Lacteal junction zippering protects against diet-induced obesity

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / metabolism
  • Cadherins / antagonists & inhibitors
  • Cadherins / metabolism
  • Chylomicrons / adverse effects
  • Chylomicrons / metabolism*
  • Diet, High-Fat / adverse effects*
  • Dietary Fats / adverse effects
  • Dietary Fats / metabolism*
  • Enterocytes / metabolism
  • Gene Deletion
  • Intestinal Absorption / genetics
  • Intestinal Absorption / physiology
  • Male
  • Mice
  • Mice, Knockout
  • Neuropilin-1 / genetics*
  • Obesity / etiology*
  • Obesity / genetics*
  • Signal Transduction
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor Receptor-1 / genetics*
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Antigens, CD
  • Cadherins
  • Chylomicrons
  • Dietary Fats
  • Vascular Endothelial Growth Factor A
  • cadherin 5
  • Neuropilin-1
  • Flt1 protein, mouse
  • Kdr protein, mouse
  • Vascular Endothelial Growth Factor Receptor-1
  • Vascular Endothelial Growth Factor Receptor-2