Abstract
Insulin resistance in the brain is a pathological mechanism that is shared between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). Although aberrant expression and phosphorylation of insulin receptor substrate 1 (IRS-1) contribute to insulin resistance, the underlying mechanism remains elusive. In this study, we used several approaches, including adeno-associated virus-based protein overexpression, immunoblotting, immunoprecipitation, immunohistochemistry, and in situ proximal ligation assays, to investigate the function of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) in IRS-1 regulation and the downstream insulin signaling in neurons. We found that DYRK1A overexpression up-regulated IRS-1 expression by slowing turnover of the IRS-1 protein. We further observed that DYRK1A directly interacted with IRS-1 and phosphorylated IRS-1's multiple serine residues. Of note, DYRK1A and IRS-1 were coordinately up-regulated in the prefrontal cortex of db/db mice brain. Furthermore, DYRK1A overexpression ameliorated chronic high insulin-induced insulin resistance in SH-SY5Y cells as well as in primary rat neurons. These findings suggest that DYRK1A protects against insulin resistance in the brain by elevating IRS-1 expression.
Highlights
Insulin resistance in the brain is a pathological mechanism that is shared between Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM)
insulin receptor substrate 1 (IRS-1) is a key molecule in insulin signaling and its downregulation leads to insulin resistance
Endogenous insulin receptor substrate (IRS)-1 expression was increased by dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) to 149.6 Ϯ 4.8% of control (Fig. 1, E and F, lane 2 versus 1; p ϭ 0.0006) and decreased by DYRK1A inhibitor harmine to 74.8 Ϯ 6.1% of control (Fig. 1, E and F, lane 4 versus 3; p ϭ 0.0181) in neuroblastoma SH-SY5Y cells
Summary
Insulin resistance in the brain is a pathological mechanism that is shared between Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM). DYRK1A up-regulation of IRS-1 ameliorates insulin resistance induced by chronic high insulin exposure in SH-SY5Y cells and rat primary neurons. Results showed that ectopic DYRK1A expression markedly increased the IRS-1 protein level to 218.5 Ϯ 14.0% of control (Fig. 1, A and B, lane 2 versus 1; p ϭ 0.0011).
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