Endothelial NOX1 Drives Obesity via Skeletal Muscle Mitochondrial Dysfunction

作者：Kai Huang, Yuanli Huang, Y Zhang, Yixuan Zhang, Nicholas Hatch, Julie K. Freed, Hua Cai · 发表于：Circulation Research · 年份：2026 · DOI：10.1161/circresaha.125.326768 · 被引用次数：2 · 研究领域：Adipose Tissue and Metabolism、GDF15 and Related Biomarkers、Adipokines, Inflammation, and Metabolic Diseases

BACKGROUND: Presently, we investigated hypothesized roles and mechanisms of cell type–specific, selective activation of different vascular NOX (NADPH oxidase) isoforms in obesity and metabolic syndrome. Methods: Wild-type, NOX1/2/4 global knockout mice, endothelial/VSMC-specific NOX1 knockout mice, or vascular endothelial-speicifc NOX1 knockin mice were exposed to high-fat diet feeding prior to phenotypical analyses of obesity and metabolic syndrome, as well as of exercise capacity, skeletal muscle mitochondrial function, and novel genetic signatures. Results: Expression of NOX1 was significantly upregulated in wild-type mice fed a high-fat diet. Global knockout of NOX1 (NOX1 −/y ), rather than of NOX2/NOX4, markedly abrogated high-fat feeding–induced body weight/fat mass gain, preadipocyte differentiation, fatty liver, glucose intolerance, and insulin/leptin resistance. Intriguingly, endothelial-specific NOX1 knockout (Cdh5cre [cadherin 5 (vascular endothelial cadherin) promoter–driven Cre recombinase (endothelial-specific Cre expression)]-NOX1CKO), rather than vascular smooth muscle-specific NOX1 knockout (Myh11cre [myosin heavy chain 11 promoter–driven Cre recombinase (smooth muscle–specific Cre expression)]-NOX1CKO), substantially alleviated obesity and metabolic syndrome. Consistently, endothelial-specific NOX1 knockin mice (Cdh5cre-NOX1CKI) fed a high-fat diet displayed exaggerated metabolic disorders. Endothelial cell–specific knockout/knockin of NOX1 was confirmed usi...