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Updated: Jul 2, 2025
A Chronic High-Intensity Interval Training and Diet-Induced Obesity Model to Maximize Exercise Effort and Induce Physiologic Changes in Rats
Published on: April 28, 2023
Aerobic exercise mitigates high-fat diet-induced cardiac dysfunction, pyroptosis, and inflammation by inhibiting
Zujie Xu1, Zheying Ma2, Xiaoqin Zhao2
1College of Physical Education, Taiyuan University of Technology, Taiyuan Shanxi, 030024, China. zjxu2023@163.com.
Abstract:
Obesity has been identified as an independent risk factor for cardiovascular disease. Recent reports have highlighted the significance of stimulator of interferon genes (STING)-NOD-like receptor protein 3 (NLRP3) signaling pathway mediated pyroptosis, and inflammation in cardiovascular disease. Previous studies have demonstrated that exercise training effectively prevents cardiac pyroptosis and inflammation in high-fat diet (HFD)-fed mice. However, it is currently unknown whether exercise reduces pyroptosis and inflammation in obese hearts by targeting the STING-NLRP3 signaling pathway. We investigated the impact of an 8-week aerobic exercise regimen on cardiac function, pyroptosis, inflammation, and the STING-NLRP3 signaling pathway in HFD-induced obese mice. Additionally, to explore the underlying mechanism of STING in exercise-mediated cardioprotection, we administered intraperitoneal injections of the STING agonist diABZI to the mice. Furthermore, to investigate the role of the STING-NLRP3 signaling pathway in HFD-induced cardiac dysfunction, we administered adeno-associated virus 9 (AAV9) encoding shRNA targeting STING (shRNA-STING) via tail vein injection to knockdown STING expression specifically in mouse hearts. After one week of AAV9 injection, we intraperitoneally injected nigericin as an NLRP3 agonist. We first found that aerobic exercise effectively suppressed HFD-mediated upregulation of STING and NLRP3 in the hearts. Moreover, we demonstrated that the protective effect of aerobic exercise in HFD-induced cardiac dysfunction, pyroptosis, and inflammation was impaired by stimulating the STING pathway using diABZI. Additionally, activation of the NLRP3 with nigericin abolished the ameliorative effect of STING deficiency in HFD-induced cardiac dysfunction, pyroptosis, and inflammation. Based on these findings, we concluded that 8-week aerobic exercise alleviates HFD-induced cardiac dysfunction, pyroptosis, and inflammation by targeting STING-NLRP3 signaling pathway. Inhibition of STING-NLRP3 signaling pathway may serve as a promising therapeutic strategy against obesity-induced cardiomyopathy.
Insights
Aerobic exercise combats obesity-related heart problems by targeting the STING-NLRP3 pathway, reducing inflammation and pyroptosis. This suggests inhibiting this pathway could treat obesity-induced cardiomyopathy.
Area of Science:
- Cardiovascular Disease Research
- Molecular and Cellular Biology
- Exercise Physiology
Background:
- Obesity is a major risk factor for cardiovascular disease.
- The stimulator of interferon genes (STING)-NOD-like receptor protein 3 (NLRP3) pathway is implicated in cardiovascular inflammation and pyroptosis.
- Exercise is known to prevent cardiac pyroptosis and inflammation, but its effect on the STING-NLRP3 pathway in obesity is unclear.
Purpose of the Study:
- To investigate the impact of aerobic exercise on cardiac function, pyroptosis, inflammation, and the STING-NLRP3 pathway in diet-induced obese mice.
- To explore the role of STING in exercise-mediated cardioprotection.
- To elucidate the involvement of the STING-NLRP3 pathway in high-fat diet-induced cardiac dysfunction.
Main Methods:
- An 8-week aerobic exercise regimen was implemented in high-fat diet (HFD)-fed mice.
- Mice received STING agonist (diABZI) or STING knockdown (shRNA-STING) via AAV9, followed by NLRP3 agonist (nigericin) administration.
- Cardiac function, pyroptosis, inflammation markers, and STING-NLRP3 pathway activation were assessed.
Main Results:
- Aerobic exercise suppressed STING and NLRP3 upregulation in HFD-induced obese mouse hearts.
- Stimulating STING with diABZI impaired exercise's protective effects against cardiac dysfunction, pyroptosis, and inflammation.
- NLRP3 activation abolished the benefits of STING deficiency in HFD-induced cardiac issues.
Conclusions:
- Aerobic exercise alleviates HFD-induced cardiac dysfunction, pyroptosis, and inflammation by targeting the STING-NLRP3 signaling pathway.
- Inhibiting the STING-NLRP3 pathway presents a potential therapeutic strategy for obesity-induced cardiomyopathy.
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