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.


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*


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