Journal
MOLECULES
Volume 27, Issue 19, Pages -Publisher
MDPI
DOI: 10.3390/molecules27196384
Keywords
obesity; insulin resistance; NLRP3 inflammasome; IL-1 beta; n-3 PUFAs; docosahexaenoic acid; fat-1
Funding
- Zhejiang Province Public Welfare Technology Application Research Project [LGN19C200010, LGN20C200013]
- National Key R&D Program of China [2018YFD0901105]
- Zhejiang Key Laboratory of Pathophysiology [201802]
- Clinical Research Fund of Zhejiang Medical Association [2019ZYC-A112]
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"In this study, researchers found that n-3 polyunsaturated fatty acids (PUFAs) protect against insulin resistance and type 2 diabetes by reducing inflammation and promoting the anti-inflammatory effects. They also discovered that n-3 PUFAs can reverse the insulin resistance induced by a high-fat diet through modulation of the NLRP3 inflammasome and antioxidant pathways. Furthermore, GSK-3β was identified as a key player in this process."
High-fat (HF) diets and low-grade chronic inflammation contribute to the development of insulin resistance and type 2 diabetes (T2D), whereas n-3 polyunsaturated fatty acids (PUFAs), due to their anti-inflammatory effects, protect against insulin resistance. Interleukin (IL)-1 beta is implicated in insulin resistance, yet how n-3 PUFAs modulate IL-1 beta secretion and attenuate HF diet-induced insulin resistance remains elusive. In this study, a HF diet activated NLRP3 inflammasome via inducing reactive oxygen species (ROS) generation and promoted IL-1 beta production primarily from adipose tissue preadipocytes, but not from adipocytes and induced insulin resistance in wild type (WT) mice. Interestingly, endogenous synthesized n-3 polyunsaturated fatty acids (PUFAs) reversed this process in HF diet-fed fat-1 transgenic mice although the HF diet induced higher weight gain in fat-1 mice, compared with the control diet. Mechanistically, palmitic acid (PA), the main saturated fatty acid in an HF diet inactivated AMPK and led to decreased GSK-3 beta phosphorylation, at least partially through reducing Akt activity, which ultimately blocked the Nrf2/Trx1 antioxidant pathway and induced TXNIP cytoplasm translocation and NLRP3 inflammasome activation, whereas docosahexaenoic acid (DHA), the most abundant n-3 PUFA in fat-1 adipose tissue, reversed this process via inducing Akt activation. Our GSK-3 beta shRNA knockdown study further revealed that GSK-3 beta played a pivot role between the upstream AMPK/Akt pathway and downstream Nrf2/Trx1/TXNIP pathway. Given that NLRP3 inflammasome is implicated in the development of most inflammatory diseases, our results suggest the potential of n-3 PUFAs in the prevention or adjuvant treatment of NLRP3 inflammasome-driven diseases.
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