SOX2 modulated astrocytic process plasticity is involved in arsenic-induced metabolic disorders

Abstract

Metabolic disorders induced by arsenic exposure have attracted great public concern. However, it remains unclear whether hypothalamus-based central regulation mechanisms are involved in this process. Here, we exposed mice to 100 μg/L arsenic in drinking water and established a chronic arsenic exposure model. Our study revealed that chronic arsenic exposure caused metabolic disorders in mice including impaired glucose metabolism and decreased energy expenditure. Arsenic exposure also impaired glucose sensing and the activation of proopiomelanocortin (POMC) neurons in the hypothalamus. In particular, arsenic exposure damaged the plasticity of hypothalamic astrocytic process. Further research revealed that arsenic exposure inhibited the expression of sex-determining region Y-Box 2 (SOX2), which decreased the expression level of insulin receptors (INSRs) and the phosphorylation of AKT. The conditional deletion of astrocytic SOX2 exacerbated arsenic-induced effects on metabolic disorders, the impairment of hypothalamic astrocytic processes, and the inhibition of INSR/AKT signaling. Furthermore, the arsenic-induced impairment of astrocytic processes and inhibitory effects on INSR/AKT signaling were reversed by SOX2 overexpression in primary hypothalamic astrocytes. Together, we demonstrated here that chronic arsenic exposure caused metabolic disorders by impairing SOX2-modulated hypothalamic astrocytic process plasticity in mice. Our study provides evidence of novel central regulatory mechanisms underlying arsenic-induced metabolic disorders and emphasizes the crucial role of SOX2 in regulating the process plasticity of adult astrocytes.