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

Abstract

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/βcatenin 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.

Dysregulation of BMP, Wnt, and Insulin Signaling in Fragile X Syndrome

“…We need to explore how Wnt signaling may work together with secreted BMP and ILP signals to regulate glial phagocytosis during brain circuit remodeling. Numerous studies suggest that both Wnt and BMP signaling bidirectionally regulate an insulin-dependent network for developmental homeostasis ( Chen et al, 2010 ; Foley, 2012 ; Cabrae et al, 2020 ; Baboota et al, 2021 ; Mao et al, 2021 ; Tian et al, 2021 ). BMP-Wnt cross interactions also help maintain physiological processes ( Thorne et al, 2018 ; Chhabra et al, 2019 ; Wang et al, 2020 ).…”

Investigation Genomic Landscapes, Molecular Mechanisms, and Extracellular Vesicles MiRNAs in Astrocyte and Oligodendrocyte Derived Amyotrophic Lateral Sclerosis

“…In both circumstances, NGF decreases insulin resistance. Nutrient growth factor promotes IRS1, c-Fos, and glucose metabolism (34). Activated IRS1 on the NGF receptor TrkA is unaffected.…”

Insulin Signaling Disruption and INF-γ Upregulation Induce Aβ1–42 and Hyperphosphorylated-Tau Proteins Synthesis and Cell Death after Paraquat Treatment of Primary Hippocampal Cells

“…IFN-γ decreases insulin levels and insulin signaling pathway activation through JAK/STAT1 pathway upregulation, which increases IRS1 phosphorylation of serine residues, supporting the results observed. The Wnt pathway regulates the insulin pathway, and PQ disrupts the Wnt signaling pathway . Thus, the PQ Wnt pathway alteration could also mediate the insulin pathway disruption.…”

“…The Wnt pathway regulates the insulin pathway, 23 and PQ disrupts the Wnt signaling pathway. 24 Thus, the PQ Wnt pathway alteration could also mediate the insulin pathway disruption. PQ also decreased p-AKT (Ser473) (Figure 2A,B) and p-GSK3β protein levels (Figure 3A,B) and increased glucose levels (Figure 2C,D), following 1 (starting at 10 μM) and 14 days of treatment (starting at 1 μM).…”

“…The Wnt pathway regulates the insulin pathway, 23 and PQ disrupts the Wnt signaling pathway. 24 Thus, the PQ Wnt pathway alteration could also mediate the insulin pathway disruption.…”