KLF14, adipose dysfunction, insulin resistance and type 2 diabetes: from genetic discovery to biological mechanisms and translation.

KLF14、脂肪功能障碍、胰岛素抵抗和 2 型糖尿病：从遗传发现到生物机制和转化。

• 批准号: MR/J010642/1
• 负责人: Mark Maccarthy
• 金额: $ 77.12万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FJ010642%2F1
• 关键词: KLF14; adipose; dysfunction; insulin; resistance

Type 2 diabetes is a major and growing cause of illness and death across the world. However, incomplete understanding of the processes involved in the development of this condition acts as a barrier to the development of better ways for treating and preventing the disease. In the past few years, collaborative efforts in human genetic discovery have identified over fifty positions in the human genome where individual sequence variation is associated with risk of type 2 diabetes. In principle, each of these genetic "signals" holds important clues to the mechanisms that are responsible for the maintenance of normal metabolic health. However, in most of these regions, we have yet to define the specific genetic variants responsible for the signal, or the particular genes through which the effects on diabetes-risk are mediated. As a result, the pace of biological insights has lagged behind that of genetic discovery. A key challenge for the field is to develop strategies that enable genetic signals such as these to be mined for the biological clues they can provide. We recently demonstrated that one of these diabetes signals maps near a gene named KLF14, and that this effect on risk of diabetes is driven by a reduced ability of insulin-sensitive tissues, including muscle and liver, to respond to insulin. We have also shown that, in fat tissue, the same variants near KLF14 have widespread effects on the levels of expression of a wide range of genes, including KLF14 itself. These data are consistent with a model whereby KLF14 acts as a major regulator of events in fat tissue, with these alterations in the levels of KLF14 leading, through as yet unspecified mechanisms, to peripheral insulin resistance and type 2 diabetes. The overall aim of this research is to define the molecular, cellular and physiological mechanisms which are responsible for the relationship between KLF14 and type 2 diabetes. To do this, we will pursue a number of complementary research strategies which include studies of human genetics and physiology and cellular studies in fat cells.More specifically, our work aims to:(a) define the specific sequence variants that are responsible for all of these effects, and how they influence levels of KLF14 within fat cells;(b) characterise the suite of genes that are turned on and off by KLF14, and understand the consequences of those secondary changes on the function of fat tissue; and(c) understand how it is that these KLF14-dependent changes in fat tissue lead to changes in the ability of remote tissues (such as muscle and liver) to respond to insulin. We expect that, by focusing on the role of KLF14 and the ways in which it leads to an increased risk of diabetes, we will gain valuable, generic insights into the mechanisms whereby events in fat have widespread metabolic effects in other tissues. An answer to this question would help us improve our understanding of the connections between obesity and diabetes, an issue of supreme importance given that much of the increase in diabetes prevalence around the world is driven by changes in the amount, distribution and function of fat. The research provides an opportunity to capitalise on recent discoveries in human genetics to advance understanding of disease biology. In the application, we explain how the biological information generated by this project can be exploited in directly translational studies to define novel approaches for treating, preventing, diagnosing and monitoring type 2 diabetes.

2 型糖尿病是全世界疾病和死亡的一个主要且日益严重的原因。然而，对这种疾病的发展过程的不完全了解阻碍了开发更好的治疗和预防该疾病的方法。在过去的几年中，人类基因发现领域的合作已经确定了人类基因组中 50 多个位置，其中个体序列变异与 2 型糖尿病的风险相关。原则上，这些遗传“信号”中的每一个都掌握着负责维持正常代谢健康的机制的重要线索。然而，在大多数这些区域中，我们尚未确定负责信号的特定遗传变异，或介导对糖尿病风险的影响的特定基因。结果，生物学洞察的步伐落后于基因发现的步伐。该领域的一个关键挑战是制定策略，使诸如此类的遗传信号能够被挖掘以获取它们可以提供的生物学线索。我们最近证明，其中一个糖尿病信号位于一个名为 KLF14 的基因附近，这种对糖尿病风险的影响是由胰岛素敏感组织（包括肌肉和肝脏）对胰岛素反应能力降低所致。我们还表明，在脂肪组织中，KLF14 附近的相同变异对多种基因（包括 KLF14 本身）的表达水平具有广泛影响。这些数据与 KLF14 作为脂肪组织事件的主要调节因子的模型一致，KLF14 水平的这些变化通过尚未明确的机制导致外周胰岛素抵抗和 2 型糖尿病。这项研究的总体目标是确定 KLF14 与 2 型糖尿病之间关系的分子、细胞和生理机制。为此，我们将采取一系列互补的研究策略，包括人类遗传学和生理学研究以及脂肪细胞的细胞研究。更具体地说，我们的工作旨在：(a) 定义导致所有这些影响的特定序列变体，以及它们如何影响脂肪细胞内 KLF14 的水平；(b) 描述由 KLF14 打开和关闭的基因组的特征，并了解这些二次变化对脂肪细胞的影响。 脂肪组织的功能； (c) 了解脂肪组织中这些 KLF14 依赖性变化如何导致远端组织（例如肌肉和肝脏）对胰岛素作出反应的能力发生变化。我们期望，通过关注 KLF14 的作用及其导致糖尿病风险增加的方式，我们将获得关于脂肪事件对其他组织产生广泛代谢影响的机制的有价值的、一般性的见解。这个问题的答案将有助于我们加深对肥胖与糖尿病之间关系的理解，鉴于世界各地糖尿病患病率的增加很大程度上是由脂肪数量、分布和功能的变化驱动的，这一问题至关重要。该研究提供了一个利用人类遗传学的最新发现来增进对疾病生物学的理解的机会。在申请中，我们解释了如何在直接转化研究中利用该项目生成的生物信息来定义治疗、预防、诊断和监测 2 型糖尿病的新方法。

项目成果

Regulatory variants at KLF14 influence type 2 diabetes risk via a female-specific effect on adipocyte size and body composition.

• DOI: 10.1038/s41588-018-0088-x
• 发表时间: 2018-04
• 期刊: Nature genetics
• 影响因子: 30.8
• 作者: Small KS;Todorčević M;Civelek M;El-Sayed Moustafa JS;Wang X;Simon MM;Fernandez-Tajes J;Mahajan A;Horikoshi M;Hugill A;Glastonbury CA;Quaye L;Neville MJ;Sethi S;Yon M;Pan C;Che N;Viñuela A;Tsai PC;Nag A;Buil A;Thorleifsson G;Raghavan A;Ding Q;Morris AP;Bell JT;Thorsteinsdottir U;Stefansson K;Laakso M;Dahlman I;Arner P;Gloyn AL;Musunuru K;Lusis AJ;Cox RD;Karpe F;McCarthy MI
• 通讯作者: McCarthy MI

New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk.

• DOI: 10.1038/ncomms10495
• 发表时间: 2016-02-01
• 期刊: Nature communications
• 影响因子: 16.6
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• 通讯作者: Loos RJ