Endothelial cystathionine-γ-lyase (CTH) regulates body weight and insulin resistance in mice fed a high-fat diet

Hydrogen sulfide (H₂S) has been reported to play a critical role in vascular function and metabolism, yet specific molecular mechanisms remain largely unknown. Given this importance and the role of endothelium in metabolic health, we hypothesized that endothelial cystathionine-γ-lyase deficiency (ecCTH-KO) could modulate metabolic function influencing insulin sensitivity and weight gain. To test this, we examined body weight, adipose tissue inflammation, glucose metabolism, and insulin signaling in ecCTH-KO and wild-type (WT) mice under a high-fat diet (HFD) (45% fat). ecCTH-KO mice exhibited significantly greater weight gain than WT mice despite similar food intake, with increased epididymal (eWAT) and mesenteric white adipose tissue (mWAT), but unchanged brown adipose tissue (BAT) mass. Importantly, reduced UCP1 expression was observed in eWAT suggesting decreased energy expenditure, while MCP-1 and IL-6 expression was elevated in mWAT, indicating augmented adipose-specific inflammation. Metabolically, ecCTH-KO mice displayed significantly reduced sulfane sulfur levels in adipose tissue and skeletal muscle along with impaired glucose tolerance and insulin resistance, confirmed by increased HOMA-IR values and reduced insulin-stimulated AKT phosphorylation in skeletal muscle and liver. Lastly, insulin dependent GLUT4 translocation was also impaired in skeletal muscle. These findings demonstrate that endothelial CTH deficiency significantly contributes to weight gain and insulin resistance by increasing adiposity and inflammation with concomitant disruption of skeletal muscle insulin signaling, revealing a crucial and previously unknown role of vascular sulfane sulfur in weight gain and glucose metabolism in skeletal muscle.