity is not all bad: evidence from animal and human studies. Am J Physiol Endocrinol Metab. 2013;304:E466–77.
Vazquez-Vela ME, Torres N, Tovar AR. White adipose tissue as endocrine organ and its role in obesity. Arch Med Res. 2008;39:715–28.
Yadav A, Kataria MA, Saini V. Role of leptin and adiponectin in insulin resistance. Clin Chim Acta. 2013;417:80–4.
Lenz A, Diamond Jr FB. Obesity: the hormonal milieu. Curr Opin Endocrinol Diabetes Obes. 2008;15:9–20.
Yamauchi T, Kadowaki T. Physiological and pathophysiological roles of adiponectin and adiponectin receptors in the integrated regulation of metabolic and cardiovascular diseases. Int J Obes (Lond). 2008;32 Suppl 7:S13–8.
Lago F, Gomez R, Gomez-Reino JJ, Dieguez C, Gualillo O. Adipokines as novel modulators of lipid metabolism. Trends Biochem Sci. 2009;34:500–10.
Pereira SS, Alvarez-Leite JI. Adipokines: biological functions and metabolically healthy obese profile. J Recept Ligand Channel Res. 2014;7:1–11.
Galic S, Oakhill JS, Steinberg GR. Adipose tissue as an endocrine organ. Mol Cell Endocrinol. 2010;316:129–39.
Zou C, Shao J. Role of adipocytokines in obesity-associated insulin resistance. J Nutr Biochem. 2008;19:277–86.
Maury E, Brichard SM. Adipokine dysregulation, adipose tissue inflammation and metabolic syndrome. Mol Cell Endocrinol. 2010;314:1–16.
Balistreri CR, Caruso C, Candore G. The role of adipose tissue and adipokines in obesity-related inflammatory diseases. Mediat Inflamm. 2010;2010:802078.
Guilherme A, Virbasius JV, Puri V, Czech MP. Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat Rev Mol Cell Biol. 2008;9:367–77.
Hermsdorff HH, Angeles Zulet M, Bressan J, Alfredo Martinez J. Effect of diet on the low-grade and chronic inflammation associated with obesity and metabolic syndrome. Endocrinol Nutr. 2008;55:409–19.
Bray GA, Clearfield MB, Fintel DJ, Nelinson DS. Overweight and obesity: the pathogenesis of cardiometabolic risk. Clin Cornerstone. 2009;9:30–40. discussion 41–32.
Lee J. Adipose tissue macrophages in the development of obesity-induced inflammation, insulin resistance and type 2 Diabetes. Arch Pharm Res. 2013;36:208–22.
Sun S, Ji Y, Kersten S, Qi L. Mechanisms of inflammatory responses in obese adipose tissue. Annu Rev Nutr. 2012;32:261–86.
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.
Itoh M, Suganami T, Hachiya R, Ogawa Y. Adipose tissue remodeling as homeostatic inflammation. Int J Inflamm. 2011;2011:720926.
Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J, Nayer A, et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med. 2009;15:930–9.
Gotoh K, Inoue M, Masaki T, Chiba S, Shimasaki T, Ando H, et al. A novel anti-inflammatory role for spleen-derived interleukin-10 in obesity-induced inflammation in white adipose tissue and liver. Diabetes. 2012;61:1994–2003.
Chen W, Konkel JE. TGF-beta and ‘adaptive’ Foxp3(+) regulatory T cells. J Mol Cell Biol. 2010;2:30–6.
Chen X, Oppenheim JJ. Resolving the identity myth: key markers of functional CD4 + FoxP3+ regulatory T cells. Int Immunopharmacol. 2011;11:1489–96.
Yadav H, Quijano C, Kamaraju AK, Gavrilova O, Malek R, Chen W, et al. Protection from obesity and diabetes by blockade of TGF-beta/Smad3 signaling. Cell Metab. 2011;14:67–79.
Tan CK, Chong HC, Tan EH, Tan NS. Getting ‘Smad’ about obesity and diabetes. Nutr Diabetes. 2012;2:e29.
Cristancho AG, Lazar MA. Forming functional fat: a growing understanding of adipocyte differentiation. Nat Rev Mol Cell Biol. 2011;12:722–34.
Chmelar J, Chung KJ, Chavakis T. The role of innate immune cells in obese adipose tissue inflammation and development of insulin resistance. Thromb Haemost. 2013;109:399–406.
Kalupahana NS, Moustaid-Moussa N, Claycombe KJ. Immunity as a link between obesity and insulin resistance. Mol Aspects Med. 2012;33:26–34.
Harford KA, Reynolds CM, McGillicuddy FC, Roche HM. Fats, inflammation and insulin resistance: insights to the role of macrophage and T-cell accumulation in adipose tissue. Proc Nutr Soc. 2011;70:408–17.
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.
Lolmede K, Duffaut C, Zakaroff-Girard A, Bouloumie A. Immune cells in adipose tissue: key players in metabolic disorders. Diabetes Metab. 2011;37:283–90.
