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

doi:10.1016/j.cmet.2013.03.005

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

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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 language	English
Pages (from-to)	534-548
Number of pages	15
Journal	Cell Metabolism
Volume	17
Issue number	4
DOIs	https://doi.org/10.1016/j.cmet.2013.03.005
Publication status	Published - 2 Apr 2013
Externally published	Yes

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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

@article{6158c92fa7e243f0a3a61d4fbcafe955,

title = "Imbalance between neutrophil elastase and its inhibitor α1-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 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.",

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

note = "Funding Information: 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. ",

year = "2013",

month = apr,

day = "2",

doi = "10.1016/j.cmet.2013.03.005",

language = "English",

volume = "17",

pages = "534--548",

journal = "Cell Metabolism",

issn = "1550-4131",

publisher = "Cell Press",

number = "4",

}

Mansuy-Aubert, V, Zhou, QL, Xie, X, Gong, Z, Huang, JY, Khan, AR, Aubert, G, Candelaria, K, Thomas, S, Shin, DJ, Booth, S, Baig, SM, Bilal, A, Hwang, D, Zhang, H, Lovell-Badge, R, Smith, SR, Awan, FR & Jiang, ZY 2013, 'Imbalance between neutrophil elastase and its inhibitor α1-antitrypsin in obesity alters insulin sensitivity, inflammation, and energy expenditure', Cell Metabolism, vol. 17, no. 4, pp. 534-548. https://doi.org/10.1016/j.cmet.2013.03.005

TY - JOUR

T1 - Imbalance between neutrophil elastase and its inhibitor α1-antitrypsin in obesity alters insulin sensitivity, inflammation, and energy expenditure

AU - Mansuy-Aubert, Virginie

AU - Zhou, Qiong L.

AU - Xie, Xiangyang

AU - Gong, Zhenwei

AU - Huang, Jun Yuan

AU - Khan, Abdul R.

AU - Aubert, Gregory

AU - Candelaria, Karla

AU - Thomas, Shantele

AU - Shin, Dong Ju

AU - Booth, Sarah

AU - Baig, Shahid M.

AU - Bilal, Ahmed

AU - Hwang, Daehee

AU - Zhang, Hui

AU - Lovell-Badge, Robin

AU - Smith, Steven R.

AU - Awan, Fazli R.

AU - Jiang, Zhen Y.

N1 - Funding Information: 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.

PY - 2013/4/2

Y1 - 2013/4/2

N2 - 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.

AB - 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.

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U2 - 10.1016/j.cmet.2013.03.005

DO - 10.1016/j.cmet.2013.03.005

M3 - Article

C2 - 23562077

AN - SCOPUS:84875900576

SN - 1550-4131

VL - 17

SP - 534

EP - 548

JO - Cell Metabolism

JF - Cell Metabolism

IS - 4

ER -

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

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