Abstract P240: Activation Of Toll-like Receptor 4 (tlr4) Signaling In Mesenteric Arteries During Obesity Is Not Reversed By Weight Loss

Abstract

Obesity in the United States is associated with overconsumption of the high fat and high carbohydrate western diet. It is a major risk factor for hypertension. The mechanisms by which obesity contributes to the development of hypertension remain unresolved. While obese women are three-fold more likely to develop hypertension than lean women, the majority of obesity-induced hypertension research has been conducted using male cohorts. Thus, there is an urgent need to investigate the pathophysiology of obesity-induced hypertension in women. A previous study from our lab demonstrated that endothelial dysfunction found in obese female rats is associated with TLR4 signaling activation in the aorta revealing an inflammatory state in a conduit artery during obesity. The goal of this present study is to investigate whether weight loss by reversal of western diet-induced obesity normalizes TLR4 signaling in conduit and resistance arteries. To address this question, eight-week-old female Wistar rats were randomized into three experimental groups: the Obese group (n=10) was fed a western diet (21% fat, 50% carbohydrate [34% sucrose], 20% protein) and the Lean group (n=10) was fed a standard chow diet (5% fat, 48.7% carbohydrate [3.2% sucrose], 24.1% protein) for 20 weeks. The weight loss group (n=10) was fed a western diet for 20 weeks and a standard chow diet for 8 weeks. While weight loss reduced BMI (0.65 ±0.03 vs.0.82 ±0.02 obese, p<0.01), systolic blood pressure consistently measured at 7pm by tail-cuff plethysmography remained elevated (139.83 ± 15.3 vs.150.06 ± 4.5, p=0.09). At the experimental endpoint, thoracic aortas and mesenteric arteries were obtained for molecular analysis of TLR4 signaling. As previously shown, aortic TLR4 signaling of the obese group was activated. Weight loss normalized TLR4 and MyD88 expression in thoracic aortas; however, expression of MyD88 remained increased in mesenteric arteries (2.8 fold increase, p<0.01, n=6). This suggests that persistent hypertension despite weight loss is associated with a failure of TLR4-MyD88 signaling to normalize in the resistance vessels.