Reinstating insulin sensitivity in metabolic disorders via regulation of selenoproteins

通过调节硒蛋白恢复代谢紊乱中的胰岛素敏感性

• 批准号: 505665051
• 负责人: Professor Dr. André Kleinridders
• 金额: --
• 依托单位: Institut für Ernährungswissenschaft
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/505665051?language=en
• 关键词: Reinstating; insulin; sensitivity; metabolic; disorders

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.

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。这两种疾病的特征都是胰岛素信号不足。1型糖尿病患者胰岛素抵抗的发生率为100%，而2型糖尿病患者胰岛素抵抗的发生率为100%。脂肪组织中的胰岛素抵抗不允许适当的能量储存，这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，改善脂肪组织中的胰岛素作用是治疗代谢性疾病的一个潜在策略，脂肪组织中的胰岛素抵抗的特征在于抑制胰岛素信号蛋白的丝氨酸磷酸化事件，以及降低胰岛素受体（IR）表达从而减弱胰岛素作用。最近，我们已经表明，改变硒蛋白的转录调控与减少IR在脂肪组织中的表达是存在于肥胖和长期胰岛素抵抗的条件。与饲喂常规HFD的小鼠相比，饲喂补充有超生理水平的亚硒酸盐的高脂肪饮食（HFD）的瘦小鼠改善胰岛素敏感性，脂肪组织中IR表达增加。此外，我们发现硒蛋白谷胱甘肽过氧化物酶3（GPx 3）可以调节IR的表达。为什么GPx 3在代谢紊乱中失调，以及GPx 3如何机械地调节脂肪组织中的IR表达，目前尚不清楚。此外，GPx 3的缺失是否足以改变体内胰岛素敏感性尚不确定，因此，我们将在不同的小鼠模型中研究GPx 3、IR和各种硒蛋白的调控，以了解其表达模式的调节。此外，我们将研究亚硒酸盐和GPx 3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GPx 3缺陷小鼠进行代谢表征，以阐明GPX 3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改善脂肪组织代谢，提高GPx 3和IR表达，而这种饮食不会以类似的方式影响这种相互作用和代谢，当喂食饮食诱导的肥胖小鼠时。这些数据将阐明硒对人体胰岛素敏感性影响的相反结果，并揭示GPx 3与IR的积极相互作用对人体代谢的相关性。总体目标是建立脂肪组织中GPx 3的调节作为肥胖症中恢复胰岛素敏感性的新机制。