Most recent update: Friday, February 21, 2020 - 10:45

Bariatric News - Cookies & privacy policy

You are here

LTB4 and insulin resistance

LTB4 promotes insulin resistance, possible treatment

In obesity, extra fat triggers inflammation by releasing LTB4, which binds to receptors on nearby macrophages and activates them. Credit: UC San Diego School of Medicine
Genetically removing the cell receptor that responds to LTB4, or blocking it with a drug, improves insulin sensitivity in obese mice

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. They also found that genetically removing the cell receptor that responds to LTB4, or blocking it with a drug, improves insulin sensitivity in obese mice.

"This study is important because it reveals a root cause of type 2 diabetes," said Dr Jerrold M Olefsky, 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."

The study, published in Nature Medicine, reports that extra fat, particularly in the liver, activates resident macrophages, the immune cells living there. These macrophages then release LTB4 and other immune signalling 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. However, 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. 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," said Olefsky. "Even though they were still obese, they were in much better.

Want more stories like this? Subscribe to Bariatric News!

Bariatric News
Keep up to date! Get the latest news in your inbox. NOTE: Bariatric News WILL NOT pass on your details to 3rd parties. However, you may receive ‘marketing emails’ sent by us on behalf of 3rd parties.