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.

• Authors: 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
• Journal: Cell metabolism (Cell Metab) Vol. 17 Issue 4 Pg. 534-48 (Apr 02 2013) ISSN: 1932-7420 [Electronic] United States
• PMID: 23562077 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Adiponectin
• Fatty Acids
• GW 311616
• Ion Channels
• Leptin
• Mitochondrial Proteins
• Piperidines
• UCP1 protein, human
• Ucp1 protein, mouse
• Uncoupling Protein 1
• alpha 1-Antitrypsin
• Protein Kinases
• AMP-Activated Protein Kinase Kinases
• Leukocyte Elastase

Topics

• AMP-Activated Protein Kinase Kinases
• Adiponectin (blood)
• Adipose Tissue, Brown (metabolism)
• Animals
• Diet, High-Fat
• Energy Metabolism
• Fatty Acids (chemistry, metabolism)
• Fatty Liver (complications, metabolism, pathology)
• Hep G2 Cells
• Humans
• Inflammation
• Insulin Resistance
• Ion Channels (metabolism)
• Leptin (metabolism)
• Leukocyte Elastase (antagonists & inhibitors, blood, metabolism)
• Liver (metabolism)
• Metabolome
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Obese
• Mice, Transgenic
• Mitochondrial Proteins (metabolism)
• Obesity (complications, metabolism, pathology)
• Oxidation-Reduction
• Phosphorylation
• Piperidines (pharmacology)
• Protein Kinases (metabolism)
• Uncoupling Protein 1
• Weight Gain (drug effects)
• alpha 1-Antitrypsin (blood, genetics, metabolism)