Angiopoietin-2–integrin α5β1 signaling enhances vascular fatty acid transport and prevents ectopic lipid-induced insulin resistance

Hosung Bae, Ki Yong Hong, Choong-kun Lee, Cholsoon Jang, Seung-Jun Lee, Kibaek Choe, Stefan Offermanns, Yulong He (), Hyuek Jong Lee and Gou Young Koh ()
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Hosung Bae: Institute for Basic Science
Ki Yong Hong: Dongguk University Ilsan Hospital
Choong-kun Lee: Institute for Basic Science
Cholsoon Jang: Princeton University
Seung-Jun Lee: Institute for Basic Science
Kibaek Choe: Korea Advanced Institute of Science and Technology (KAIST)
Stefan Offermanns: Max Planck Institute for Heart and Lung Research
Yulong He: Soochow University
Hyuek Jong Lee: Institute for Basic Science
Gou Young Koh: Institute for Basic Science

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: Abstract Proper storage of excessive dietary fat into subcutaneous adipose tissue (SAT) prevents ectopic lipid deposition-induced insulin resistance, yet the underlying mechanism remains unclear. Here, we identify angiopoietin-2 (Angpt2)–integrin α5β1 signaling as an inducer of fat uptake specifically in SAT. Adipocyte-specific deletion of Angpt2 markedly reduced fatty acid uptake and storage in SAT, leading to ectopic lipid accumulation in glucose-consuming organs including skeletal muscle and liver and to systemic insulin resistance. Mechanistically, Angpt2 activated integrin α5β1 signaling in the endothelium and triggered fatty acid transport via CD36 and FATP3 into SAT. Genetic or pharmacological inhibition of the endothelial integrin α5β1 recapitulated adipocyte-specific Angpt2 knockout phenotypes. Our findings demonstrate the critical roles of Angpt2–integrin α5β1 signaling in SAT endothelium in regulating whole-body fat distribution for metabolic health and highlight adipocyte–endothelial crosstalk as a potential target for prevention of ectopic lipid deposition-induced lipotoxicity and insulin resistance.

Date: 2020
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DOI: 10.1038/s41467-020-16795-4

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