Rapid and Body Weight-Independent Improvement of Endothelial and High-Density Lipoprotein Function After Roux-en-Y Gastric Bypass: Role of Glucagon-Like Peptide-1.
Osto, Elena MD, PhD *; Doytcheva, Petia MSc *; Corteville, Caroline MD; Bueter, Marco MD, PhD; Dorig, Claudia MSc; Stivala, Simona PhD; Buhmann, Helena MD; Colin, Sophie PhD; Rohrer, Lucia PhD; Hasballa, Reda MSc; Tailleux, Anne PhD; Wolfrum, Christian PhD; Tona, Francesco MD, PhD; Manz, Jasmin MSc; Vetter, Diana MD; Spliethoff, Kerstin DVM; Vanhoutte, Paul M. MD, PhD; Landmesser, Ulf MD; Pattou, Francois MD, PhD; Staels, Bart MD; Matter, Christian M. MD; Lutz, Thomas A. DVM, PhD *; Luscher, Thomas F. MD *
131(10):871-881, March 10, 2015.
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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 high-density 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 exendin9-39 (10 [mu]g[middle dot]kg-1[middle dot]h-1). 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 HDL-mediated 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.
(C) 2015 by the American College of Cardiology Foundation and the American Heart Association, Inc.