title: Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase.
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.
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Saswata
authors.initials: S
authors.lastname: Talukdar
authors.forename: Da Young
authors.initials: DY
authors.lastname: Oh
authors.forename: Gautam
authors.initials: G
authors.lastname: Bandyopadhyay
authors.forename: Dongmei
authors.initials: D
authors.lastname: Li
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Xu
authors.forename: Joanne
authors.initials: J
authors.lastname: McNelis
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.forename: Pingping
authors.initials: P
authors.lastname: Li
authors.forename: Qingyun
authors.initials: Q
authors.lastname: Yan
authors.forename: Yimin
authors.initials: Y
authors.lastname: Zhu
authors.forename: Jachelle
authors.initials: J
authors.lastname: Ofrecio
authors.forename: Michael
authors.initials: M
authors.lastname: Lin
authors.forename: Martin B
authors.initials: MB
authors.lastname: Brenner
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Olefsky
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D003720:Densitometry; D059305:Diet, High-Fat; D005434:Flow Cytometry; D022781:Hepatocytes / Q000187:drug effects; D007249:Inflammation / Q000209:etiology / Q000276:immunology*; D007333:Insulin Resistance / Q000276:immunology*; D051379:Mice; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D009765:Obesity / Q000150:complications*; D010196:Pancreatic Elastase / Q000378:metabolism* / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D010196:Pancreatic Elastase