Taurochenodeoxycholic acid alleviates obesity-induced endothelial dysfunction

Abstract Background and Aims Obesity is a global health challenge significantly increasing cardiovascular disease (CVD) burden. Effective prevention and treatment necessitate targeting early pathological changes, particularly obesity-induced endothelial dysfunction (ED). This study aimed to characterize ED heterogeneity in non-hypertensive obese (NHO) individuals, investigate the association of serum metabolites with obesity-induced ED, and identify potentially predictive and therapeutic metabolites. Methods Utilizing wire myograph, this study assessed ED of ex vivo arterioles from omental adipose tissue of 213 NHO patients, categorized into metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO). Targeted metabolomic profiling identified associations between serum metabolites and ED. Results Obesity-induced ED in NHO patients lacked correlations with many traditional cardiovascular risk factors. The MHO and MUO individuals exhibited similar ED and metabolomic profile characteristics. Serum metabolomics identified bile acids (BAs), particularly chenodeoxycholic acid (CDCA), as negatively correlated with ED in NHO patients. Taurochenodeoxycholic acid (TCDCA), a taurine-conjugated derivative of CDCA, protected against obesity-induced ED and hypertension. Mechanistically, endothelial Farnesoid X receptor (FXR) deletion aggravated obesity-induced ED and hypertension, negating the beneficial effects of bariatric surgery or TCDCA treatment. The TCDCA-FXR activation in endothelial cells upregulated ATF4 transcription, which was suppressed by PHB1, thereby enhancing serine and one-carbon metabolism. Conclusions This study suggests CDCA as a promising biomarker for identification of obesity-induced ED. Taurochenodeoxycholic acid demonstrates significant therapeutic potential for alleviating various forms of obesity-induced ED. This effect is mediated by the endothelial TCDCA-FXR-PHB1-ATF4 axis, which upregulates serine and one-carbon metabolism, thereby offering a novel strategy to delay the onset of hypertension and other CVDs.