Neutrophils Mediate Insulin Resistance in Mice Fed a High-fat Diet Through Secreted Elastase

Overview

Journal Nat Med

Specialties General Medicine
Molecular Biology

Date 2012 Aug 7

PMID 22863787

Citations 493

Authors

Saswata Talukdar

Da Young Oh

Gautam Bandyopadhyay

Dongmei Li

Jianfeng Xu

Joanne McNelis

Min Lu

Pingping Li

Qingyun Yan

Yimin Zhu

Jachelle Ofrecio

Michael Lin

Martin B Brenner

Jerrold M Olefsky

Affiliations

Soon will be listed here.

Abstract

Chronic low-grade adipose tissue and liver inflammation is a major cause of systemic insulin resistance and is a key component of the low degree of insulin sensitivity that exists in obesity and type 2 diabetes. Immune cells, such as macrophages, T cells, B cells, mast cells and eosinophils, have all been implicated as having a role in this process. Neutrophils are typically the first immune cells to respond to inflammation and can exacerbate the chronic inflammatory state by helping to recruit macrophages and by interacting with antigen-presenting cells. Neutrophils secrete several proteases, one of which is neutrophil elastase, which can promote inflammatory responses in several disease models. Here we show that treatment of hepatocytes with neutrophil elastase causes cellular insulin resistance and that deletion of neutrophil elastase in high-fat-diet–induced obese (DIO) mice leads to less tissue inflammation that is associated with lower adipose tissue neutrophil and macrophage content. These changes are accompanied by improved glucose tolerance and increased insulin sensitivity. Taken together, we show that neutrophils can be added to the extensive repertoire of immune cells that participate in inflammation-induced metabolic disease.

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References

Borregaard N . Neutrophils, from marrow to microbes. Immunity. 2010; 33(5):657-70. DOI: 10.1016/j.immuni.2010.11.011. View

MacDonald S, Dowle M, Harrison L, Shah P, Johnson M, Inglis G . The discovery of a potent, intracellular, orally bioavailable, long duration inhibitor of human neutrophil elastase--GW311616A a development candidate. Bioorg Med Chem Lett. 2001; 11(7):895-8. DOI: 10.1016/s0960-894x(01)00078-6. View

WALSH D, Greene C, Carroll T, Taggart C, Gallagher P, ONeill S . Interleukin-8 up-regulation by neutrophil elastase is mediated by MyD88/IRAK/TRAF-6 in human bronchial epithelium. J Biol Chem. 2001; 276(38):35494-9. DOI: 10.1074/jbc.M103543200. View

Talukdar S, Hillgartner F . The mechanism mediating the activation of acetyl-coenzyme A carboxylase-alpha gene transcription by the liver X receptor agonist T0-901317. J Lipid Res. 2006; 47(11):2451-61. DOI: 10.1194/jlr.M600276-JLR200. View

Olefsky J, Glass C . Macrophages, inflammation, and insulin resistance. Annu Rev Physiol. 2010; 72:219-46. DOI: 10.1146/annurev-physiol-021909-135846. View

Liu J, Divoux A, Sun J, Zhang J, Clement K, Glickman J . Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice. Nat Med. 2009; 15(8):940-5. PMC: 2736875. DOI: 10.1038/nm.1994. View

Wu D, Molofsky A, Liang H, Ricardo-Gonzalez R, Jouihan H, Bando J . Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science. 2011; 332(6026):243-7. PMC: 3144160. DOI: 10.1126/science.1201475. View

Winer S, Chan Y, Paltser G, Truong D, Tsui H, Bahrami J . Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med. 2009; 15(8):921-9. PMC: 3063199. DOI: 10.1038/nm.2001. View

Li P, Lu M, Audrey Nguyen M, Bae E, Chapman J, Feng D . Functional heterogeneity of CD11c-positive adipose tissue macrophages in diet-induced obese mice. J Biol Chem. 2010; 285(20):15333-15345. PMC: 2865288. DOI: 10.1074/jbc.M110.100263. View

10.

Snelgrove R, Jackson P, Hardison M, Noerager B, Kinloch A, Gaggar A . A critical role for LTA4H in limiting chronic pulmonary neutrophilic inflammation. Science. 2010; 330(6000):90-4. PMC: 3072752. DOI: 10.1126/science.1190594. View

11.

Oh D, Talukdar S, Bae E, Imamura T, Morinaga H, Fan W . GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell. 2010; 142(5):687-98. PMC: 2956412. DOI: 10.1016/j.cell.2010.07.041. View

12.

Nathan C . Neutrophils and immunity: challenges and opportunities. Nat Rev Immunol. 2006; 6(3):173-82. DOI: 10.1038/nri1785. View

13.

Winer D, Winer S, Shen L, Wadia P, Yantha J, Paltser G . B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat Med. 2011; 17(5):610-7. PMC: 3270885. DOI: 10.1038/nm.2353. View

14.

Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J, Nayer A . Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med. 2009; 15(8):930-9. PMC: 3115752. DOI: 10.1038/nm.2002. View

15.

Rensen S, Slaats Y, Nijhuis J, Jans A, Bieghs V, Driessen A . Increased hepatic myeloperoxidase activity in obese subjects with nonalcoholic steatohepatitis. Am J Pathol. 2009; 175(4):1473-82. PMC: 2751544. DOI: 10.2353/ajpath.2009.080999. View

16.

Pham C . Neutrophil serine proteases: specific regulators of inflammation. Nat Rev Immunol. 2006; 6(7):541-50. DOI: 10.1038/nri1841. View

17.

Lu M, Sarruf D, Talukdar S, Sharma S, Li P, Bandyopadhyay G . Brain PPAR-γ promotes obesity and is required for the insulin-sensitizing effect of thiazolidinediones. Nat Med. 2011; 17(5):618-22. PMC: 3380629. DOI: 10.1038/nm.2332. View

18.

Gregor M, Hotamisligil G . Inflammatory mechanisms in obesity. Annu Rev Immunol. 2011; 29:415-45. DOI: 10.1146/annurev-immunol-031210-101322. View

19.

Elgazar-Carmon V, Rudich A, Hadad N, Levy R . Neutrophils transiently infiltrate intra-abdominal fat early in the course of high-fat feeding. J Lipid Res. 2008; 49(9):1894-903. DOI: 10.1194/jlr.M800132-JLR200. View

20.

Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M . CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med. 2009; 15(8):914-20. DOI: 10.1038/nm.1964. View