Imbalance between neutrophil elastase and its inhibitor α1-antitrypsin in obesity alters insulin sensitivity, inflammation, and energy expenditure

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

Research output: Contribution to journalArticle

109 Scopus citations

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 α1-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.

Original languageEnglish (US)
Pages (from-to)534-548
Number of pages15
JournalCell Metabolism
Volume17
Issue number4
DOIs
StatePublished - Apr 2 2013

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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    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. (2013). Imbalance between neutrophil elastase and its inhibitor α1-antitrypsin in obesity alters insulin sensitivity, inflammation, and energy expenditure. Cell Metabolism, 17(4), 534-548. https://doi.org/10.1016/j.cmet.2013.03.005