Activation of Wnt/β‐catenin signaling restores insulin sensitivity in insulin resistant neurons through transcriptional regulation of IRS‐1

• Published in: Journal of neurochemistry 2021-05, Vol.157 (3), p.467-478
• Main Authors: Tian, Shijiao, Tan, Shichuan, Jia, Wenming, Zhao, Juan, Sun, Xiulian
• Format: Article
• Language: English
• Subjects: Brain; Catenin; Gene regulation; Insulin; Insulin receptor substrate 1; Insulin resistance; Kinases; Neurons; Phosphorylation; Signaling; Substrates; Transcription activation; Wnt protein
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.15277

Aberrant expression and phosphorylation of insulin receptor substrate 1 (IRS‐1) contribute to brain insulin resistance. However, the underlying mechanism remains elusive. The insulin signaling and Wnt/β‐catenin signaling are two critical pathways for normal cellular function, which interact in both peripheral tissues and the brain and may contribute to insulin resistance. In this study, we aimed to investigate the regulation of IRS‐1 and its downstream insulin signaling by Wnt/β‐catenin signaling in primary neurons. We found that the Wnt agonist Wnt3a enhances the insulin signaling in neurons at the basal state via up‐regulation of IRS‐1. Moreover, Wnt3a up‐regulates IRS‐1 expression and effectively ameliorates insulin resistance in rat primary neurons induced by chronic high insulin exposure. The insulin‐mediated glucose uptake is also stimulated by Wnt3a at both basal and insulin resistant states. We observed that Wnt activation up‐regulates IRS‐1 gene transcription and the subsequent protein expression in SH‐SY5Y cells and rat primary neurons via different means of Wnt/β‐catenin signaling activation, including S33Y β‐catenin over‐expression, CHIR99021 and Wnt3a treatment. We further clarified the molecular mechanism of IRS‐1 transcriptional activation by Wnt/β‐catenin signaling. The Wnt transcription factor TCF4 binds to the −529 bp to −516 bp of the human IRS‐1 promoter fragment and activates IRS‐1 transcription. Overall, these data suggested that Wnt/β‐catenin signaling positively regulates IRS‐1 and insulin signaling and protects against insulin resistance in neurons. Aberrant expression and phosphorylation of insulin receptor substrate 1 (IRS‐1) contribute to brain insulin resistance. However, the underlying mechanism remains elusive. In this study, we found that Wnt3a (the Wnt agonist) up‐regulates IRS‐1 expression. In detail, Wnt3a treatment leads to the stabilization and nuclear translocation of β‐catenin. In the nucleus, β‐catenin interacts with T cell factor 4 (TCF4) and they bind with the Wnt responsive element (WRE) of IRS‐1 promoter fragment and initiate its transcription. Through inducing IRS‐1 expression, Wnt3a partially restores insulin‐induced phosphorylation of pAKT Thr308, pAKT Ser473, and pGSK3β Ser9 and increases insulin‐mediated glucose uptake in insulin‐resistant neurons.