Editors' ChoicePhysiology

Neutrophils Suppress Insulin Signaling

Science Signaling  25 Sep 2012:
Vol. 5, Issue 243, pp. ec250
DOI: 10.1126/scisignal.2003633

Infiltration of adipose tissue by immune cells and inflammation of this tissue contribute to metabolic disorders associated with obesity. Neutrophils are one of the first cells recruited to sites of inflammation. Neutrophil elastase is secreted and has been reported to be taken up by cells, which results in the degradation of an insulin receptor substrate (IRS) adaptor protein important for insulin signaling. Neutrophil elastase can also stimulate Toll-like receptor 4 (TLR4) to promote proinflammatory signaling, which recruits other immune cells. Talukdar et al. examined the effect of neutrophil recruitment and neutrophil elastase on insulin signaling and glucose handling in obese mice fed a high-fat diet (DIO mice). The number of adipose tissue neutrophils and the mRNA abundance and activity of neutrophil elastase were increased in DIO mice compared with mice fed a normal diet. Treatment of DIO mice with a pharmacological inhibitor of neutrophil elastase improved glucose tolerance without affecting their weight. When fed the high-fat diet, neutrophil elastase knockout (NEKO) mice exhibited improved insulin sensitivity and markedly reduced numbers of adipose tissue neutrophils compared with wild-type mice. In vivo tests of liver function showed increased hepatocyte responsiveness to insulin and decreased lipogenesis in NEKO mice. Western blotting of liver and white adipose tissue confirmed that insulin stimulation of downstream components was increased in NEKO mice. The liver and adipose tissue of NEKO mice had increased abundance of Irs1, and administration of neutrophil elastase to wild-type mice reduced the abundance of Irs1 in the liver and insulin-induced and basal phosphorylation of Akt (a kinase in the insulin pathway). On the basis of studies with recombinant neutrophil elastase and intraperitoneal macrophages from wild-type and Tlr4-deficient mice, neutrophil elastase triggered the Tlr4-dependent induction of a proinflammatory response. Consistent with the ability of neutrophil elastase to induce the expression of proinflammatory genes, transcripts for such proinflammatory markers were less abundant in NEKO mouse liver. These data suggest that neutrophil infiltration of fat and liver and the release of neutrophil elastase in these tissues contribute to insulin resistance and compromised organ function as a result of reduced Irs1 and induction of inflammation.

S. Talukdar, D. Y. Oh, G. Bandyopadhyay, D. Li, J. Xu, J. McNelis, M. Lu, P. Li, Q. Yan, Y. Zhu, J. Ofrecio, M. Lin, M. B. Brenner, J. M. Olefsky, Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat. Med. 18, 1407–1412 (2012). [PubMed]