Endothelial NOX1 Drives Obesity via Skeletal Muscle Mitochondrial Dysfunction.

Area of Science:

• Cardiovascular Biology
• Metabolic Syndrome Research
• Oxidative Stress Mechanisms

Background:

• Obesity and metabolic syndrome involve complex cellular mechanisms.
• NADPH oxidase (NOX) isoforms play roles in vascular function and disease.
• Cell type-specific functions of NOX isoforms in metabolic disorders are not fully understood.

Purpose of the Study:

• To investigate the role of endothelial NADPH oxidase 1 (NOX1) in obesity and metabolic syndrome.
• To elucidate the mechanisms by which NOX1 influences metabolic phenotypes.
• To identify potential therapeutic targets for metabolic disorders.

Main Methods:

• Utilized high-fat diet-induced obesity mouse models with global and cell-specific NOX1 knockouts (endothelial and vascular smooth muscle).
• Assessed metabolic parameters including body weight, fat mass, glucose tolerance, and insulin/leptin resistance.
• Evaluated energy expenditure, mitochondrial function in skeletal muscle, and endothelial function.
• Performed RNA-sequencing to identify gene expression changes.

Main Results:

• Global and endothelial-specific NOX1 knockout significantly ameliorated obesity, fatty liver, and insulin/leptin resistance without altering energy intake.
• Endothelial NOX1 knockout improved skeletal muscle mitochondrial function, exercise capacity, and endothelial vasorelaxation.
• Knockout of NOX2 or NOX4 isoforms did not show similar protective effects.
• Upregulation of NOX1 was observed in coronary arteries of human obesity patients.

Conclusions:

• Endothelial NOX1 is a key driver of obesity and metabolic syndrome, primarily through impaired skeletal muscle mitochondrial function.
• Targeting endothelial NOX1 and associated novel genetic factors presents a promising therapeutic strategy for metabolic diseases.