Could a glaucoma drug also fight obesity?

Scientists have examined many ways to "beige" unhealthy white fat, turning it into energy-burning brown fat to fight obesity. But what if we could stop fat from entering body tissues in the first place? Researchers at Yale University believe they’ve found a target for preventing fat uptake at the point of entry, and a new class of glaucoma drugs that could help accomplish that feat.

Once consumed, dietary fats are carried by little packets known as chylomicrons from the digestive system to the bloodstream. Those chylomicrons are absorbed into the body’s cells through lymphatic vessels called lacteals. The team found that if they narrowed lacteal junctions, they could stop chylomicrons from entering tissues.

Previous studies had shown that inhibiting production of vascular endothelial growth factor A (VEGF-A)—a protein known to stimulate the formation of blood vessels—can block the growth of lacteals. That appeared to limit fat uptake, but the exact mechanism was not clear.

The Yale study involved mice that normally express two VEGF-A receptors called FLT1 and NRP1, said lead author Feng Zhang, Ph.D., a scientist with the Yale Cardiovascular Research Center, in an interview with FierceBiotechResearch. The team genetically modified the mice to delete FLT1 and NRP1 in endothelial cells and fed them a high-fat diet for eight weeks. Mice that had the receptors disabled didn’t gain weight, while normal mice doubled in weight, the researchers reported in their paper, which was published in Science.

What exactly happened with those receptors knockout mice? Normally, lacteals have button-like gaps along the lining, through which chylomicrons can slip into the surrounding tissues. However, in the engineered mice, the gaps turned into narrower, zipper-shaped openings, which made it hard for fat-carrying chylomicrons to pass through.

"We show that FLT1 and NRP1 are decoy factors of VEGF-A signaling. When we remove the two receptors, VEGF-A signaling is over-activated," Zhang said. Therefore, he believes VEGF-A signaling activating agents would achieve the same results. What's more, the team found an inhibitor of Rho kinase (ROCK) can also induce lacteal junction zippering and prevent fat absorption.

ROCK inhibition is a well-established treatment path for glaucoma. Last December, Aerie Pharmaceuticals’ Rhopressa became the first FDA-approved ROCK inhibitor to treat that disease.

Many recent studies have focused on treating obesity by lowering levels of unhealthy white fat and increasing brown fat. Researchers at American University discovered a reservoir of dormant stem cells in the body that could transform into healthy fat, for example. Another team from American University and the University of Michigan identified a signaling pathway called CHRNA2 that helps turn white fat into brown fat, and they found that nicotine can promote the process.

But Zhang and collaborators now suggest that lacteal could be a target for future obesity therapies, especially because there are already drugs on the market targeting key players like ROCK. "Based on our results, we believe that such drugs should be tested for effects on lipid absorption and weight loss," Zhang said.

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