Western Diet‐Induced Hypertension involves HMGB1/TLR4 Signaling in Perivascular Adipose Tissue of Female Rats

Abstract

BackgroundOverconsumption of a Western Diet (WD), a high‐fat and high‐sugar diet, is a major factor implicated in rising obesity rates in the US. Perivascular adipose tissue (PVAT) possesses a vasculo‐protective role. In obesity, PVAT expands and becomes inflamed, contributing to vascular complications. High motility group box 1 (HMGB1), a cytokine, has been demonstrated to mediate vascular inflammation. Recent studies also suggest that PVAT plays a role in obesity‐related hypertension; however, the underlying mechanisms are still not well understood. We hypothesize that WD increases HMGB1 production in PVAT which in turn activates Toll‐like receptor 4 (TLR4) signaling in an autocrine/paracrine manner, resulting in hypertension.MethodsWe have established a model of WD‐induced hypertension in female rats. Adult female Wistar rats (n= 9) were randomized into two groups. Control Group (n= 4) received a regular chow diet (5% fat, 48.7% carbohydrates [3.2% sucrose], and 24.1% protein) and WD group (n= 5) received WD (40% fat, 43% carbohydrates [34% sucrose], and 17% protein) for 28 weeks. Metabolic parameters (body weight, body mass index (BMI), triglycerides, and non‐esterified free fatty acids [NEFA]) were assessed. Arterial blood pressure was measured via carotid catherization at the end of the experimental protocol. Thoracic aortas with PVAT were obtained for vascular studies and molecular assays. Vascular studies were performed using a wire myograph to assess vasodilatory responses.ResultsBody weight (358.9 ± 10.2 vs 270.1 ± 12.3g controls, p<0.005) and BMI (0.68 ± 0.02 vs. 0.06 ± 0.03 g/cm2controls, p<0.005) were increased in the WD group, confirming obesity. The WD group also demonstrated increased serum triglycerides (49.8 ± 4.7 vs. 14.3 ± 1.8mg/dL controls, p<0.05) and NEFA (0.57 ± 0.02 vs. 0.79 ± 0.04 mM controls, p<0.05). WD increased systolic blood pressure (144.04 ± 2.8 vs. 115.1 ± 3.9 mmHg controls, p<0.001), diastolic blood pressure (108.3 ± 3.1 vs. 89.5 ± 4.3 mmHg controls, p<0.01), and heart rate (386.1 ± 8.8 vs. 307.7 ± 40.3 bpm controls, p<0.05). Impaired vasodilation in the WD group in comparison to controls was worsened in the presence of PVAT, suggesting dysfunctional PVAT. Histological analysis of PVAT revealed a switch from brown‐like adipose tissue to white‐like adipose tissue, along with a significant decrease in uncoupling protein 1 (UCP‐1) expression (1.5‐fold decreased, p<0.05), a marker of thermogenesis. An oxidative/inflammatory state in the PVAT was confirmed by a 50% increase in reactive oxygen species levels (p<0.01). Strikingly, the novelty of this study revealed increased HMGB1 expression (2.0‐fold increased, p<0.05) along with increased TLR4 expression (2.5‐fold increased, p<0.05) in the PVAT of the WD group.ConclusionOur findings suggest that upregulated HMGB1/TLR4 signaling in the PVAT may induce a local inflammatory response through an autocrine/paracrine manner in the vasculature, contributing to dysregulation of blood pressure in the context of obesity.Support or Funding InformationNIH