Arsenic induces metabolome remodeling in mature human adipocytes

Abstract

Human lifetime exposure to arsenic through drinking water, food supply or industrial pollution leads to its accumulation in many organs such as liver, kidneys, lungs or pancreas but also adipose tissue. Recently, population-based studies revealed the association between arsenic exposure and the development of metabolic diseases such as obesity and type 2 diabetes. To shed light on the molecular bases of such association, we determined the concentration that inhibited 17% of cell viability and investigated the effects of arsenic acute exposure on adipose-derived human mesenchymal stem cells differentiated in vitro into mature adipocytes and treated with sodium arsenite (NaAsO2, 10 nM to 10 µM). Untargeted metabolomics and gene expression analyses revealed a strong dose-dependent inhibition of lipogenesis and lipolysis induction, reducing the cellular ability to store lipids. These dysregulations were emphasized by the inhibition of the cellular response to insulin, as shown by the perturbation of several genes and metabolites involved in the mentioned biological pathways. Our study highlighted the activation of an adaptive oxidative stress response with the strong induction of metallothioneins and increased glutathione levels in response to arsenic accumulation that could exacerbate the decreased insulin sensitivity of the adipocytes. Arsenic exposure strongly affected the expression of arsenic transporters, responsible for arsenic influx and efflux, and induced a pro-inflammatory state in adipocytes by enhancing the expression of the inflammatory interleukin 6 (IL6). Collectively, our data showed that an acute exposure to low levels of arsenic concentrations alters key adipocyte functions, highlighting its contribution to the development of insulin resistance and the pathogenesis of metabolic disorders.