Reinstating insulin sensitivity in metabolic disorders via regulation of selenoproteins

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Worldwide more than 650 million adults are obese and more than 400 million are diabetic. Obesity increases the risk to suffer from diabetes. Both diseases are characterized by insufficient insulin signaling. While type 1 diabetes display insulin deficiency, type 2 diabetes presents insulin resistance. Insulin resistance in adipose tissue disallows proper energy storage, which leads to lipid accumulation in non-adipose tissues such as liver or muscle. This lipotoxic effect can further induce an inflammatory response and insulin resistance, thereby worsening metabolism. Thus, the improvement of insulin action in adipose tissue represents a potential strategy to treat metabolic diseases.Insulin resistance in adipose tissue is characterized by inhibitory serine phosphorylation events on insulin signaling proteins, as well as decreased insulin receptor (IR) expression which attenuate insulin action. Recently, we have shown that an altered transcriptional regulation of selenoproteins with a reduction of IR expression in adipose tissue is present in obesity and long-term insulin resistant conditions. Feeding lean mice a high fat diet (HFD) supplemented with supraphysiological levels of selenite, improves insulin sensitivity with increased IR expression in adipose tissue compared to mice fed a conventional HFD. Further, we showed that the selenoprotein glutathione peroxidase 3 (GPx3) can regulate IR expression. Why GPx3 is dysregulated in metabolic disorders and how GPx3 mechanistically regulates IR expression in adipose tissue is so far unknown. Moreover it is uncertain whether the loss of GPx3 is sufficient to alter insulin sensitivity in vivo.Therefore, we will investigate the regulation of GPx3, IR and various selenoproteins in different mouse models to gain insights into the modulation of their expression patterns. Additionally, we will investigate the mechanism how selenite and GPx3 can specifically modulate IR expression and aim to confirm this in a human adipocyte cell model. Furthermore, we will metabolically characterize GPx3 deficient mice to decipher the effect of loss of GPX3 on adipose tissue metabolism and insulin sensitivity. Lastly, we will deliver scientific insights why a preventive selenite supplementation is able to improve adipose tissue metabolism with elevated GPx3 and IR expression, whereas this diet does not affect this interplay and metabolism in a similar manner, when fed to diet-induced obese mice. These data will shed light on opposing results regarding the effect of selenium on insulin sensitivity in humans and shall reveal the relevance of the positive interaction of GPx3 with IR for human metabolism. The overall goal is to establish the modulation of GPx3 in adipose tissue as a novel mechanism to re-instate insulin sensitivity in obesity.