Down-regulation of O-GlcNAcylation alleviates insulin signaling pathway impairment following arsenic exposure via suppressing the AMPK/mTOR-autophagy pathway

Impairment of the Insulin signaling pathway is a key contributor to Insulin resistance under arsenic exposure. Specifically, O-GlcNAcylation, an important post-translational modification, plays a crucial role in Insulin resistance. Nevertheless, the concrete effect and mechanism of O-GlcNAcylation in arsenic-induced impairment of the Insulin signaling pathway remain elusive. Herein, C57BL/6 mice were continuously fed arsenic-containing food, with a total arsenic concentration of 30 mg/kg. We observed that the IRS/Akt/GSK-3β Insulin signaling pathway was impaired, and Autophagy was activated in mouse livers and HepG2 cells exposed to arsenic. Additionally, O-GlcNAcylation expression in mouse livers and HepG2 cells was elevated, and the key O-GlcNAcylation homeostasis Enzyme, O-GlcNAc transferase (OGT), was upregulated. In vitro, non-targeted metabolomic analysis showed that metabolic disorder was induced, and inhibition of O-GlcNAcylation restored the metabolic profile of HepG2 cells exposed to arsenic. In addition, we found that the compromised Insulin signaling pathway was dependent on AMPK activation. Inhibition of AMPK mitigated Autophagy activation and impairment of Insulin signaling pathway under arsenic exposure. Furthermore, down-regulation of O-GlcNAcylation inhibited AMPK activation, thereby suppressing Autophagy activation, and improving the impaired Insulin signaling pathway. Collectively, our findings indicate that arsenic can impair the Insulin signaling pathway by regulating O-GlcNAcylation homeostasis. Importantly, O-GlcNAcylation inhibition alleviated the impaired Insulin signaling pathway by suppressing the AMPK/mTOR-autophagy pathway. This indicates that regulating O-GlcNAcylation may be a potential intervention for the impaired Insulin signaling pathway induced by arsenic.

AMPK; Arsenic; Insulin signaling pathway; O-GlcNAcylation.