BCL6 is Upregulated in Perivascular Adipose Tissue (PVAT) in Western Diet‐Induced Obesity‐Related Hypertension in Female Rats

Background Overconsumption of a Western Diet (WD), characterized by high‐fat and high sugar, frequently results in obesity‐related hypertension. During obesity, PVAT switches from a vasculo‐protective to an inflammatory phenotype contributing to vascular dysfunction and hypertension. The transcriptional repressor B‐Cell Lymphoma 6 (BCL6) has recently emerged as a negative regulator of adiposity. However, whether obesity alters BCL6 levels in the PVAT remains unknown. We hypothesized that WD upregulates BCL6 in PVAT resulting in dysfunctional PVAT‐induced hypertension. Methods Recently, our lab established a model of WD‐induced obesity in female rats. Eight‐week‐old female Wistar rats were randomized into two experimental groups: Control group (n=6) received a regular chow diet (5% fat, 48.7% carbohydrate [3.2% sucrose], 24.1% protein) while the WD group (n=7) received a WD (21% fat, 50% carbohydrate [34% sucrose], 20% protein), for 20 weeks. Cardiovascular parameters, including direct blood pressure and endothelium‐independent vasodilation measurements, were assessed by carotid catheterization and cumulative concentration curve for sodium nitroprusside (SNP) by using a wire myography, respectively. Metabolic parameters were obtained by biochemical assays and homeostatic model of insulin resistance (HOMA‐IR) calculation. At terminal experiments, thoracic aorta and PVAT were collected for molecular and histological analysis. Results As expected, the WD group exhibited exacerbated cardiometabolic alterations including increased body weight (412 ± 22 vs. 299 ± 5 g, p<0.01), serum triglycerides (184.2±7.44 vs. 51.5±4.9 mg/dl, p<0.001), nonesterified free fatty acid (0.98±0.05 vs. 0.05±0.02 mM, p<0.05) and insulin resistance (HOMA‐IR: 10.22 ± 1.45 vs. 1.43 ± 0.03 a.u, p<0.05), compared to controls. WD caused an increase in systolic blood pressure (147.3±7 vs. 122.7±5.29 mmHg controls, p<0.01), along with increased heart rate (381.91±11 vs. 334.26±22 bpm controls, p<0.05). SNP‐induced relaxation in aortas was reduced in the WD group (Emax: 78.55±4% vs. 96.88±6% controls, p<0.01), indicating that the decreased vasodilation caused by a WD involves vascular smooth muscle cell dysfunction. More importantly, these vascular complications were directly associated with robust phenotypic changes in aortic PVAT, which included switches from a brown‐like to a white‐like adipose tissue as evidenced by enlarged adipocytes, 60% reduction on mitochondrial density (p<0.01) and increased expression of inflammatory marker MCP‐1 (2.5‐fold increased, p<0.001) compared to controls. Strikingly, BCL6 expression was markedly elevated in PVAT from the WD group (2.1‐fold increased, p<0.05). Conclusion Our results show for the first time that BCL6 is upregulated in the aortic PVAT under obesogenic conditions. BCL6 has the potential to be a therapeutic target for obesity‐associated vascular dysfunction and hypertension. Support or Funding Information NIH