How controlling fat 'doormen' could lead to new obesity treatments

Targeting the enzyme O-GlcNAc transferase with drugs may offer a new way to combat obesity, Yale researchers say. (Creative Commons CC0)

In healthy people, fat cells take in nutrients and let out energy-supplying lipids in a finely tuned process that prevents the excessive buildup of belly fat. When this process goes wrong, however, obesity can emerge.

Scientists at Yale University have discovered a new regulator of fat transport—an enzyme they believe could be targeted with drugs to help control obesity. They described the discovery in the journal Nature Communications.

The enzyme is called O-GlcNAc transferase (OGT), and its role in maintaining a healthy metabolism has been widely reported. In 2015, for example, a Johns Hopkins University team discovered that high levels of OGT disrupt energy production in a way that leads to high blood sugar.

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The new study from Yale focuses on OGT’s impact on “fat droplet sentinels,” which are molecules inside of fat cells that act like “doormen” for nutrients and fat, according to a statement from the university. The researchers discovered mice that lack the enzyme are lean and their cells burn off lipids at a faster rate than they take in carbohydrates. Mice that overexpress OGT, by contrast, take in more carbohydrates, they reported.

"The commander of this doorman makes it easier for nutrients to get in, but harder for lipids to get out," said senior author Xiaoyong Yang, Ph.D., associate professor of comparative medicine and of cellular and molecular physiology at Yale's medical school, in a statement.

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Yale has undertaken a variety of research efforts aimed at reducing the buildup of unhealthy fat in the body. In 2018, a team at the Yale Cardiovascular Research Center published a mouse study that showed that inhibiting the VEGF-A receptor FLT1 normalized fat transport in the body and prevented weight gain.

As for OGT overexpression, it doesn’t just control the flow of nutrients and fats. It also sends signals to the brain that trigger overeating, Yang’s team previously discovered. "This makes OGT a very attractive target to pharmaceutically treat obesity," he said.

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