Exercise reverses high-fat diet-induced perivascular adipose tissue dysfunction through modulation of UCP2 and TXNIP/NLRP3 pathways.

Perivascular adipose tissue (PVAT) dysfunction is associated with impaired vascular contractile properties, oxidative stress, and inflammation. We investigated the protective effect of exercise training against high-fat diet (HFD)-induced PVAT dysfunction, and explored the underlying molecular events in oxidative stress, endoplasmic reticulum (ER) stress and inflammation. Six-week-old male Sprague-Dawley rats were randomized into control, high-fat diet (HFD), and HFD plus exercise (HEx) groups. Following 6-week treatment, glycemic levels, vascular function, oxidative stress, ER stress, and inflammatory mediators were determined. We found that HFD-induced weight gain, hyperglycemia, and impaired vascular function were significantly attenuated by exercise training. HFD-induced redox imbalance in PVAT, represented by decreased antioxidant status and increased lipid peroxidation, was significantly inhibited by exercise. This was supported by a substantial restoration of UCP2 signaling and inhibition of p66shc, PKCβ, and Pin1 expressions in HEx group. Furthermore, exercise inhibited ER stress transducers, including IRE1, ATF6, eIF-2α, and GRP78, which were overexpressed with HFD. Inhibition of ER stress was accompanied by a significant inhibition of pro-inflammatory (NF-κB, TNF-α, IL-6, TXNIP, and NLRP3) and restoration of anti-inflammatory (FGF21) mediators against HFD. Exercise further reversed the transcriptional activation and deposition of NLRP3 inflammasome in PVAT. Exercise also reversed the HFD-induced macrophage polarization, as visualized by stabilized CD206 and iNOS levels. Exercise can restore HFD-induced vascular dysfunctions by promoting the UCP2 signaling and inhibiting the ER stress-associated TXNIP/NLRP3-mediated inflammatory response in PVAT.