O besity is a worldwide health problem because of the associated increased morbidity and cardiovascular mortality. Accompanying metabolic disorders such as insulin resistance and type 2 diabetes mellitus and risk factors such as dyslipidemia increase the disease risk linked to obesity. In particular, obesity induces endothelial dysfunction, which precedes atherosclerosis, but also contributes to insulin resistance in tissues Background-Roux-en-Y gastric bypass (RYGB) reduces body weight and cardiovascular mortality in morbidly obese patients. Glucagon-like peptide-1 (GLP-1) seems to mediate the metabolic benefits of RYGB partly in a weight lossindependent manner. The present study investigated in rats and patients whether obesity-induced endothelial and highdensity lipoprotein (HDL) dysfunction is rapidly improved after RYGB via a GLP-1-dependent mechanism. Methods and Results-Eight days after RYGB in diet-induced obese rats, higher plasma levels of bile acids and GLP-1 were associated with improved endothelium-dependent relaxation compared with sham-operated controls fed ad libitum and sham-operated rats that were weight matched to those undergoing RYGB. Compared with the sham-operated rats, RYGB improved nitric oxide (NO) bioavailability resulting from higher endothelial Akt/NO synthase activation, reduced c-Jun amino terminal kinase phosphorylation, and decreased oxidative stress. The protective effects of RYGB were prevented by the GLP-1 receptor antagonist exendin 9-39 (10 μg·kg). Furthermore, in patients and rats, RYGB rapidly reversed HDL dysfunction and restored the endothelium-protective properties of the lipoprotein, including endothelial NO synthase activation, NO production, and anti-inflammatory, antiapoptotic, and antioxidant effects. Finally, RYGB restored HDLmediated cholesterol efflux capacity. To demonstrate the role of increased GLP-1 signaling, sham-operated control rats were treated for 8 days with the GLP-1 analog liraglutide (0.2 mg/kg twice daily), which restored NO bioavailability and improved endothelium-dependent relaxations and HDL endothelium-protective properties, mimicking the effects of RYGB. Conclusions-RYGB rapidly reverses obesity-induced endothelial dysfunction and restores the endothelium-protective properties of HDL via a GLP-1-mediated mechanism. The present translational findings in rats and patients unmask novel, weight-independent mechanisms of cardiovascular protection in morbid obesity. Furthermore, obesity and insulin resistance result in proatherogenic dyslipidemia, 4 characterized by high low-density lipoprotein and triglyceride and low high-density lipoprotein (HDL) cholesterol plasma levels.1,5 Abnormal HDL remodeling and maturation have been reported in obese subjects with an HDL profile similar to that of subjects with established cardiovascular disease. 5 In addition, pathological situations associated with obesity, in particular type 2 diabetes mellitus 6 and coronary artery disease, 7 impair the physiological protective properties of HDL, which preserves en...

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