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

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 &mgr;g·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.

[1]  Michael J. Davies,et al.  Glutathionylation Mediates Angiotensin II–Induced eNOS Uncoupling, Amplifying NADPH Oxidase‐Dependent Endothelial Dysfunction , 2014, Journal of the American Heart Association.

[2]  G. Schuler,et al.  Impaired HDL function in obese adolescents: Impact of lifestyle intervention and bariatric surgery , 2013, Obesity.

[3]  L. Aronne,et al.  Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: The SCALE Maintenance randomized study , 2014, International Journal of Obesity.

[4]  E. Topol,et al.  Relationship of paraoxonase 1 (PON1) gene polymorphisms and functional activity with systemic oxidative stress and cardiovascular risk. , 2008, JAMA.

[5]  A. Baron Insulin resistance and vascular function. , 2002, Journal of diabetes and its complications.

[6]  D. Kotler,et al.  Gastrointestinal changes after bariatric surgery. , 2014, Diabetes & metabolism.

[7]  G. Lewis,et al.  Mechanisms of incretin effects on plasma lipids and implications for the cardiovascular system. , 2012, Cardiovascular & hematological agents in medicinal chemistry.

[8]  S. Hunt,et al.  Health benefits of gastric bypass surgery after 6 years. , 2012, JAMA.

[9]  N. Alp,et al.  EPR quantification of vascular nitric oxide production in genetically modified mouse models. , 2004, Nitric oxide : biology and chemistry.

[10]  B. Franklin,et al.  Bariatric surgery and cardiovascular risk factors: a scientific statement from the American Heart Association. , 2011, Circulation.

[11]  J. Pernow,et al.  Glucagon-like peptide-1 relaxes rat conduit arteries via an endothelium-independent mechanism , 2005, Regulatory Peptides.

[12]  R. Busse,et al.  Phosphorylation of Thr495 Regulates Ca2+/Calmodulin-Dependent Endothelial Nitric Oxide Synthase Activity , 2001 .

[13]  M. Bessler,et al.  Comparison of Glucostatic Parameters After Hypocaloric Diet or Bariatric Surgery and Equivalent Weight Loss , 2011, Obesity.

[14]  A. Akhmedov,et al.  Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease. , 2011, The Journal of clinical investigation.

[15]  D. Mikhailidis,et al.  Glucagon‐like peptide‐1‐based therapies and cardiovascular disease: looking beyond glycaemic control , 2011, Diabetes, obesity & metabolism.

[16]  L. Aronne,et al.  Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: The SCALE Maintenance randomized study , 2013, International Journal of Obesity.

[17]  A. Remaley,et al.  Diet-Induced Weight Loss in Overweight or Obese Women and Changes in High-Density Lipoprotein Levels and Function , 2012, Obesity.

[18]  A. Dear,et al.  A GLP-1 receptor agonist liraglutide inhibits endothelial cell dysfunction and vascular adhesion molecule expression in an ApoE-/- mouse model , 2011, Diabetes & vascular disease research.

[19]  B. Green,et al.  GLP-1 and related peptides cause concentration-dependent relaxation of rat aorta through a pathway involving KATP and cAMP. , 2008, Archives of biochemistry and biophysics.

[20]  Avis J. Thomas,et al.  Roux-en-Y gastric bypass vs intensive medical management for the control of type 2 diabetes, hypertension, and hyperlipidemia: the Diabetes Surgery Study randomized clinical trial. , 2013, JAMA.

[21]  P. Schauer,et al.  Early effects of gastric bypass on endothelial function, inflammation, and cardiovascular risk in obese patients , 2011, Surgical Endoscopy.

[22]  C. L. le Roux,et al.  Roux-en-Y gastric bypass operation in rats. , 2012, Journal of visualized experiments : JoVE.

[23]  R. Gómez-Huelgas [Bariatric surgery versus conventional medical therapy for type 2 diabetes]. , 2012, Revista clinica espanola.

[24]  L. Kaplan,et al.  Roux-en-Y gastric bypass normalizes the blunted postprandial bile acid excursion associated with obesity , 2013, International Journal of Obesity.

[25]  Costantina Manes,et al.  Endothelial-Vasoprotective Effects of High-Density Lipoprotein Are Impaired in Patients With Type 2 Diabetes Mellitus but Are Improved After Extended-Release Niacin Therapy , 2010, Circulation.

[26]  J. Holst,et al.  Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. , 2004, American journal of physiology. Endocrinology and metabolism.

[27]  C. Calhau,et al.  Acute Improvement in Insulin Resistance After Laparoscopic Roux-en-Y Gastric Bypass: Is 3 Days Enough to Correct Insulin Metabolism? , 2012, Obesity Surgery.

[28]  J. Borén,et al.  c-Jun N-Terminal Kinase 2 Deficiency Protects Against Hypercholesterolemia-Induced Endothelial Dysfunction and Oxidative Stress , 2008, Circulation.

[29]  M. Raffaelli,et al.  Effect of Gastric Bypass Versus Diet on Cardiovascular Risk Factors , 2014, Annals of surgery.

[30]  A. Vollmar,et al.  Reliable in vitro measurement of nitric oxide released from endothelial cells using low concentrations of the fluorescent probe 4,5‐diaminofluorescein , 2001, FEBS letters.

