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Science. 2018 Aug 10;361(6402):599-603. doi: 10.1126/science.aap9331.

Lacteal junction zippering protects against diet-induced obesity.

Author information

1
Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06510-3221, USA.
2
Department of Basic, Preventive and Clinical Science, University of Transylvania, 500019 Brasov, Romania.
3
INSERM U970, Paris Cardiovascular Research Center, 75015 Paris, France.
4
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
5
Departments of Comparative Medicine and Pathology, Vascular Biology and Therapeutics Program and Integrative Cell Signaling and Neurobiology of Metabolism Program, Yale University School of Medicine, New Haven, CT, USA.
6
Department of Cell Biology, University of Connecticut Health Center, Farmington, CT, 06030-3501, USA.
7
Department of Pathology and Laboratory Medicine, Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH 45237-0507, USA.
8
Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA.
9
Department of Pharmacology, Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA.
10
Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06510-3221, USA. anne.eichmann@yale.edu.

Abstract

Excess dietary lipid uptake causes obesity, a major global health problem. Enterocyte-absorbed lipids are packaged into chylomicrons, which enter the bloodstream through intestinal lymphatic vessels called lacteals. Here, we show that preventing lacteal chylomicron uptake by inducible endothelial genetic deletion of Neuropilin1 (Nrp1) and Vascular endothelial growth factor receptor 1 (Vegfr1; also known as Flt1) renders mice resistant to diet-induced obesity. Absence of NRP1 and FLT1 receptors increased VEGF-A bioavailability and signaling through VEGFR2, inducing lacteal junction zippering and chylomicron malabsorption. Restoring permeable lacteal junctions by VEGFR2 and vascular endothelial (VE)-cadherin signaling inhibition rescued chylomicron transport in the mutant mice. Zippering of lacteal junctions by disassembly of cytoskeletal VE-cadherin anchors prevented chylomicron uptake in wild-type mice. These data suggest that lacteal junctions may be targets for preventing dietary fat uptake.

PMID:
30093598
PMCID:
PMC6317738
DOI:
10.1126/science.aap9331
[Indexed for MEDLINE]
Free PMC Article

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