Imbalance between neutrophil elastase and its inhibitor alpha1-antitrypsin in obesity alters insulin sensitivity, inflammation, and energy expenditure Journal Article

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Authors: Mansuy-Aubert, V; Zhou, Q. L.; Xie, X; Gong, Z.; Huang, J. Y.; Khan, A. R.; Aubert, G; Candelaria, K.; Thomas, S.; Shin, D. J.; Booth, S.; Baig, S. M.; Bilal, A.; Hwang, D.; Zhang, H; Lovell-Badge, R.; Smith, S. R.; Awan, F. R.; Jiang, Z. Y.
Article Title: Imbalance between neutrophil elastase and its inhibitor alpha1-antitrypsin in obesity alters insulin sensitivity, inflammation, and energy expenditure
Abstract: The molecular mechanisms involved in the development of obesity and related complications remain unclear. Here, we report that obese mice and human subjects have increased activity of neutrophil elastase (NE) and decreased serum levels of the NE inhibitor alpha1-antitrypsin (A1AT, SerpinA1). NE null (Ela2(-/-)) mice and A1AT transgenic mice were resistant to high-fat diet (HFD)-induced body weight gain, insulin resistance, inflammation, and fatty liver. NE inhibitor GW311616A reversed insulin resistance and body weight gain in HFD-fed mice. Ela2(-/-) mice also augmented circulating high molecular weight (HMW) adiponectin levels, phosphorylation of AMP-activated protein kinase (AMPK), and fatty acid oxidation (FAO) in the liver and brown adipose tissue (BAT) and uncoupling protein (UCP1) levels in the BAT. These data suggest that the A1AT-NE system regulates AMPK signaling, FAO, and energy expenditure. The imbalance between A1AT and NE contributes to the development of obesity and related inflammation, insulin resistance, and liver steatosis.
Journal Title: Cell metabolism
Volume: 17
Issue: 4
ISSN: 1932-7420; 1550-4131
Publisher: Elsevier Inc  
Journal Place: United States
Date Published: 2013
Start Page: 534
End Page: 548
Language: eng
DOI/URL:

10.1016/j.cmet.2013.03.005
Notes: LR: 20150409; CI: Copyright (c) 2013; GR: MC_U117562207/Medical Research Council/United Kingdom; GR: R01 DK094025/DK/NIDDK NIH HHS/United States; GR: R01 DK094025/DK/NIDDK NIH HHS/United States; GR: U117512772/Medical Research Council/United Kingdom; JID: 101233170; 0 (Adiponectin); 0 (Fatty Acids); 0 (GW 311616); 0 (Ion Channels); 0 (Leptin); 0 (Mitochondrial Proteins); 0 (Piperidines); 0 (alpha 1-Antitrypsin); 0 (mitochondrial uncoupling protein); EC 2.7.- (Protein Kinases); EC 2.7.1.- (AMP-activated protein kinase kinase); EC 3.4.21.37 (Leukocyte Elastase); NIHMS458557; OID: NLM: NIHMS458557; OID: NLM: PMC3646573; 2012/08/20 [received]; 2013/01/02 [revised]; 2013/03/11 [accepted]; ppublish