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Published on: June 25, 2018
Irisin Ameliorates Oxidative Stress-Induced Injury in Pancreatic Beta-Cells by Inhibiting Txnip and Inducing
Chongxiao Liu1, Jianhua Zhou1, Yanhong Xu1
1Department of Endocrinology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai 200137, China.
Abstract:
Lipotoxicity can lead to beta-cell dysfunction and apoptosis because it induces oxidative stress. Recent studies have found that Irisin prevents pancreatic beta-cell dysfunction induced by palmitic acid (PA). However, an association between the protection against oxidative stress conferred by Irisin and beta-cell dysfunction has not been fully elucidated. In this study, we observed that Irisin treatment prevented INS-1 cell apoptosis induced by PA treatment and preserved the insulin-secreting function of INS-1 cells in vitro. These effects probably resulted from the Irisin-induced decrease in intracellular ROS levels triggered by PA treatment. In addition, PA treatment induced oxidative stress partially by inhibiting the activation of thioredoxin 2 (Trx2) through its increase of thioredoxin-interacting protein (Txnip) expression. However, Irisin administration blocked the increase in Txnip expression, which reversed the PA-induced inactivation of Trx2. Irisin also increased the nuclear translocation of Stat3, and the inhibition of Stat3 by siRNAs blocked Irisin-induced Trx2 expression, indicating that both Txnip and Stat3 are involved in Irisin-induced activation of Trx2. Furthermore, blockade of Stat3 by siRNAs led to the decreased gene expression of MafA and Ins and to cessation of glucose-induced insulin secretion that had been enhanced by Irisin. In vivo, HFD treatment led to reduced glucose tolerance and an increase in the level of the oxidative marker malondialdehyde (MDA) compared to that in the control group. However, these effects were ameliorated by Irisin injection due to the inhibition of beta-cell apoptosis and the activation of Trx2, probably through Txnip inhibition and Stat3 activation. In conclusion, our results reveal a possible mechanism for Irisin-induced beta-cell protection, which is mediated through Txnip inhibition and activation of the Stat3-Trx2 pathway.
Insights
Irisin protects pancreatic beta cells from lipotoxicity by reducing oxidative stress and preserving insulin secretion. It achieves this by inhibiting Txnip and activating the Stat3-Trx2 pathway, improving glucose tolerance in vivo.
Area of Science:
- Endocrinology
- Cell Biology
- Metabolic Diseases
Background:
- Lipotoxicity impairs pancreatic beta-cell function and survival via oxidative stress.
- Irisin has shown potential in preventing lipotoxicity-induced beta-cell dysfunction.
- The precise mechanisms linking Irisin's antioxidant effects to beta-cell protection remain unclear.
Purpose of the Study:
- To elucidate the protective mechanisms of Irisin against lipotoxicity in pancreatic beta cells.
- To investigate the role of oxidative stress, Txnip, Stat3, and Trx2 in Irisin's protective effects.
- To evaluate Irisin's efficacy in ameliorating high-fat diet-induced metabolic dysfunction in vivo.
Main Methods:
- In vitro studies using INS-1 cells treated with palmitic acid (PA) and Irisin.
- Assessment of cell apoptosis, insulin secretion, reactive oxygen species (ROS) levels, and protein/gene expression (Txnip, Trx2, Stat3, MafA, Ins).
- In vivo studies involving high-fat diet (HFD) fed mice treated with Irisin, assessing glucose tolerance and oxidative stress markers.
Main Results:
- Irisin prevented PA-induced INS-1 cell apoptosis and preserved insulin secretion by reducing ROS levels.
- Irisin inhibited PA-induced Txnip expression, thereby preventing Trx2 inactivation.
- Irisin promoted Stat3 nuclear translocation, which is crucial for Trx2 activation and subsequent expression of MafA and Ins, enhancing glucose-induced insulin secretion.
- In vivo, Irisin improved glucose tolerance and reduced oxidative stress in HFD-fed mice by inhibiting beta-cell apoptosis and activating Trx2.
Conclusions:
- Irisin protects pancreatic beta cells from lipotoxicity through a mechanism involving Txnip inhibition and Stat3-mediated activation of Trx2.
- This pathway is critical for maintaining beta-cell function, insulin secretion, and overall glucose homeostasis.
- Irisin represents a potential therapeutic agent for metabolic disorders characterized by beta-cell dysfunction and lipotoxicity.
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