Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase

• Published in: Nature medicine Vol. 18; no. 9; pp. 1407 - 1412
• Main Authors: Talukdar, Saswata, Oh, Da Young, Bandyopadhyay, Gautam, Li, Dongmei, Xu, Jianfeng, McNelis, Joanne, Lu, Min, Li, Pingping, Yan, Qingyun, Zhu, Yimin, Ofrecio, Jachelle, Lin, Michael, Brenner, Martin B, Olefsky, Jerrold M
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.09.2012; Nature Publishing Group
• Subjects: 631/250/2504/223/1699; 631/250/256; 692/699/2743/393; Adipose tissue; Animals; Antigen presentation; Biomedical and Life Sciences; Biomedicine; Blotting, Western; Body fat; Body Weight - drug effects; Cancer Research; Densitometry; Diet; Diet, High-Fat; Flow Cytometry; Hepatocytes - drug effects; Immune system; Infectious Diseases; Inflammation - etiology; Inflammation - immunology; Insulin resistance; Insulin Resistance - immunology; letter; Liver diseases; Metabolic Diseases; Metabolic disorders; Mice; Molecular Medicine; Neurosciences; Neutrophils - immunology; Neutrophils - secretion; Obesity; Obesity - complications; Pancreatic Elastase - pharmacology; Pancreatic Elastase - secretion; Real-Time Polymerase Chain Reaction
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.2885

Infiltration of various immune cell types into the fat tissue and liver has been implicated in obesity-induced insulin resistance. Jerry Olefsky and his colleagues now show that neutrophils are one of the earliest immune cells to arrive in these tissues, that they release the protease neutrophil elastase and that this enzyme degrades IRS-1, a key member of the insulin signaling pathway. These results show that neutrophils contribute to insulin resistance and how they may do so. 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 1 , 2 . Immune cells, such as macrophages, T cells, B cells, mast cells and eosinophils, have all been implicated as having a role in this process 3 , 4 , 5 , 6 , 7 , 8 . 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 9 , 10 , 11 . Neutrophils secrete several proteases, one of which is neutrophil elastase, which can promote inflammatory responses in several disease models 12 . 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.