Bertola A, Ciucci T, Rousseau D, Bourlier V, Duffaut C, Bonnafous S, et al. Identification of adipose tissue dendritic cells correlated with obesity-associated insulin-resistance and inducing Th17 responses in mice and patients. Diabetes. 2012;61:2238–47. This paper shows for the first time the presence of specific DCs in adipose tissue in mouse and human obesity.
Patel PS, Buras ED, Balasubramanyam A. The role of the immune system in obesity and insulin resistance. J Obes. 2013;2013:616193.
Chen Y, Tian J, Tian X, Tang X, Rui K, Tong J, et al. Adipose tissue dendritic cells enhances inflammation by prompting the generation of Th17 cells. PLoS ONE. 2014;9:e92450. The results of this study indicates the existence of CD11c + DCs in adipose tissue, which displays an immature phenotype but possessing pro-inflammatory function.
Talukdar S, Oh DY, Bandyopadhyay G, Li D, Xu J, McNelis J, et al. Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat Med. 2012;18:1407–12. The authors show that treatment of hepatocytes with neutrophil elastase causes insulin resistance and that deletion of neutrophil elastase in obese mice reduce inflammation.
Wu D, Molofsky AB, Liang HE, Ricardo-Gonzalez RR, Jouihan HA, Bando JK, et al. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science. 2011;332:243–7.
Molofsky AB, Nussbaum JC, Liang HE, Van Dyken SJ, Cheng LE, Mohapatra A, et al. Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages. J Exp Med. 2013;210:535–49.
Moro K, Yamada T, Tanabe M, Takeuchi T, Ikawa T, Kawamoto H, et al. Innate production of T(H)2 cytokines by adipose tissue-associated c-Kit(+)Sca-1(+) lymphoid cells. Nature. 2010;463:540–4.
Winer S, Chan Y, Paltser G, Truong D, Tsui H, Bahrami J, et al. Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med. 2009;15:921–9.
Cipolletta D, Feuerer M, Li A, Kamei N, Lee J, Shoelson SE, et al. PPAR-gamma is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature. 2012;486:549–53.
Eller K, Kirsch A, Wolf AM, Sopper S, Tagwerker A, Stanzl U, et al. Potential role of regulatory T cells in reversing obesity-linked insulin resistance and diabetic nephropathy. Diabetes. 2011;60:2954–62.
Cipolletta D, Kolodin D, Benoist C, Mathis D. Tissular T(regs): a unique population of adipose-tissue-resident Foxp3 + CD4+ T cells that impacts organismal metabolism. Semin Immunol. 2011;23:431–7.
Deiuliis J, Shah Z, Shah N, Needleman B, Mikami D, Narula V, et al. Visceral adipose inflammation in obesity is associated with critical alterations in tregulatory cell numbers. PLoS ONE. 2011;6:e16376.
Tiemessen MM, Jagger AL, Evans HG, van Herwijnen MJ, John S, Taams LS. CD4 + CD25 + Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages. Proc Natl Acad Sci U S A. 2007;104:19446–51.
Chen, X., Wu, Y., and Wang, L. Fat-resident Tregs: an emerging guard protecting from obesity-associated metabolic disorders. Obes Rev. 2013;14:568–78.
Huh JY, Park YJ, Ham M, Kim JB. Crosstalk between Adipocytes and Immune Cells in Adipose Tissue Inflammation and Metabolic Dysregulation in Obesity. Mol Cells. 2014;37(5):365–71.
Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M, et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med. 2009;15:914–20.
Kotas ME, Lee HY, Gillum MP, Annicelli C, Guigni BA, Shulman GI, et al. Impact of CD1d deficiency on metabolism. PLoS ONE. 2011;6:e25478.
Mantell BS, Stefanovic-Racic M, Yang X, Dedousis N, Sipula IJ, O’Doherty RM. Mice lacking NKT cells but with a complete complement of CD8+ T-cells are not protected against the metabolic abnormalities of diet-induced obesity. PLoS ONE. 2011;6:e19831.
Nishimura, S., Manabe, I., Takaki, S., Nagasaki, M., Otsu, M., Yamashita, H., Sugita, J., Yoshimura, K., Eto, K., Komuro, I., et al. (2013). Adipose Natural Regulatory B Cells Negatively Control Adipose Tissue Inflammation. Cell Metab.
Liu J, Divoux A, Sun J, Zhang J, Clément K, Glickman JN, et al. Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice. Nat Med. 2009;15:940–5.
Robbins GR, Wen H, Ting JP. Inflammasomes and Metabolic Disorders: Old Genes in Modern Diseases. Mol Cell. 2014;54:297–308.
Wieser V, Moschen AR, Tilg H. Inflammation, cytokines and insulin resistance: a clinical perspective. Arch Immunol Ther Exp (Warsz). 2013;61:119–25.
Skeldon AM, Faraj M, Saleh M. Caspases and inflammasomes in metabolic inflammation. Immunol Cell Biol. 2014;92:304–13.
