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Left: In fat tissue from a lean mouse, neutrophil elastase and a1-antitrypsin levels are
balanced. Right: In fat tissue from an obese mouse, they are imbalanced -- neutrophil
elastase levels are high (dark staining) and a1-antitrypsin levels are low.
Image Credit: Sanford-Burnham Medical Research Instituten.
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White blood cells contribute to inflammation and obesity
An imbalance between the neutrophil elastase enzyme 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 α1-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, α1-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 occurs with reduced neutrophil elastase levels
This study began when Jiang and his team noticed that neutrophil elastase levels are particularly high and α1-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 α1-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.
Original article: http://www.eurekalert.org/pub_releases/2013-04/smri-wbc040213.php
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