Reinstating insulin sensitivity in metabolic disorders via regulation of selenoproteins

全世界有超过6.5亿成年人肥胖，超过4亿人患有糖尿病。肥胖会增加患糖尿病的风险。这两种疾病都以胰岛素信号传导不足为特征。1型糖尿病表现为胰岛素缺乏，而2型糖尿病表现为胰岛素抵抗。脂肪组织中的胰岛素抵抗不允许适当的能量储存，从而导致非脂肪组织（如肝脏或肌肉）中的脂质积累。这种脂毒性作用可进一步诱导炎症反应和胰岛素抵抗，从而使代谢恶化。因此，改善脂肪组织中胰岛素的作用代表了治疗代谢性疾病的潜在策略。脂肪组织中胰岛素抵抗的特征是胰岛素信号蛋白丝氨酸磷酸化抑制事件，以及胰岛素受体（IR）表达降低，从而减弱胰岛素作用。最近，我们发现在肥胖和长期胰岛素抵抗的情况下，脂肪组织中硒蛋白转录调控的改变与IR表达的减少是存在的。与喂食常规高脂饮食的小鼠相比，喂食添加超生理水平亚硒酸盐的高脂饮食（HFD）可以改善胰岛素敏感性，增加脂肪组织中IR的表达。此外，我们发现硒蛋白谷胱甘肽过氧化物酶3 （GPx3）可以调节IR的表达。为什么GPx3在代谢紊乱中失调，GPx3如何机械地调节脂肪组织中的IR表达，目前尚不清楚。此外，还不确定GPx3的缺失是否足以改变体内的胰岛素敏感性。因此，我们将研究GPx3， IR和各种硒蛋白在不同小鼠模型中的调控，以深入了解其表达模式的调节。此外，我们将研究亚硒酸盐和GPx3如何特异性调节IR表达的机制，并旨在在人类脂肪细胞模型中证实这一点。此外，我们将对GPx3缺陷小鼠进行代谢表征，以破译GPx3缺失对脂肪组织代谢和胰岛素敏感性的影响。最后，我们将提供科学见解，为什么预防性亚硒酸盐补充剂能够通过提高GPx3和IR表达来改善脂肪组织代谢，而这种饮食对饮食诱导的肥胖小鼠的相互作用和代谢没有类似的影响。这些数据将阐明关于硒对人类胰岛素敏感性影响的相反结果，并揭示GPx3与IR对人类代谢的积极相互作用的相关性。总体目标是建立脂肪组织中GPx3的调节作为肥胖症中恢复胰岛素敏感性的新机制。

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.