内皮NOX1通过骨骼肌线粒体功能障碍驱动肥胖

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 using endothelial cell washout experiments. Food/water intakes were not different from corresponding controls in high-fat fed NOX1-/y, Cdh5cre-NOX1CKO, or Cdh5cre-NOX1CKI mice, indicating no difference in energy intake. Instead, spontaneous activity, exercise capacity, mitochondrial oxygen consumption/ATP production, skeletal muscle mitochondrial function (ROS production and swelling activity), and mitochondrial cristae structure were all substantially improved in NOX1-/y or Cdh5cre-NOX1CKO mice, indicating augmented energy expenditure attributed to preserved skeletal muscle mitochondrial function. Supportively, Cdh5cre-NOX1CKI mice displayed deteriorated exercise capacity and skeletal muscle mitochondrial dysfunction. Endothelium-dependent vasorelaxation was restored in high-fat fed NOX1-/y or Cdh5cre-NOX1CKO mice, confirming improved endothelial function. RNA-sequencing identified 4 genes (Cntnap4 [contactin-associated protein-like 4], Sgsm1, Tll2, and Syt9) and 7 genes (Odf3l2, Col9a1 [collagen type IX alpha 1 chain], Cldn23, Atp5g2, Nkx6-3, Ntsr2, and Zfp69) significantly downregulated/upregulated in high-fat fed Cdh5cre-NOX1CKO mice, among which Cntnap4 and Col9a1 linked to muscular disorders. Importantly, we observed marked upregulation of NOX1 in isolated coronary arteries from human patients with obesity. Conclusions: Taken together, our data for the first time establish a novel and paradigm-shifting concept that endothelial NOX1 drives systematic metabolic phenotypes, via impairment in skeletal muscle mitochondrial dysfunction with novel genetic signatures. Tissue-specific targeting of endothelial NOX1 and novel candidate genes may prove to be robustly effective in treating obesity and metabolic syndrome.