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， 需要的为了解开这种多变综合征的复杂生物学，我们必须应用遗传学方法， 技术来探测基因功能和与代谢相关的组织相互作用， 2型糖尿病的药物干预靶点。在颁发优异奖的十年里， 这项拨款对我们认识胰岛素抵抗综合症的显著贡献包括：（i） 绘制胰岛素抵抗对糖尿病发病和进展的组织特异性贡献; (ii)中枢神经系统中不同细胞类型的鉴定和分子表征， 介导胰岛素和反调节激素对血糖水平，饱腹感， 和能量平衡;（iii）发现和分子表征Gpr 17，一种孤儿受体， 介导胰岛素在下丘脑中的促胰岛素生成作用;（iv） 肠内分泌细胞转化为葡萄糖反应性胰岛素产生细胞的特性 在实验动物以及人类类器官培养中。在此基础上，重点是 更新的应用是了解胰岛素信号通路调节肝脏的分歧， 葡萄糖和脂质的生产，同时带来了前面的FoxO独立的转录机制， 胰岛素的调节。为此，PI提供了初步数据，确定了一系列广泛的激素- 反应性肝转录因子，并概述了两个目的，以表征他们的贡献，胰岛素 阻力目的1将深入研究转录因子FoxK 1和FoxK 2在介导细胞凋亡中的作用。 葡萄糖产生和甘油三酯合成增加的矛盾混合物，其特征是 糖尿病肝具体来说，实验将测试Akt和mTOR的差异磷酸化是否 这些蛋白质上的位点影响它们的转录输出。目标2将分析高收入群体的贡献 迁移率族转录因子TOX 4参与了细胞的新生和甘油三酯的重新合成。无论是 目的，将采用与现有胰岛素抵抗模型的广泛上位性来回答 新确定的因素是否独立于已知胰岛素或与已知胰岛素重叠的问题 信号形式。拟议的工作将促进我们对胰岛素抵抗的理解。 综合征在生化，遗传和综合生理水平，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.