Loss of Bone Morphogenetic Protein-Binding Endothelial Regulator Causes Insulin Resistance

Authors

Hua Mao
Luge Li
Qiying Fan
Aude Angelini
Pradip K Saha
Huaizhu Wu
Christie M Ballantyne
Sean M Hartig
Liang Xie
Xinchun Pi

Publication Date

3-26-2021

Journal

Nature Communications

DOI

10.1038/s41467-021-22130-2

PMID

33772019

PMCID

PMC7997910

PubMedCentral® Posted Date

3-26-2021

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Blood Glucose, Carrier Proteins, Cells, Cultured, Diabetes Mellitus, Type 2, Endothelium, Vascular, Glucose Intolerance, HEK293 Cells, Humans, Hyperinsulinism, Insulin Resistance, Mice, Inbred C57BL, Mice, Knockout, Niemann-Pick C1 Protein, Receptors, Leptin, Signal Transduction, Mice, Insulin signalling, Type 2 diabetes, Endocrine system and metabolic diseases

Abstract

Accumulating evidence suggests that chronic inflammation of metabolic tissues plays a causal role in obesity-induced insulin resistance. Yet, how specific endothelial factors impact metabolic tissues remains undefined. Bone morphogenetic protein (BMP)–binding endothelial regulator (BMPER) adapts endothelial cells to inflammatory stress in diverse organ microenvironments. Here, we demonstrate that BMPER is a driver of insulin sensitivity. Both global and endothelial cell-specific inducible knockout of BMPER cause hyperinsulinemia, glucose intolerance and insulin resistance without increasing inflammation in metabolic tissues in mice. BMPER can directly activate insulin signaling, which requires its internalization and interaction with Niemann-Pick C1 (NPC1), an integral membrane protein that transports intracellular cholesterol. These results suggest that the endocrine function of the vascular endothelium maintains glucose homeostasis. Of potential translational significance, the delivery of BMPER recombinant protein or its overexpression alleviates insulin resistance and hyperglycemia in high-fat diet-fed mice and Leprdb/db (db/db) diabetic mice. We conclude that BMPER exhibits therapeutic potential for the treatment of diabetes.

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