Can molecular ‘doormen’ pave way for new obesity treatments?

A new discovery could lead to new treatments for obesity, researchers report.

Fat cells are filled with droplets coated by molecules that act like hotel doormen. These doormen control cellular access for nutrients and for the exit of energy-supplying molecules called lipids.

In healthy individuals, there’s a fine balance between outgoing and incoming traffic in fat cells, supplying energy while preventing excessive spread of undesirable fat in the belly.

But in people with obesity, these cellular doormen open the gates far too wide in certain key fat cells, known as visceral fat cells, and let in too many carbohydrates without first burning off lipids. This leads to a ballooning of the size of visceral fat cells in the belly.

Researchers now report they have found the molecular regulator of this fat droplet doorman, and potential new treatments for obesity based on restoring healthy balance found in lean individuals.

The regulator, or commander, of these fat droplet sentinels is an enzyme called O-GlcNAc transferase (OGT), the researchers say.

Mice lacking the enzyme are lean, exhibit a dramatic reduction in the size of fat cells, and tend to burn off lipids first rather than taking in more carbohydrate fuel.

Conversely, the overexpression of OGT in mice triggers obesity by increasing intake of carbohydrates without burning off excess lipids.

“The commander of this doorman makes it easier for nutrients to get in, but harder for lipids to get out,” says Xiaoyong Yang, associate professor of comparative medicine and of cellular & molecular physiology at Yale University School of Medicine and senior author of the paper in Nature Communications.

In previous studies, Yang’s team found that overexpression of OGT in fat cells has another side effect—it signals the brain to consume more calories (essentially asking the brain to order another pizza).

“This makes OGT a very attractive target to pharmaceutically treat obesity,” Yang says.

The National Institutes of Health funded the work.

Source: Yale University

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