UCSD. US: Inflammatory molecule LTB4 promotes insulin resistance in obese mice and blocking the LTB4 receptor prevents and reverses type 2 diabetes in this model.
Obesity causes inflammation, which can in turn lead to type 2
diabetes. What isn’t well established is how inflammation causes
diabetes — or what we can do to stop it. Researchers at University of
California, San Diego School of Medicine have discovered that the
inflammatory molecule LTB4 promotes insulin resistance, a first step in
developing type 2 diabetes. What’s more, the team found that genetically
removing the cell receptor that responds to LTB4, or blocking it with a
drug, improves insulin sensitivity in obese mice. The study is
published Feb. 23 by Nature Medicine.
“This study is important because it reveals a root cause of type 2
diabetes,” said Jerrold M. Olefsky, MD, professor of medicine, associate
dean for scientific affairs and senior author of the study. “And now
that we understand that LTB4 is the inflammatory factor causing insulin
resistance, we can inhibit it to break the link between obesity and
diabetes.”
Here’s what’s happening in obesity, according to Olefsky’s study.
Extra fat, particularly in the liver, activates resident macrophages,
the immune cells living there. These macrophages then do what they’re
supposed to do when activated — release LTB4 and other immune signaling
molecules to call up an influx of new macrophages. Then, in a positive
feedback loop, the newly arriving macrophages also get activated and
release even more LTB4 in the liver.
This inflammatory response would be a good thing if the body was
fighting off an infection. But when inflammation is chronic, as is the
case in obesity, all of this extra LTB4 starts activating other cells,
too. Like macrophages, nearby liver, fat and muscle cells also have LTB4
receptors on their cell surfaces and are activated when LTB4 binds
them. Now, in obesity, those cells become inflamed as well, rendering
them resistant to insulin.
Once Olefsky and his team had established this mechanism in their
obese mouse models, they looked for ways to inhibit it. First, they
genetically engineered mice that lack the LBT4 receptor. When that
approach dramatically improved the metabolic health of obese mice, they
also tried blocking the receptor with a small molecule inhibitor. This
particular compound was at one time being tested in clinical trials, but
was dropped when it didn’t prove all that effective in treating its
intended ailment. Olefsky’s team fed the prototype drug to their mice
and found that it worked just as well as genetic deletion at preventing —
and reversing — insulin resistance.
“When we disrupted the LTB4-induced inflammation cycle either through
genetics or a drug, it had a beautiful effect — we saw improved
metabolism and insulin sensitivity in our mice,” Olefsky said. “Even
though they were still obese, they were in much better shape.”
Co-authors of this study include Pingping Li, Da Young Oh, Gautam
Bandyopadhyay, William S. Lagakos, Saswata Talukdar, Olivia Osborn,
Andrew Johnson, Heekyung Chung, Rafael Mayoral, Michael Maris, Jachelle M
Ofrecio, Sayaka Taguchi, Min Lu, all at UC San Diego.
This research was funded, in part, by the National Institute of
Diabetes and Digestive and Kidney Diseases (DK033651, DK074868,
DK063491, DK09062), the Eunice Kennedy Shriver National Institute of
Child Health and Human Development, and Merck, Inc.