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

Elena Osto; Petia Doytcheva; Caroline Corteville; Marco Bueter; Claudia Dörig; Simona Stivala; Helena Buhmann; Sophie Colin; Lucia Rohrer; Reda Hasballa; Anne Tailleux; Christian Wolfrum; Francesco Tona; Jasmin Manz; Diana Vetter; Kerstin Spliethoff; Paul M Vanhoutte; Ulf Landmesser; Francois Pattou; Bart Staels; Christian M Matter; Thomas A Lutz; Thomas F Lüscher

doi:10.1161/CIRCULATIONAHA.114.011791

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

Circulation. 2015 Mar 10;131(10):871-81. doi: 10.1161/CIRCULATIONAHA.114.011791. Epub 2015 Feb 11.

Authors

Elena Osto¹, Petia Doytcheva², Caroline Corteville², Marco Bueter², Claudia Dörig², Simona Stivala², Helena Buhmann², Sophie Colin², Lucia Rohrer², Reda Hasballa², Anne Tailleux², Christian Wolfrum², Francesco Tona², Jasmin Manz², Diana Vetter², Kerstin Spliethoff², Paul M Vanhoutte², Ulf Landmesser², Francois Pattou², Bart Staels², Christian M Matter², Thomas A Lutz², Thomas F Lüscher²

Affiliations

¹ From Centre for Molecular Cardiology, University of Zurich and University Heart Center, Cardiology, University Hospital Zurich, Switzerland (E.O., P.D., S.S., J.M., U.L., C.M.M., T.F.L.); Institute of Veterinary Physiology, University of Zurich, Switzerland (P.D., C.C., C.D., H.B., K.S., T.A.L.); Department of Surgery (M.B., D.V.) and Institute of Clinical Chemistry (L.R., R.H.), University Hospital Zurich, Switzerland; Université Lille 2, INSERM UMR1011, EGID, Institut Pasteur de Lille, France (S.C., A.T., B.S.); Department of Health Sciences and Technology, ETH Zurich, Switzerland (C.W.); Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Italy (F.T.); State Key Laboratory for Pharmaceutical Biotechnology and Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, University of Hong Kong, SAR (P.M.V.); and Department of Endocrine Surgery, Lille University Hospital, France (F.P.). elena.osto@uzh.ch.
² From Centre for Molecular Cardiology, University of Zurich and University Heart Center, Cardiology, University Hospital Zurich, Switzerland (E.O., P.D., S.S., J.M., U.L., C.M.M., T.F.L.); Institute of Veterinary Physiology, University of Zurich, Switzerland (P.D., C.C., C.D., H.B., K.S., T.A.L.); Department of Surgery (M.B., D.V.) and Institute of Clinical Chemistry (L.R., R.H.), University Hospital Zurich, Switzerland; Université Lille 2, INSERM UMR1011, EGID, Institut Pasteur de Lille, France (S.C., A.T., B.S.); Department of Health Sciences and Technology, ETH Zurich, Switzerland (C.W.); Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Italy (F.T.); State Key Laboratory for Pharmaceutical Biotechnology and Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, University of Hong Kong, SAR (P.M.V.); and Department of Endocrine Surgery, Lille University Hospital, France (F.P.).

PMID: 25673670
DOI: 10.1161/CIRCULATIONAHA.114.011791

Abstract

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 μg·kg(-1)·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.

Keywords: bariatric surgery; endothelium; glucagon-like peptide-1; lipoproteins; nitric oxide; obesity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Animals
Antioxidants / physiology
Body Weight / physiology*
Case-Control Studies
Cells, Cultured
Diet, High-Fat / adverse effects
Disease Models, Animal
Endothelium, Vascular / pathology
Endothelium, Vascular / physiology*
Female
Gastric Bypass
Glucagon-Like Peptide 1 / physiology*
Humans
Lipoproteins, HDL / physiology*
Male
Nitric Oxide / physiology
Obesity / physiopathology
Obesity / surgery*
Oxidative Stress / physiology
Proto-Oncogene Proteins c-akt / physiology
Rats
Rats, Wistar
Signal Transduction
Treatment Outcome
Weight Loss / physiology*

Substances

Antioxidants
Lipoproteins, HDL
Nitric Oxide
Glucagon-Like Peptide 1
Proto-Oncogene Proteins c-akt