JNK downregulation improves olanzapine-induced insulin resistance by suppressing IRS1Ser307 phosphorylation and reducing inflammation - 18/09/21
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Abstract |
Aims |
c-jun N-terminal kinase (JNK) plays pivotal roles in many physiological processes, including inflammation and glucose metabolism. However, the effects of JNK on olanzapine-induced insulin resistance and the underlying mechanisms have not been fully elucidated. The aim of our study was to explore the role of JNK in olanzapine-induced insulin resistance and the underlying mechanisms.
Methods |
We studied glucose metabolism in olanzapine-treated female C57B/J mice and mice with adeno-associated virus (AAV)-mediated downregulation of JNK1 in epididymal white adipose tissue (eWAT). 3T3-L1 adipocytes were used to investigate the mechanism of JNK1 regulating insulin signaling after olanzapine treatment.
Results |
JNK was activated in eWAT after olanzapine treatment. JNK1 downregulation in eWAT ameliorated the insulin resistance and adipose tissue inflammation in olanzapine-treated mice. Furthermore, overexpression of JNK1 in adipocytes exacerbated the glucose disorder while JNK1 knockdown alleviated the impaired insulin signaling on olanzapine challenge, which was likely mediated by the reduced inflammation and insulin receptor substrate 1 (IRS1) phosphorylation. Moreover, the effect of JNK1 was attenuated by downregulation of IRS1 in adipocytes. Finally, the JNK1-IRS1 interaction and IRS1S307 phosphorylation were required for JNK1-regulated olanzapine-induced insulin resistance in adipocytes.
Conclusions |
Our results demonstrated that JNK1 activation by olanzapine induced insulin resistance by promoting IRS1Ser307 phosphorylation and inflammation in eWAT. These results highlighted the importance of JNK1 in eWAT as a promising drug target for olanzapine-induced insulin resistance.
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Keywords : Olanzapine, Insulin resistance, JNK1, IRS1, Adipose tissue
Plan
Vol 142
Article 112071- octobre 2021 Retour au numéro
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