Neutrophils mediate insulin resistance in high fat diet fed mice via secreted elastase

By Saswata Talukdar, D. Oh, G. Bandyopadhyay, Dongmei Li, Jianfeng Xu, Joanne C. McNelis, Min Lu, Pingping Li, Qingyun Yan, Yimin Zhu and 4 more. Nature Medicine, 2012

621 citations recorded by the source corpus.

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.

Subfields: Epidemiology, Immunology

View Paper: https://www.semanticscholar.org/paper/3d7dcfb79651ee2a586a4a1991008bf117d766a2

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Epidemiology

1. Jamal Naderi
2. M. Longo
3. Byung-Cheol Lee
4. C. Rosales
5. C. Miele
6. Jongsoon Lee
7. G. A. Raciti
8. F. Beguinot

In Immunology

1. Byung-Cheol Lee
2. C. Rosales
3. Jongsoon Lee

Citations in the corpus

• Neutrophil Extracellular Traps and Its Implications in Inflammation: An Overview (2017, background): “As a consequence, it is possible that neutrophils could play a role in triggering the inflammatory cascade in response to obesity (207).”
• Adipose Tissue Remodeling: Its Role in Energy Metabolism and Metabolic Disorders (2016, background): “It was reported that the expression levels of neutrophilderived elastase and myeloperoxidase (MPO) were elevated after only 3 days of HFD feeding in mice and that neutrophils quickly accumulated in the obese adipose tissue (131, 132).”
• Neutrophil: A Cell with Many Roles in Inflammation or Several Cell Types? (2018, background): “This enzyme can destroy insulin receptor substrate 1 (IRS1) in adipocytes and hepatocytes, and in consequence induce insulin resistance and lipogenesis (Talukdar et al., 2012).”
• Cellular and Molecular Players in Adipose Tissue Inflammation in the Development of Obesity-induced Insulin Resistance (2013, positive): “This question was answered by a study that assessed the expression of MPO in total AT [71] and by a flow cytometric study of AT immune cells [72].”
• Chronic Adipose Tissue Inflammation Linking Obesity to Insulin Resistance and Type 2 Diabetes (2020, background): “Genetic deletion of elastase attenuates macrophage influx into the AT of obese mice and results in improved insulin sensitivity (Talukdar et al., 2012; Hotamisligil, 2017).”
• Increased oxidative stress in obesity: implications for metabolic syndrome, diabetes, hypertension, dyslipidemia, atherosclerosis, and cancer. (2013, background): “[50] Talukdar S, Oh da Y, Bandyopadhyay G, Li D, Xu J, McNelis”