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White blood cell enzyme contributes to inflammation and obesity

03.04.2013
An imbalance between an enzyme called neutrophil elastase and its inhibitor causes inflammation, obesity, insulin resistance, and fatty liver in mice and humans -- providing a new therapeutic target for these health conditions

Many recent studies have suggested that obesity is associated with chronic inflammation in fat tissues. Researchers at Sanford-Burnham Medical Research Institute (Sanford-Burnham) have discovered that an imbalance between an enzyme called neutrophil elastase and its inhibitor causes inflammation, obesity, insulin resistance, and fatty liver disease.

This enzyme is produced by white blood cells called neutrophils, which play an important role in the body's immune defense against bacteria. The researchers found that obese humans and mice have increased neutrophil elastase activity and decreased levels of á1-antitrypsin, a protein that inhibits the elastase. When the team reversed this imbalance in a mouse model and fed them a high-fat diet, the mice were resistant to body weight gain, insulin resistance (a precursor to type 2 diabetes), and fatty liver disease. Their study appears April 2 in Cell Metabolism.

"The imbalance between neutrophil elastase and its inhibitor, á1-antitrypsin, is likely an important contributing factor in the development of obesity, inflammation, and other health problems. Shifting this balance—by either reducing one or increasing the other—could provide a new therapeutic approach to preventing and treating obesity and several obesity-related conditions," said Zhen Jiang, Ph.D., assistant professor in Sanford-Burnham's Diabetes and Obesity Research Center at Lake Nona, Orlando and senior author of the study.

What happens when you reduce neutrophil elastase levels

This study began when Jiang and his team noticed that neutrophil elastase levels are particularly high and á1-antitrypsin levels are low in a mouse model of obesity. Then they saw the same thing in blood samples from human male volunteers.

To further probe this curious neutrophil elastase-obesity relationship, the researcher turned once again to mouse models. They found that mice completely lacking the neutrophil elastase enzyme don't get as fat as normal mice, even when fed a high-fat diet. Those mice were also protected against inflammation, insulin resistance, and fatty liver. The same was true in a mouse model genetically modified to produce human á1-antitrypsin, which inhibits neutrophil elastase.

Normal mice on a high-fat diet were also protected against inflammation, insulin resistance, and fatty liver when they were given a chemical compound that inhibits neutrophil elastase. This finding helps validate the team's conclusions about neutrophil elastase's role in inflammation and metabolism and also suggests that a medicinal drug could someday be developed to target this enzyme.

Mechanism: how neutrophil elastase influences inflammation and metabolism

How do high neutrophil elastase levels increase inflammation and cause weight gain and other metabolic problems?

Jiang and his team began connecting the mechanistic dots. They discovered that neutrophil elastase-deficient mice have increased levels of several factors, including adiponectin, AMPK, and fatty acid oxidation. These are known for their roles in increasing energy expenditure, thus helping the body burn excess fat.

This research was funded by a Sanford-Burnham start-up fund, the American Diabetes Association (grant 7-11-BS-72), U.S. National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases grant R01DK094025), and U.K. Medical Research Council (grant U117512772).

The study was co-authored by Virginie Mansuy-Aubert, Sanford-Burnham; Qiong L. Zhou, Sanford-Burnham; Xiangyang Xie, Sanford-Burnham; Zhenwei Gong, Sanford-Burnham; Jun-Yuan Huang, Sanford-Burnham; Abdul R. Khan, Sanford-Burnham, National Institute for Biotechnology and Genetic Engineering, Pakistan; Gregory Aubert, Sanford-Burnham; Karla Candelaria, Sanford-Burnham; Shantele Thomas, Sanford-Burnham; Dong-Ju Shin, Sanford-Burnham; Sarah Booth, U.K. National Institute of Medical Research; Shahid M. Baig, National Institute for Biotechnology and Genetic Engineering, Pakistan; Ahmed Bilal, Allied Hospital, Punjab Medical College; Daehee Hwang, Institute for Systems Biology; Hui Zhang, Institute for Systems Biology, Johns Hopkins University; Robin Lovell-Badge, U.K. National Institute of Medical Research; Steven R. Smith, Sanford-Burnham, Translational Research Institute, Florida Hospital; Fazli R. Awan, National Institute for Biotechnology and Genetic Engineering, Pakistan; Zhen Y. Jiang, Sanford-Burnham

About Sanford-Burnham Medical Research Institute

Sanford-Burnham Medical Research Institute is dedicated to discovering the fundamental molecular causes of disease and devising the innovative therapies of tomorrow. Sanford-Burnham takes a collaborative approach to medical research with major programs in cancer, neurodegeneration, diabetes, and infectious, inflammatory, and childhood diseases. The Institute is recognized for its National Cancer Institute-designated Cancer Center and expertise in drug discovery technologies. Sanford-Burnham is a nonprofit, independent institute that employs 1,200 scientists and staff in San Diego (La Jolla), California and Orlando (Lake Nona), Florida. For more information, visit us at sanfordburnham.org.

Heather Buschman | EurekAlert!
Further information:
http://www.sanfordburnham.org

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