Body Weight-Independent Improvement of Endothelial and HDL Function After Roux-en-Y Gastric Bypass | Journal Scan

Study Questions:

Are the obesity-induced endothelial and high-density lipoprotein (HDL) dysfunction that rapidly improve after roux-en-Y gastric bypass surgery (RYGB) related to a glucagon-like peptide-1 (GLP-1) dependent mechanism?

Methods:

Obese male Wistar rats underwent two experiments: 1) RYGB sham-operated rats were either fed ad libitum (controls) or weight-matched to RYGB and followed for 8 days. 2) Rats were randomized to two treatment groups for the 8 days of follow-up: controls treated with either vehicle or liraglutide (0.2 mg/kg twice daily), and RYGB treated with either vehicle or the GLP-1 inhibitor exendin9-39 (10 ug/kg/h). Human studies consisted of a surgery group of 29 patients undergoing primary laparoscopic proximal RYGB. The control group consisted of 29 obese patients matched for body mass index, body weight, age, and gender to the RYGB group at week 12 after surgery.

Results:

Eight days after undergoing RYGB, the rats had higher plasma levels of bile acids and GLP-1, which was associated with improved endothelium-dependent relaxation compared to sham-operated controls. Compared to sham-operated rats, RYGB improved nitric oxide (NO) bioavailability due to higher endothelial Akt/NO synthase activation, reduced JNK-phosphorylation, and decreased oxidative stress. The protective effects of RYGB were prevented by exendin. Further, in patients and rats, RYGB rapidly reversed HDL dysfunction and restored the endothelium-protective properties including endothelial NO synthase activation, NO production, as well as anti-inflammatory, anti-apoptotic and anti-oxidant effects. Finally, RYGB restored HDL-mediated cholesterol efflux capacity. Sham-operated control rats treated with the GLP-1 analog liraglutide had 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.

Perspective:

RYGB has been shown to induce stable weight loss, improve obesity-associated comorbidities, and reduce cardiovascular mortality. Importantly, there is evidence that sleeve gastrectomy produces enhanced GLP-1 secretion and improvements in type 2 diabetes mellitus, independently from weight loss similar to RYGB. But the popular adjustable gastric banding, which is a restrictive and reversible procedure, is associated with comparably smaller increases in circulating GLP-1.

Clinical Topics: Dyslipidemia, Lipid Metabolism, Nonstatins

Keywords: Gastric Bypass, Gastrectomy, Cholesterol, Lipoproteins, HDL, Bile Acids and Salts, Biological Availability, Comorbidity, Control Groups, Endothelium, Glucagon-Like Peptide 1, Nitric Oxide, Nitric Oxide Synthase, Obesity, Morbid, Rats, Wistar, Weight Loss


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