Role of Dach1 in Obesity-Induced Hepatic Insulin Resistance

过多的肝葡萄糖产生（HGP）和有缺陷的胰岛素信号传导在糖尿病中是关键的。 2型糖尿病（T2 D）的发展。在过去的几年里，我们的工作揭示了新的 与这两个过程相关的分子途径，我们最近在 临床前研究适合于新型疗法。我们发现肥胖会导致 激活由钙诱导的钙/钙调蛋白依赖性激活启动的途径 蛋白激酶II（CaMK II）。CaMKII抑制ATF 6蛋白伴侣 模块，这反过来激活PERK-ATF 4-Trb 3通路，破坏胰岛素受体 发信号。我们的新数据显示，肝CaMKII磷酸化并阻断核 IIa类组蛋白去乙酰化酶（HDAC 4）的易位，这增加了一种共- Dach1（Dachshund homolog 1）。Dach 1，以前从未被牵连 在代谢中，在肥胖小鼠和人类的肝脏中显着增加， 肥胖小鼠可防止高血糖和高胰岛素血症，确定Dach 1是关键的 肥胖、胰岛素抵抗和代谢功能障碍之间的联系。我们提出了一系列 研究确定肝细胞Dach 1缺陷改善胰岛素的机制 肥胖抵抗（目的1），并阐明肥胖如何在近端信号事件 调节Dach 1和Dach 1介导的抑制Dach 1的下游分子机制， 胰岛素信号传导（Aim 2）。肝Dach 1基因在老年人代谢紊乱中的作用 肥胖是一个全新的、未经探索的概念。我们相信，在完成拟议的 研究表明，肝脏Dach 1通过其对胰岛素抵抗的影响， 胰岛素信号传导可以揭示新的见解，并提供治疗策略， 2型糖尿病

Excessive hepatic glucose production (HGP) and defective insulin signaling are critical in the development of type 2 diabetes (T2D). Over the past few years, our work has revealed new molecular pathways relevant to these two processes—pathways that we have shown recently in pre-clinical studies are amenable to a new type of therapy. We showed that obesity leads to the activation of a pathway initiated by calcium-induced activation of calcium/calmodulin-dependent protein kinase II (CaMKII) in hepatocytes (HCs). CaMKII suppresses an ATF6-protein chaperone module, which in turn activates a PERK-ATF4-Trb3 pathway that disrupts insulin receptor signaling. Our new data has revealed that hepatic CaMKII phosphorylates and blocks nuclear translocation of a class IIa histone deacetylase (HDAC4), which increases the level of a co- repressor called Dachshund homolog 1 (Dach1). Dach1, which has never before been implicated in metabolism, is dramatically increased in the livers of obese mice and humans and its inhibition in obese mice protects against hyperglycemia and hyperinsulinemia, identifying Dach1 as a critical link between obesity, insulin resistance, and metabolic dysfunction. We have proposed a series of studies to determine the mechanisms by which hepatocyte Dach1 deficiency improves insulin resistance in obesity (Aim 1) and to elucidate the proximal signaling events of how obesity regulates Dach1 and the downstream molecular mechanisms of Dach1-mediated suppression of insulin signaling (Aim 2). The involvement of hepatic Dach1 in the metabolic disturbances of obesity is a completely new and unexplored concept. We believe upon completion of the proposed studies, the integrated role of hepatic Dach1 in mediating insulin resistance through its effects on insulin signaling could reveal novel insights and provide therapeutic strategies for the treatment of T2D.