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 reports about: > Biotechnology > Cancer > Diabetes > Genetic clues > Lake Baikal > Pakistan > Translational Research > blood cell > blood sample > childhood disease > fatty liver > health problem > high-fat diet > insulin resistance > liver disease > mouse model > synthetic biology > weight gain > white blood cell
Rochester scientists discover gene controlling genetic recombination rates
23.04.2018 | University of Rochester
One step closer to reality
20.04.2018 | Max-Planck-Institut für Entwicklungsbiologie
Physicists at the Laboratory for Attosecond Physics, which is jointly run by Ludwig-Maximilians-Universität and the Max Planck Institute of Quantum Optics, have developed a high-power laser system that generates ultrashort pulses of light covering a large share of the mid-infrared spectrum. The researchers envisage a wide range of applications for the technology – in the early diagnosis of cancer, for instance.
Molecules are the building blocks of life. Like all other organisms, we are made of them. They control our biorhythm, and they can also reflect our state of...
University of Connecticut researchers have created a biodegradable composite made of silk fibers that can be used to repair broken load-bearing bones without the complications sometimes presented by other materials.
Repairing major load-bearing bones such as those in the leg can be a long and uncomfortable process.
Study published in the journal ACS Applied Materials & Interfaces is the outcome of an international effort that included teams from Dresden and Berlin in Germany, and the US.
Scientists at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) together with colleagues from the Helmholtz-Zentrum Berlin (HZB) and the University of Virginia...
Novel highly efficient and brilliant gamma-ray source: Based on model calculations, physicists of the Max PIanck Institute for Nuclear Physics in Heidelberg propose a novel method for an efficient high-brilliance gamma-ray source. A giant collimated gamma-ray pulse is generated from the interaction of a dense ultra-relativistic electron beam with a thin solid conductor. Energetic gamma-rays are copiously produced as the electron beam splits into filaments while propagating across the conductor. The resulting gamma-ray energy and flux enable novel experiments in nuclear and fundamental physics.
The typical wavelength of light interacting with an object of the microcosm scales with the size of this object. For atoms, this ranges from visible light to...
Stable joint cartilage can be produced from adult stem cells originating from bone marrow. This is made possible by inducing specific molecular processes occurring during embryonic cartilage formation, as researchers from the University and University Hospital of Basel report in the scientific journal PNAS.
Certain mesenchymal stem/stromal cells from the bone marrow of adults are considered extremely promising for skeletal tissue regeneration. These adult stem...
13.04.2018 | Event News
12.04.2018 | Event News
09.04.2018 | Event News
23.04.2018 | Physics and Astronomy
23.04.2018 | Physics and Astronomy
23.04.2018 | Trade Fair News