Jin C, Flavell RA. Innate sensors of pathogen and stress: linking inflammation to obesity. J Allergy Clin Immunol. 2013;132:287–94.
Stienstra R, van Diepen JA, Tack CJ, Zaki MH, van de Veerdonk FL, Perera D, et al. Inflammasome is a central player in the induction of obesity and insulin resistance. Proc Natl Acad Sci U S A. 2011;108:15324–9.
Koenen TB, Stienstra R, van Tits LJ, Joosten LA, van Velzen JF, Hijmans A, et al. The inflammasome and caspase-1 activation: a new mechanism underlying increased inflammatory activity in human visceral adipose tissue. Endocrinology. 2011;152:3769–78.
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.
Tilg, H., and Moschen, AR.Microbiota and diabetes: an evolving relationship. Gut. 2014. The paper reviews the role of the microbiota in diabetes and provide new aspects regarding its pathophysiological relevance.
Remely M, Aumueller E, Jahn D, Hippe B, Brath H, Haslberger AG. Microbiota and epigenetic regulation of inflammatory mediators in type 2 diabetes and obesity. Benef Microbes. 2014;5:33–43.
Moreno-Indias I, Cardona F, Tinahones FJ, Queipo-Ortuño MI. Impact of the gut microbiota on the development of obesity and type 2 diabetes mellitus. Front Microbiol. 2014;5:190.
Kemp DM. Does chronic low-grade endotoxemia define susceptibility of obese humans to insulin resistance via dietary effects on gut microbiota? Adipocyte. 2013;2:188–90.
Jumpertz R, Le DS, Turnbaugh PJ, Trinidad C, Bogardus C, Gordon JI, et al. Energy-balance studies reveal associations between gut microbes, caloric load, and nutrient absorption in humans. Am J Clin Nutr. 2011;94:58–65.
Furet JP, Kong LC, Tap J, Poitou C, Basdevant A, Bouillot JL, et al. Differential adaptation of human gut microbiota to bariatric surgery-induced weight loss: links with metabolic and low-grade inflammation markers. Diabetes. 2010;59:3049–57.
Mai V, McCrary QM, Sinha R, Glei M. Associations between dietary habits and body mass index with gut microbiota composition and fecal water genotoxicity: an observational study in African American and Caucasian American volunteers. Nutr J. 2009;8:49.
Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM, et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes. 2008;57:1470–81.
Mehta NN, Heffron SP, Patel PN, Ferguson J, Shah RD, Hinkle CC, et al. A human model of inflammatory cardio-metabolic dysfunction; a double blind placebo-controlled crossover trial. J Transl Med. 2012;10:124.
Mehta NN, McGillicuddy FC, Anderson PD, Hinkle CC, Shah R, Pruscino L, et al. Experimental endotoxemia induces adipose inflammation and insulin resistance in humans. Diabetes. 2010;59:172–81.
Turnbaugh PJ, Bäckhed F, Fulton L, Gordon JI. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe. 2008;3:213–23.
Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444:1027–31.
Lee MJ, Wu Y, Fried SK. Adipose tissue remodeling in pathophysiology of obesity. Curr Opin Clin Nutr Metab Care. 2010;13:371–6.
Sun K, Kusminski CM, Scherer PE. Adipose tissue remodeling and obesity. J Clin Investig. 2011;121:2094–101.
Bluher M. The distinction of metabolically ‘healthy’ from ‘unhealthy’ obese individuals. Curr Opin Lipidol. 2010;21:38–43.
Pataky Z, Bobbioni-Harsch E, Golay A. Open questions about metabolically normal obesity. Int J Obes (Lond). 2010;34 Suppl 2:S18–23.
Esser N, L’homme L, De Roover A, Kohnen L, Scheen AJ, Moutschen M, et al. Obesity phenotype is related to NLRP3 inflammasome activity and immunological profile of visceral adipose tissue. Diabetologia. 2013;56:2487–97.
Pereira SS, Teixeira LG, Aguilar EC, Chaves OM, Savassi-Rocha AL, Pelaez JMN, et al. Modulation of Adipose Tissue Inflammation by Foxp3+ Treg Cells, Il-10 and Tgfβ In Metabolically Healthy Class Iii Obese Individuals. Nutrition. 2014. doi:10.1016/j.nut.2013.11.023. This paper studies the visceral and subcutaneous adipose tissue from grade III obese individuals showing that Treg and IL10 are the important to control inflammation in those individuals.
Compliance with Ethics Guidelines
Conflicts of Interest
Solange S. Pereira and Jacqueline I Alvarez-Leite declare that they have no conflicts of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
About this article
Cite this article
Pereira, S.S., Alvarez-Leite, J.I. Low-Grade Inflammation, Obesity, and Diabetes. Curr Obes Rep 3, 422–431 (2014). https://doi.org/10.1007/s13679-014-0124-9
- Metabolic syndrome
- Type 2 diabetes mellitus