TY - JOUR
T1 - Visceral obesity and insulin resistance associate with CD36 deletion in lymphatic endothelial cells
AU - Cifarelli, Vincenza
AU - Appak-Baskoy, Sila
AU - Peche, Vivek S.
AU - Kluzak, Andrew
AU - Shew, Trevor
AU - Narendran, Ramkumar
AU - Pietka, Kathryn M.
AU - Cella, Marina
AU - Walls, Curtis W.
AU - Czepielewski, Rafael
AU - Ivanov, Stoyan
AU - Randolph, Gwendalyn J.
AU - Augustin, Hellmut G.
AU - Abumrad, Nada A.
N1 - Funding Information:
This work was supported by National Institutes of Health grants DK060022 (NAA), DK111175 (NAA) and by the Leducq Foundation Transatlantic Network of Excellence “Lymph vessels in obesity and cardiovascular disease” (HGA). We acknowledge Pilot and Feasibility grants from the Nutrition and Obesity Research Center (NORC) P30 DK056341 (VC) and the Digestive Diseases Research Cores Center P30 DK052574 (VC) at Washington University, and the assistance of Washington University NORC Cellular and Molecular Biology Core and Animal Model Research Core. R.S.C. was supported by a fellowship award “FA-2020-01-IBD-1 from the Lawrence C. Pakula, MD IBD Education & Innovation Fund”. Confocal data were obtained in the Washington University Center for Cellular Imaging (WUCCI) using a Zeiss LSM 880 Airyscan confocal Microscope purchased with support from the Office of Research Infrastructure Programs (ORIP), NIH Office of the Director grant OD021629.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - Disruption of lymphatic lipid transport is linked to obesity and type 2 diabetes (T2D), but regulation of lymphatic vessel function and its link to disease remain unclear. Here we show that intestinal lymphatic endothelial cells (LECs) have an increasing CD36 expression from lymphatic capillaries (lacteals) to collecting vessels, and that LEC CD36 regulates lymphatic integrity and optimizes lipid transport. Inducible deletion of CD36 in LECs in adult mice (Cd36ΔLEC) increases discontinuity of LEC VE-cadherin junctions in lacteals and collecting vessels. Cd36ΔLEC mice display slower transport of absorbed lipid, more permeable mesenteric lymphatics, accumulation of inflamed visceral fat and impaired glucose disposal. CD36 silencing in cultured LECs suppresses cell respiration, reduces VEGF-C-mediated VEGFR2/AKT phosphorylation and destabilizes VE-cadherin junctions. Thus, LEC CD36 optimizes lymphatic junctions and integrity of lymphatic lipid transport, and its loss in mice causes lymph leakage, visceral adiposity and glucose intolerance, phenotypes that increase risk of T2D.
AB - Disruption of lymphatic lipid transport is linked to obesity and type 2 diabetes (T2D), but regulation of lymphatic vessel function and its link to disease remain unclear. Here we show that intestinal lymphatic endothelial cells (LECs) have an increasing CD36 expression from lymphatic capillaries (lacteals) to collecting vessels, and that LEC CD36 regulates lymphatic integrity and optimizes lipid transport. Inducible deletion of CD36 in LECs in adult mice (Cd36ΔLEC) increases discontinuity of LEC VE-cadherin junctions in lacteals and collecting vessels. Cd36ΔLEC mice display slower transport of absorbed lipid, more permeable mesenteric lymphatics, accumulation of inflamed visceral fat and impaired glucose disposal. CD36 silencing in cultured LECs suppresses cell respiration, reduces VEGF-C-mediated VEGFR2/AKT phosphorylation and destabilizes VE-cadherin junctions. Thus, LEC CD36 optimizes lymphatic junctions and integrity of lymphatic lipid transport, and its loss in mice causes lymph leakage, visceral adiposity and glucose intolerance, phenotypes that increase risk of T2D.
UR - http://www.scopus.com/inward/record.url?scp=85107527431&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-23808-3
DO - 10.1038/s41467-021-23808-3
M3 - Article
C2 - 34099721
AN - SCOPUS:85107527431
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3350
ER -