Aerobic Exercise Ameliorates Liver Injury in Db/Db Mice by Attenuating Oxidative Stress, Apoptosis and Inflammation Through the Nrf2 and JAK2/STAT3 Signalling Pathways

Meiyan Sun; Xiaoyong Zhao; Xingyue Li; Chunling Wang; Lili Lin; Kaifang Wang; Yingui Sun; Wei Ye; Haiyan Li; Ye Zhang; Chaolu Huang

doi:10.2147/JIR.S426581

Aerobic Exercise Ameliorates Liver Injury in Db/Db Mice by Attenuating Oxidative Stress, Apoptosis and Inflammation Through the Nrf2 and JAK2/STAT3 Signalling Pathways

J Inflamm Res. 2023 Oct 24:16:4805-4819. doi: 10.2147/JIR.S426581. eCollection 2023.

Authors

Meiyan Sun^#^{1

2}, Xiaoyong Zhao^#², Xingyue Li², Chunling Wang², Lili Lin³, Kaifang Wang², Yingui Sun², Wei Ye³, Haiyan Li³, Ye Zhang¹, Chaolu Huang^{2

4}

Affiliations

¹ Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, People's Republic of China.
² Department of Anesthesiology, Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, 261053, People's Republic of China.
³ The First Clinical Medical College, Wenzhou Medical University, Wenzhou, 325000, People's Republic of China.
⁴ Department of Clinical Medicine, Qiandongnan Ethnic Vocational and Technical College, Kaili, 556000, People's Republic of China.

^# Contributed equally.

Abstract

Objective: Diabetes mellitus (DM) implicates oxidative stress, apoptosis, and inflammation, all of which may contribute liver injury. Aerobic exercise is assured to positively regulate metabolism in the liver. This project was designed to investigate whether and how aerobic exercise improves DM-induced liver injury.

Methods: Seven-week-old male db/db mice and age-matched m/m mice were randomly divided into a rest control group or a group that received 12 weeks of aerobic exercise by treadmill training (10 m/min). Haematoxylin and eosin (HE) staining, electron microscopy, Oil Red O staining and TUNEL assays were used to evaluate the histopathological changes in mouse liver. The serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TRIG), cholesterol (CHOL) were analyzed by serum biochemical analysis. Interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), and tissue levels of malondialdehyde (MDA) and superoxide dismutase (SOD) were analyzed via ELISA. Nuclear factor E2-associated factor-2 (Nrf2), nuclear factor κB (NF-κB) and JAK2/STAT3 pathway-related proteins were measured by immunofluorescence, Western blotting and q-PCR. F4/80 expression in liver tissues was assessed by immunohistochemistry.

Results: In diabetic mice, exercise training significantly decreased the levels of serum TRIG, CHOL, IL-6, TNF-α, ALT and AST; prevented weight gain, hyperglycaemia, and impaired glucose and insulin tolerance. Morphologically, exercise mitigated the diabetes-induced increase in liver tissue microvesicles, inflammatory cells, F4/80 (macrophage marker) levels, and TUNEL-positive cells. In addition, exercise reduced the apoptosis index, which is consistent with the results for caspase-3 and Bax. Additionally, exercise significantly increased SOD activity, decreased MDA levels, activated Nrf2 and decreased the expression of NF-kB, phosphorylated JAK2 and STAT3 proteins in the livers of diabetic mice.

Conclusion: This study demonstrated that aerobic exercise reversed liver dysfunction in db/db mice with T2DM by reducing oxidative stress, apoptosis and inflammation, possibly by enhancing Nrf2 expression and inhibiting the JAK2/STAT3 cascade response.

Keywords: JAK2/STAT3; Nrf2; aerobic exercise; apoptosis; db/db mice; inflammation.

Grants and funding

This research was funded by the Postgraduate Scientific Research Project of Higher Education Institutions of Anhui Province (YJS20210276); the Shandong Province Medical and Health Science and Technology Development Plan Project Fund (202104110334, 202104010549).