Rapid and Body Weight-Independent Improvement of Endothelial and HDL Function After Roux-en-Y Gastric Bypass: Role of Glucagon-Like Peptide-1
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 loss-independent manner. The present study investigated in rats and patients whether obesity-induced endothelial and HDL dysfunction are 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 to sham-operated controls fed ad libitum and sham-operated rats that were weight-matched to those undergoing RYGB. Compared to sham-operated rats, RYGB improved nitric oxide (NO) bioavailability due to higher endothelial Akt/NO synthase activation, reduced JNK-phosphorylation and decreased oxidative stress. The protective effects of RYGB were prevented by the GLP-1 receptor antagonist exendin9-39 (10ug/kg/h). Further, in patients and rats RYGB rapidly reversed HDL dysfunction and restored the endothelium-protective properties of the lipoprotein, including eNOS activation, NO production as well as anti-inflammatory, anti-apoptotic and anti-oxidant effects. Finally, RYGB restored HDL-mediated cholesterol efflux capacity. To demonstrate the role of increased GLP-1 signaling, sham-operated control rats were treated for eight days with the GLP-1 analog liraglutide (0.2 mg/kg twice daily), which restored NO bioavailability, 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.
- Received June 18, 2014.
- Revision received November 26, 2014.
- Accepted December 29, 2014.