[31]  R. Mahley,et al.  Swine lipoproteins and atherosclerosis. Changes in the plasma lipoproteins and apoproteins induced by cholesterol feeding. , 1975, Biochemistry.

[32]  T. Murata,et al.  Bile Acid Receptor TGR5 Agonism Induces NO Production and Reduces Monocyte Adhesion in Vascular Endothelial Cells , 2013, Arteriosclerosis, thrombosis, and vascular biology.

[33]  D. Drucker,et al.  Cardioprotective and Vasodilatory Actions of Glucagon-Like Peptide 1 Receptor Are Mediated Through Both Glucagon-Like Peptide 1 Receptor–Dependent and –Independent Pathways , 2008, Circulation.

[34]  Svati H Shah,et al.  Differential Metabolic Impact of Gastric Bypass Surgery Versus Dietary Intervention in Obese Diabetic Subjects Despite Identical Weight Loss , 2011, Science Translational Medicine.

[35]  D. Sorescu,et al.  Glp-1 analog, liraglutide, ameliorates hepatic steatosis and cardiac hypertrophy in C57BL/6J mice fed a Western diet. , 2012, American journal of physiology. Gastrointestinal and liver physiology.

[36]  A. Schürmann,et al.  Hepatic trans-Golgi action coordinated by the GTPase ARFRP1 is crucial for lipoprotein lipidation and assembly[S] , 2014, Journal of Lipid Research.

[37]  J. Holst,et al.  The effect of glucagon-like peptide 1 on cardiovascular risk , 2012, Nature Reviews Cardiology.

[38]  F. Horber,et al.  Laparoscopic Gastric Bypass Is Superior to Laparoscopic Gastric Banding for Treatment of Morbid Obesity , 2004, Annals of surgery.

[39]  Michael Karin,et al.  A central role for JNK in obesity and insulin resistance , 2002, Nature.

[40]  B. Wolfe,et al.  Effects of weight loss, induced by gastric bypass surgery, on HDL remodeling in obese women. , 2010, Journal of lipid research.

[41]  J. Ortega,et al.  Endothelial dysfunction in morbid obesity. , 2013, Current pharmaceutical design.

[42]  T. Münzel,et al.  Advanced spin trapping of vascular nitric oxide using colloid iron diethyldithiocarbamate. , 2002, Methods in enzymology.

[43]  D. Drucker,et al.  Pharmacology, physiology, and mechanisms of incretin hormone action. , 2013, Cell metabolism.

[44]  M. Melchiorre,et al.  Glucagon-like peptide-1 counteracts oxidative stress-dependent apoptosis of human cardiac progenitor cells by inhibiting the activation of the c-Jun N-terminal protein kinase signaling pathway. , 2012, Endocrinology.

[45]  K. Clément,et al.  Effect of bariatric surgery-induced weight loss on SR-BI-, ABCG1-, and ABCA1-mediated cellular cholesterol efflux in obese women. , 2011, The Journal of clinical endocrinology and metabolism.

[46]  D. Drucker,et al.  A Glucagon-Like Peptide-1 Analog Reverses the Molecular Pathology and Cardiac Dysfunction of a Mouse Model of Obesity , 2013, Circulation.

[47]  Gangyi Yang,et al.  GLP‐1 analogue prevents NAFLD in ApoE KO mice with diet and Acrp30 knockdown by inhibiting c‐JNK , 2013, Liver international : official journal of the International Association for the Study of the Liver.

[48]  A. von Eckardstein,et al.  Altered Activation of Endothelial Anti- and Proapoptotic Pathways by High-Density Lipoprotein from Patients with Coronary Artery Disease: Role of High-Density Lipoprotein–Proteome Remodeling , 2013, Circulation.

[49]  Alan C. Wilson,et al.  Lipid risk profile and weight stability after gastric restrictive operations for morbid obesity , 2000, Journal of Gastrointestinal Surgery.

[50]  A. von Eckardstein,et al.  High-density lipoprotein: vascular protective effects, dysfunction, and potential as therapeutic target. , 2014, Circulation research.

[51]  C. Kahn,et al.  Loss of insulin signaling in vascular endothelial cells accelerates atherosclerosis in apolipoprotein E null mice. , 2010, Cell metabolism.

[52]  L. Aronne,et al.  Obesity, adiposity, and dyslipidemia: a consensus statement from the National Lipid Association. , 2013, Journal of clinical lipidology.

[53]  J. Teixeira,et al.  Effect of weight loss by gastric bypass surgery versus hypocaloric diet on glucose and incretin levels in patients with type 2 diabetes. , 2008, The Journal of clinical endocrinology and metabolism.

[54]  R. Busse,et al.  Phosphorylation of Thr(495) regulates Ca(2+)/calmodulin-dependent endothelial nitric oxide synthase activity. , 2001, Circulation research.

[55]  Hua Xu,et al.  Exendin-4 protects endothelial cells from lipoapoptosis by PKA, PI3K, eNOS, p38 MAPK, and JNK pathways. , 2013, Journal of molecular endocrinology.

[56]  Yunan Tang,et al.  Overexpression of Endothelial Nitric Oxide Synthase Prevents Diet-Induced Obesity and Regulates Adipocyte Phenotype , 2012, Circulation research.

[57]  A. Dossat,et al.  Maintenance on a high-fat diet impairs the anorexic response to glucagon-like-peptide-1 receptor activation , 2011, Physiology & Behavior.