Endothelial NPR-C promotes insulin resistance via Caveolin-1-mediated insulin transcytosis.

Obesity-induced insulin resistance contributes to metabolic dysfunction and type 2 diabetes, yet the endothelial mechanisms involved remain incompletely understood. Here, we identify endothelial natriuretic peptide receptor C (NPR-C) as a key regulator of insulin transport and insulin sensitivity. NPR-C expression was increased in endothelial cells from adipose tissue and skeletal muscle of obese mice. Endothelial-specific deletion of NPR-C improved insulin sensitivity, whereas endothelial NPR-C overexpression aggravated insulin resistance, as demonstrated by glucose tolerance, insulin tolerance, and hyperinsulinemic-euglycemic clamp. Mechanistically, NPR-C impaired insulin uptake and transendothelial transport by reducing insulin receptor (IR) membrane localization and altering intracellular trafficking. NPR-C directly interacted with Caveolin-1 and promoted Tyr14 phosphorylation-dependent K48-linked ubiquitination and proteasomal degradation of Caveolin-1, disrupting caveolae function and impairing IR trafficking. Importantly, Cdh5 promoter-driven adeno-associated virus-mediated NPR-C knockdown improved insulin sensitivity in mice with established obesity. Together, these findings identify endothelial NPR-C as a regulator of Caveolin-1 stability and IR trafficking and suggest NPR-C as a potential therapeutic target for obesity-associated insulin resistance.