Role of Dach1 in Obesity-Induced Hepatic Insulin Resistance

肝脏葡萄糖产生过多(HGP)和胰岛素信号转导缺陷在 2型糖尿病(T2D)的发展。几年来，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 临床前研究可以采用一种新的治疗方法。我们发现肥胖会导致 钙诱导钙/钙调蛋白依赖的激活途径的激活 肝细胞中的蛋白激酶II(CaMKII)。CaMKII抑制ATF6蛋白伴侣 模块，进而激活PERK-ATF4-Trb3通路，破坏胰岛素受体 发信号。我们的新数据显示，肝脏CaMKII磷酸化并阻断核 IIa类组蛋白脱乙酰酶(HDAC4)的易位，增加了辅酶A的水平。 抑制子称为腊肠同系物1(Dach1)。Dach1，以前从未被牵连过 在代谢方面，在肥胖小鼠和人类的肝脏中显著增加，而在 肥胖小鼠预防高血糖和高胰岛素血症，认为Dach1是关键 肥胖、胰岛素抵抗和代谢功能障碍之间的联系。我们已经提出了一系列 肝细胞Dach1缺乏改善胰岛素作用机制的研究 肥胖抵抗(目标1)和阐明肥胖的近端信号事件 调节Dach1及Dach1介导的抑制血管生成的下游分子机制 胰岛素信号转导(目标2)。肝组织Dach1参与血管内皮细胞代谢紊乱 肥胖是一个全新的、未经探索的概念。我们相信在完成建议的 研究表明，肝Dach1通过其对胰岛素抵抗的影响，在介导胰岛素抵抗中的整合作用。 胰岛素信号转导可以揭示新的洞察力，并为治疗高血压提供治疗策略 T2D。

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.