Lacteal junction zippering protects against diet-induced obesity

Feng Zhang; Georgia Zarkada; Jinah Han; Jinyu Li; Alexandre Dubrac; Roxana Ola; Gael Genet; Kevin Boyé; Pauline Michon; Steffen E. Künzel; Joao Paulo Camporez; Abhishek K. Singh; Guo Hua Fong; Michael Simons; Patrick Tso; Carlos Fernández-Hernando; Gerald I. Shulman; William C. Sessa; Anne Eichmann

doi:10.1126/science.aap9331

Lacteal junction zippering protects against diet-induced obesity

Feng Zhang, Georgia Zarkada, Jinah Han, Jinyu Li, Alexandre Dubrac, Roxana Ola, Gael Genet, Kevin Boyé, Pauline Michon, Steffen E. Künzel, Joao Paulo Camporez, Abhishek K. Singh, Guo Hua Fong, Michael Simons, Patrick Tso, Carlos Fernández-Hernando, Gerald I. Shulman, William C. Sessa, Anne Eichmann^*

^*Corresponding author for this work

51 Citations (Scopus)

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.

Original language	English
Journal	Science
Volume	361
Issue number	6402
Pages (from-to)	599-603
Number of pages	5
ISSN	0036-8075
DOIs	https://doi.org/10.1126/science.aap9331
Publication status	Published - 2018
Externally published	Yes

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Zhang, F., Zarkada, G., Han, J., Li, J., Dubrac, A., Ola, R., Genet, G., Boyé, K., Michon, P., Künzel, S. E., Camporez, J. P., Singh, A. K., Fong, G. H., Simons, M., Tso, P., Fernández-Hernando, C., Shulman, G. I., Sessa, W. C., & Eichmann, A. (2018). Lacteal junction zippering protects against diet-induced obesity. Science, 361(6402), 599-603. https://doi.org/10.1126/science.aap9331

Zhang, F, Zarkada, G, Han, J, Li, J, Dubrac, A, Ola, R, Genet, G, Boyé, K, Michon, P, Künzel, SE, Camporez, JP, Singh, AK, Fong, GH, Simons, M, Tso, P, Fernández-Hernando, C, Shulman, GI, Sessa, WC & Eichmann, A 2018, 'Lacteal junction zippering protects against diet-induced obesity', Science, vol. 361, no. 6402, pp. 599-603. https://doi.org/10.1126/science.aap9331

@article{01d9e5712c0c4ae085273c6b786a8647,

title = "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 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.",

author = "Feng Zhang and Georgia Zarkada and Jinah Han and Jinyu Li and Alexandre Dubrac and Roxana Ola and Gael Genet and Kevin Boy{\'e} and Pauline Michon and K{\"u}nzel, {Steffen E.} and Camporez, {Joao Paulo} and Singh, {Abhishek K.} and Fong, {Guo Hua} and Michael Simons and Patrick Tso and Carlos Fern{\'a}ndez-Hernando and Shulman, {Gerald I.} and Sessa, {William C.} and Anne Eichmann",

year = "2018",

doi = "10.1126/science.aap9331",

language = "English",

volume = "361",

pages = "599--603",

journal = "Science",

issn = "0036-8075",

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TY - JOUR

T1 - Lacteal junction zippering protects against diet-induced obesity

AU - Zhang, Feng

AU - Zarkada, Georgia

AU - Han, Jinah

AU - Li, Jinyu

AU - Dubrac, Alexandre

AU - Ola, Roxana

AU - Genet, Gael

AU - Boyé, Kevin

AU - Michon, Pauline

AU - Künzel, Steffen E.

AU - Camporez, Joao Paulo

AU - Singh, Abhishek K.

AU - Fong, Guo Hua

AU - Simons, Michael

AU - Tso, Patrick

AU - Fernández-Hernando, Carlos

AU - Shulman, Gerald I.

AU - Sessa, William C.

AU - Eichmann, Anne

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

U2 - 10.1126/science.aap9331

DO - 10.1126/science.aap9331

M3 - Journal article

C2 - 30093598

AN - SCOPUS:85051362596

SN - 0036-8075

VL - 361

SP - 599

EP - 603

JO - Science

JF - Science

IS - 6402

ER -

Lacteal junction zippering protects against diet-induced obesity

Abstract

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