Abstract 59: Vascular Glucagon-like Peptide 1 (GLP-1) Signaling Is Reduced In Obesity-related Hypertension In Female Rats

Abstract

Obesity is a major risk factor for hypertension. Obesity-related hypertension impacts more women than men, but the underlying mechanisms remain unclear. GLP-1, an incretin released after food intake, exerts vasculo-protective effects. Human studies have shown that GLP-1 levels are decreased in obese patients. We hypothesized that vascular GLP-1 signaling is reduced in obesity and weight loss rescues this signaling. Eight-week-old female Wistar rats were randomized into three groups: LEAN (n=9) received a chow diet (5% fat, 48.7% carbohydrate [3.2% sucrose], 24.1% protein) for 28 weeks, OBESE (n=7) received a Western diet (21% fat, 50% carbohydrate [34% sucrose], 20% protein) for 28 weeks, and reverse obese (rOBESE) (n=7) received a Western diet for 18 weeks followed by 12 weeks of chow diet. The OBESE group exhibited increased body weight (395.6 vs. 285.4g LEAN, p<0.0001) and body mass index (6.8 vs. 5.1kg/m 2 LEAN, p<0.01), while the rOBESE group lost weight (337.0 vs. 395.6g OBESE, p<0.01). Direct measurement of blood pressure (BP) using a pressure-volume catheter inserted in the carotid artery revealed increased systolic (142.8 vs. 117.2mmHg LEAN, p<0.001), diastolic (125.0 vs. 92.7mmHg LEAN, p<0.001), and mean arterial BP (130.9 vs. 107.9mmHg LEAN, p<0.001) in the OBESE group. The rOBESE group sustained elevated systolic BP (139.1 vs.117.2mmHg LEAN, p<0.05). Endothelium-dependent vasodilation studies assessed by wire myograph demonstrated that the OBESE group exhibited impaired response to acetylcholine (Emax: 82.7% vs. 97.9% LEAN, p<0.001). Similar vascular impairment was observed in the rOBESE group (EMax: 81.3% vs 97.9% LEAN, p<0.001). Strikingly, while decreased GLP-1 serum levels in the OBESE group (10.6 vs. 18.4pM/mL LEAN, p<0.05) returned to normal levels in the rOBESE group (19.4 vs.18.4pM/mL LEAN), GLP-1 receptor protein expression was reduced in both groups (24% decrease in OBESE, 52% decrease in rOBESE) as compared to LEAN. Our results support that GLP-1 signaling is implicated in obesity-related vascular dysfunction in females and weight loss does not guarantee recovery of protective GLP-1 signaling nor improvement of vasodilation. Conclusion: GLP-1 is a potential therapeutic target for obesity-related hypertension in females.