91-OR: Selenite-Induced Glutathione Peroxidase 3 in the Control of Insulin Receptor Expression in Adipocytes

Selenoproteins are an important modulator of cellular redox homeostasis and metabolic processes. Previously we have demonstrated that mice fed a selenium rich HFD (SRHFD) are protected against diet-induced insulin resistance. Here, SRHFD-fed mice exhibited elevated white adipose tissue (WAT) insulin receptor (IR) expression and improved whole-body insulin sensitivity. This was due to a WAT-specific upregulation of the selenoprotein glutathione peroxidase 3 (GPx3), an important regulator of cellular redox states. Strikingly, we could demonstrate that this effect is blunted in mice with pre-existing obesity, where a failure to increase GPx3 in WAT associates with unaltered IR expression. However, the mechanism behind this interaction is unknown.

Highlighting the translational relevance, we use a human pre-adipocyte cell line to show that GPx3 expression increases IR protein levels, differentiation capacity, and protects against palmitate-induced insulin resistance.

In our current investigation using murine pre-adipocytes (3T3-L1), we show that GPx3 regulates IR expression via the transcription factor SP1, which is known to be susceptible to changes in the cellular redox state. Consequently, we demonstrate that an increase in selenite-induced GPx3 expression is associated with an increased binding of SP1 to the IR promoter. This mechanism involves a change in the oxidized glutathione pool by GPx3. Surprisingly, it is sufficient to provide cells with extracellular recombinant GPx3 to elicit this effect, suggesting either a receptor-mediated effect, or a reuptake of GPx3 into the cells. As a result, in vitro treatment with extracellular GPx3 increases IR expression and enhance mitochondrial function and differentiation capacity of 3T3-L1 cells.

In conclusion, we identify GPx3 as a novel modulator of WAT insulin receptor expression and insulin sensitivity, that potentially acts in a paracrine or autocrine manner, and is responsive to a dietary intervention.