Lacteal junction zippering protects against diet-induced obesity

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 () and (; also known as ) 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.

Identification of ILK as a critical regulator of VEGFR 3 signalling and lymphatic vascular growth

“…The importance of the lymphatic vasculature is demonstrated by its numerous physiological functions, including maintenance of fluid homeostasis, facilitation of immune response and uptake of lipids and vitamins. Moreover, it is involved in pathological conditions such as primary and secondary lymphoedema, obesity development, tumour cell dissemination and growth, reverse cholesterol transport, hypertension, glaucoma, inflammation and regeneration or damage after myocardial infarction (Karkkainen et al , ; Skobe et al , ; Harvey et al , ; Wilting et al , ; Martel et al , ; Thomson et al , ; Huang et al , ; Klotz et al , ; Escobedo et al , ; Gousopoulos et al , ; Lund et al , ; Tatin et al , ; Zhang et al , ). Growth of lymphatic vessels, known as lymphangiogenesis, is critically regulated by vascular endothelial growth factor receptor‐3 (VEGFR3) signalling, also required for normal blood vascular development (Dumont et al , ; Veikkola et al , ).…”

Heterotypic inter-GPCR ß-arrestin coupling regulates lymphatic endothelial junctional architecture in murine lymph nodes

“…We propose that junctional remodeling provides a mechanism for high permeability seen in sinus lining lymphatic endothelial cells of lymph nodes. Previous studies in lymphatic endothelial cell junctions have described the presence of button-like junctions which are actively maintained in lymph nodes (51) and in lymphatic capillaries of the small intestinal villi (65). Indeed, this property may allow lymph fluid flow and efficient lymphocyte egress under physiological conditions.…”

Lymphatic Vasculature in Energy Homeostasis and Obesity

“…In the intestine, cholesterol, long-chain fatty acids, and fatsoluble vitamins are absorbed by intestinal epithelial cells, and repackaged in enterocytes into large (200-1000 nm) triglycerideloaded particles called "chylomicrons" (Tso and Balint, 1986;Zhang et al, 2018). Each intestinal villus contains a single lacteal, which is a lymphatic capillary with button-like junctions (Zhang et al, 2018).…”

“…In the intestine, cholesterol, long-chain fatty acids, and fatsoluble vitamins are absorbed by intestinal epithelial cells, and repackaged in enterocytes into large (200-1000 nm) triglycerideloaded particles called "chylomicrons" (Tso and Balint, 1986;Zhang et al, 2018). Each intestinal villus contains a single lacteal, which is a lymphatic capillary with button-like junctions (Zhang et al, 2018). Most chylomicrons are absorbed by the lacteals, from which they are transported to submucosal and mesenteric collecting lymphatic vessels, then into the thoracic duct, and finally to the blood circulation (Oliver and Srinivasan, 2008;Randolph and Miller, 2014).…”