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.).
Circulation. 2015 Mar 10;131(10):871-81. doi: 10.1161/CIRCULATIONAHA.114.011791. Epub 2015 Feb 11.
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.
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.
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.
Roux-en-Y 胃旁路手术（RYGB）可降低病态肥胖患者的体重和心血管死亡率。胰高血糖素样肽-1（GLP-1）似乎通过一种与体重减轻无关的方式介导 RYGB 的代谢益处。本研究在大鼠和患者中探讨了肥胖诱导的内皮和高密度脂蛋白（HDL）功能障碍是否通过 GLP-1 依赖的机制在 RYGB 后迅速得到改善。
在饮食诱导肥胖大鼠接受 RYGB 8 天后，与自由喂养的假手术对照组和体重匹配的接受 RYGB 的假手术大鼠相比，更高的血浆胆汁酸和 GLP-1 水平与改善的内皮依赖性松弛相关。与假手术大鼠相比，RYGB 通过提高内皮 Akt/NO 合酶的激活、降低 c-Jun 氨基末端激酶磷酸化和减少氧化应激来改善一氧化氮（NO）生物利用度。GLP-1 受体拮抗剂 exendin9-39（10 μg·kg(-1)·h(-1)）可阻止 RYGB 的保护作用。此外，在患者和大鼠中，RYGB 迅速逆转了 HDL 功能障碍并恢复了脂蛋白的内皮保护特性，包括内皮一氧化氮合酶的激活、NO 的产生以及抗炎、抗凋亡和抗氧化作用。最后，RYGB 恢复了 HDL 介导的胆固醇流出能力。为了证明增加的 GLP-1 信号的作用，假手术对照组大鼠接受 GLP-1 类似物利拉鲁肽（0.2 mg/kg 每天两次）治疗 8 天，恢复了 NO 生物利用度并改善了内皮依赖性松弛和 HDL 内皮保护特性，模拟了 RYGB 的作用。
RYGB 通过 GLP-1 介导的机制迅速逆转肥胖诱导的内皮功能障碍并恢复 HDL 的内皮保护特性。本研究在大鼠和患者中的转化发现揭示了病态肥胖中新型、与体重无关的心血管保护机制。
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