Mouse Models of Insulin Resistance

摘要 胰岛素抵抗是对全球公共健康的重大威胁，也是一个在很大程度上没有得到满足的医学问题。 需要。为了揭开这种多变综合征的复杂生物学，我们努力应用基因 探索与新陈代谢相关的基因功能和组织相互作用的技术，并识别易处理的 2型糖尿病药物干预的靶点。在荣誉奖的十年里， 这笔赠款对我们了解胰岛素抵抗综合征的显著贡献包括：(I) 绘制胰岛素抵抗对糖尿病发生和发展的组织特异性贡献； (2)中枢神经系统中不同细胞类型的鉴定和分子特征 调节胰岛素和逆调节激素对血糖水平、饱腹感、 和能量平衡；(Iii)孤儿受体Gpr17的发现和分子鉴定 介导胰岛素在下丘脑的厌食效应；(Iv)显著 肠内分泌细胞转化为葡萄糖反应性胰岛素分泌细胞的特性 在实验动物和人类器官培养中。在此基础上，重点是 新的应用是理解胰岛素信号通路调节肝脏的分歧 葡萄糖和脂肪的产生，同时突出FoxO非依赖的转录机制 胰岛素的调节作用。为此，PI提供了初步数据，确定了一组广泛的激素- 反应性肝脏转录因子，并概述了两个目的来表征它们对胰岛素的贡献 抵抗。目标1将深入研究转录因子FoxK1和FoxK2在介导 葡萄糖产量增加和甘油三酯合成矛盾的混合物，这是 糖尿病肝。具体地说，实验将测试Akt和mTor的差异磷酸化 这些蛋白质上的位点会影响它们的转录输出。目标2将分析High的贡献 迁移率组转录因子TOX4参与糖异生和甘油三酯的从头合成。在这两个地方 AIMS，将使用现有胰岛素抵抗模型的广泛上位来回答 新确定的因素是否独立于已知的胰岛素或与已知的胰岛素重叠的问题 信令模式。拟议的工作将促进我们对胰岛素抵抗的理解 生化、遗传和综合生理水平的综合征，最终目标是 将新获得的信息转化为创新的治疗方法。

ABSTRACT Insulin resistance stands as a significant threat to public health worldwide, and a largely unmet medical need. To unravel the complex biology of this protean syndrome, we endeavored to apply genetic techniques to probe gene function and tissue interactions related to metabolism, and identify tractable targets for pharmacological intervention in type 2 diabetes. Over the ten years of the MERIT award, notable contributions of this grant to our knowledge of the insulin resistance syndrome have included: (i) mapping the tissue-specific contributions of insulin resistance to the onset and progression of diabetes; (ii) identification and molecular characterization of distinct cell types in the central nervous system that mediate different effects of insulin and counterregulatory hormones on plasma glucose levels, satiety, and energy balance; (iii) discovery and molecular characterization of Gpr17, an orphan receptor that mediates the anorexigenic effects of insulin in the hypothalamus; (iv) demonstration of the remarkable property of enteroendocrine cells to undergo conversion into glucose-responsive insulin-producing cells in experimental animals as well as human organoid cultures. Building on this foundation, the focus of this renewal application is to understand the divergence of insulin signaling pathways regulating hepatic glucose and lipid production, while bringing to the fore FoxO-independent mechanisms of transcriptional regulation by insulin. To that end, the PI presents preliminary data identifying a broad set of hormone- responsive hepatic transcription factors, and outlines two aims to characterize their contribution to insulin resistance. Aim 1 will delve into the role of transcription factors FoxK1 and FoxK2 in mediating the paradoxical admixture of increased glucose production and triglyceride synthesis that characterizes the diabetic liver. Specifically, experiments will test whether differential phosphorylation at Akt and mTOR sites on these proteins affects their transcriptional output. Aim 2 will analyze the contribution of the high mobility group transcription factor TOX4 to gluconeogenesis and de novo triglyceride synthesis. In both aims, extensive epistasis with existing models of insulin resistance will be employed to answer the question of whether the newly identified factors are independent of or overlapping with known insulin signaling modalities. The proposed body of work will advance our understanding of the insulin-resistant syndrome at the biochemical, genetic, and integrated physiological levels, with the ultimate goal of translating newly acquired information into innovative approaches to treatment.