Endothelial NPR-C drives insulin resistance by disrupting Caveolin-1 and insulin receptor trafficking in obese mice

Obesity-induced insulin resistance is a critical precursor to metabolic dysfunction and type 2 diabetes, yet the precise endothelial mechanisms contributing to this remain incompletely understood. Endothelial dysfunction, often characterized by increased oxidative stress, plays a significant role in cardiometabolic diseases. Current treatments often target systemic insulin sensitivity, but a specific focus on endothelial insulin transport could offer novel therapeutic avenues. This study investigates the role of endothelial natriuretic peptide receptor C (NPR-C) in regulating insulin sensitivity.

Researchers investigated endothelial NPR-C's role in insulin resistance using obese mouse models. They performed endothelial-specific genetic manipulations: NPR-C deletion and NPR-C overexpression. To assess therapeutic potential, they utilized Cdh5 promoter-driven adeno-associated virus (AAV)-mediated NPR-C knockdown in mice with established obesity. Primary endpoints included glucose tolerance tests, insulin tolerance tests, and hyperinsulinemic-euglycemic clamp studies to evaluate systemic insulin sensitivity. They also analyzed insulin receptor (IR) membrane localization and intracellular trafficking, alongside Caveolin-1 expression and modification.

Endothelial NPR-C expression was increased in endothelial cells from adipose tissue and skeletal muscle of obese mice. Genetic deletion of endothelial NPR-C significantly improved insulin sensitivity, while its overexpression aggravated insulin resistance, as consistently demonstrated across glucose tolerance, insulin tolerance, and hyperinsulinemic-euglycemic clamp assays. Mechanistically, NPR-C impaired insulin uptake and transendothelial transport by reducing insulin receptor (IR) membrane localization and altering intracellular trafficking. The study revealed that NPR-C directly interacted with Caveolin-1 and promoted Tyr14 phosphorylation-dependent K48-linked ubiquitination and subsequent proteasomal degradation of Caveolin-1. This degradation disrupted caveolae function, which is crucial for IR trafficking.

Importantly, Cdh5 promoter-driven AAV-mediated NPR-C knockdown improved insulin sensitivity in mice with established obesity, suggesting a therapeutic potential.