Abstract 047: PPARg Deacetylation Mitigates Aortic Stiffness And Aortic Perivascular Adipose Tissue (aPVAT) Remodeling In Obese Male Mice

Abstract

Clinical findings show that stiffening of large arteries can precede hypertension in obesity. The causality between arterial stiffness and blood pressure is complex and the underlying mechanism remains unclear. Thoracic aPVAT, a brown-like adipose tissue (AT), undergoes phenotypic changes in obesity resulting in the loss of its protective vascular effect. Our recent findings demonstrated that peroxisome proliferator-activated receptor gamma (PPARγ) deacetylation, a post-translational modification, enhances endothelium-dependent vasodilation. Based on this evidence and PPARγ’s role in regulating AT, we hypothesize that PPARγ deacetylation alleviates aortic stiffness and aPVAT remodeling in obesity . Male eight-week-old C57Bl/6 mice and genetically engineered deacetylation-mimetic mice with a double lysine to arginine mutation (K268R, K293R; 2KR mice) were randomized into two groups: Control groups of C57Bl/6 (n=8) and 2KR mice (n=5) received a regular chow diet (5% fat, 48.7% carbohydrates [3.2% sucrose]) and WD groups of C57Bl/6 (n=11) and 2KR mice (n=9) received a western diet (40% fat, 43% carbohydrates [34% sucrose]) for 20 weeks. Obesity was confirmed by markedly increased body weight in the C57Bl/6 (40.47 ± 1.71 g vs. 29.89 ± 0.76 g controls, p<0.05) and 2KR mice (34.48 ± 1.68 g vs. 24.76 ± 0.59 g controls, p<0.05) at 16 weeks on WD. Pulse wave velocity data, the gold standard measurement for arterial stiffness, revealed increased aortic stiffness in the 16 weeks (5.70 ± 0.61 m/s vs. 3.82 ± 0.24 m/s controls) and 20 weeks (4.89 ± 0.21 m/s vs. 4.02 ± 0.17 m/s controls) on WD in the C57Bl/6 group. Strikingly, WD 2KR mice did not show aortic stiffness after 16 weeks (4.36 ± 0.37 m/s vs. 4.34 ± 0.54 m/s controls, p=0.75) or 20 weeks (5.00 ± 0.65 m/s vs. 5.84 ± 0.96 m/s controls, p=0.49) of WD. aPVAT from WD C57Bl/6 group exhibited profound phenotypic changes, switching from brown- to white-like AT with larger Oil Red O stained lipid droplets, while aPVAT from WD 2KR showed reduced phenotypic modifications. Whether aPVAT contributes to aortic stiffness in obesity remains poorly understood and warrants further investigation. In conclusion, our results support a protective role of PPARγ deacetylation in obesity-related vascular complications.