3:56 PM
 | 
Aug 09, 2018
 |  BC Extra  |  Preclinical News

New biological insight could lead to obesity treatment

By identifying a mechanism in dietary fat uptake, researchers from Yale University School of Medicine suggest a compound marketed for glaucoma could have therapeutic applications in obesity. The study was published Thursday in Science.

Dietary fats are packaged into chylomicrons for transport into lymphatics through lacteal capillaries in the intestine. The mechanisms controlling chylomicron uptake into lacteal vessels are unknown.

The Yale researchers found that vascular endothelial growth factor A (VEGF-A) signaling modulates lacteal junctions, which "zip" up and block chylomicron passage when VEGF-A levels are high, thereby blocking dietary fat uptake.

The authors defined the role two VEGF-A receptors play in endothelial fat uptake: neuropilin 1 (NRP1) and vascular endothelial growth factor receptor 1 (FLT1; VEGFR-1). In a mouse model of high fat diet-induced obesity, knockout of both NRP1 and FLT1 in the endothelium reduced weight gain, increased VEGF-A signaling and developed more impermeable zipper junctions compared with one gene or none knocked out.

Feng Zhang, an associate research scientist at Yale and an author on the paper, told BioCentury expression of NRP1 and FLT1 outside the intestine could make them difficult to drug for obesity.

The researchers instead sought to target the lacteal junction adhesion molecule VE-cadherin (CD144, cadherin-5), as increased VEGF-A signaling led to loss of VE-cadherin anchoring at lacteal junctions.

They tested a tool compound inhibitor of ρ kinase, a downstream target of NRP1 and FLT1, which can inhibit VE-cadherin anchoring. In mice, the tool inhibitor mimicked the effects of NRP1/FLT1 knockout by inducing a similar zippering of the lacteal junctions to block chylomicron uptake.

The Yale researchers have filed a patent covering composition of matter for ρ kinase inhibition to prevent lipid absorption.

Zhang said the Yale team plans to next test ρ kinase knockout in mouse models of high fat diet-induced obesity and other metabolic syndromes. He noted that ρ kinase inhibitors are approved by FDA to treat glaucoma and thus are known to be safe.

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