Loss of bone morphogenetic protein-binding endothelial regulator causes insulin resistance

Nat Commun. 2021 Mar 26;12(1):1927. doi: 10.1038/s41467-021-22130-2.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Cells, Cultured
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism
  • Endothelium, Vascular / metabolism*
  • Glucose Intolerance / genetics
  • HEK293 Cells
  • Humans
  • Hyperinsulinism / genetics
  • Hyperinsulinism / metabolism
  • Insulin Resistance / genetics*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Niemann-Pick C1 Protein / genetics
  • Niemann-Pick C1 Protein / metabolism
  • Receptors, Leptin / genetics
  • Receptors, Leptin / metabolism
  • Signal Transduction / genetics*


  • Blood Glucose
  • Carrier Proteins
  • Niemann-Pick C1 Protein
  • Receptors, Leptin
  • crossveinless 2 protein, mouse