Imbalance between Neutrophil Elastase and its Inhibitor alpha(1)-Antitrypsin in Obesity Alters Insulin Sensitivity, Inflammation, and Energy Expenditure

Mansuy-Aubert, Virginie, Zhou, Qiong L., Xie, Xiangyang, Gong, Zhenwei, Huang, Jun-Yuan, Khan, Abdul R., Aubert, Gregory, Candelaria, Karla, Thomas, Shantele, Shin, Dong-Ju, Booth, Sarah, Baig, Shahid M., Bilal, Ahmed, Hwang, Daehee, Zhang, Hui, Lovell-Badge, Robin, Smith, Steven R., Awan, Fazli R., Jiang, Zhen Y.

We wish to thank Julio Ayala, Jennifer Ayala, John Shelley, and the Sanford-Burnham Medical Research Institute (SBMRI) Cardiometabolic Phenotyping Core for excellent help with the CLAMS study and histology and Annette Khaled, Rebecca Boohaker, Mangala Soundarapandian, Ling Lai, Rita Luther, Darrin Kuystermans, and Teresa Leone for technical help. We appreciate Philipp Scherer, Tim Osborne, Guy Salvesen, Dan Kelly, Dev Sikder, and Sheila Collin for comments and Shonna Small for administrative support. Z.Y.J. is supported by research grants from the American Diabetes Association (7-11-BS-72) and NIH grant R01 DK094025. X.X. is supported by a James and Esther King Postdoctoral Fellowship. R.L.-B. is funded by the UK Medical Research Council (U117512772). K.C. is supported by a minority undergraduate internship from the American Diabetes Association (1-13-MUI-04). Z.Y.J. wrote the manuscript. The authors have no conflict of interest regarding this work.

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 alpha 1-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.

Imbalance between Neutrophil Elastase and its Inhibitor alpha(1)-Antitrypsin in Obesity Alters Insulin Sensitivity, Inflammation, and Energy Expenditure Article