The role of adipocyte KLF14 in Metabolic Syndrome

项目总结 代谢综合征(MetSyn)是一组共同发生并促进 发生心血管疾病(CVD)和2型糖尿病。尽管定义的各种标准 MetSyn存在，疾病状况包括腹型肥胖、胰岛素抵抗、血清甘油三酯升高 高密度脂蛋白(高密度脂蛋白)水平降低、血糖水平升高和高血压。 随着肥胖成为全球流行病，MetSyn的发病率预计将增加。这一增长 可能会有有害的影响，实际上可能会扭转美国心血管疾病减少的趋势。遗传力 对MetSyn各个组件的估计在40%到70%之间，这表明 疾病病理学的基因成分。最近的全基因组关联研究(GWAS)已经确定 超过600个与肥胖、糖尿病、心血管疾病和心脏代谢特征相关的基因组基因座。然而， 大多数潜在的基因和相关的机制，这些基因如何在疾病过程中起作用 仍然不为人所知。位于染色体7q32.3的一种2型糖尿病基因信号具有多效性，如 它还与血清高密度脂蛋白水平和体脂分布有关。基因变异的影响显现出来 女性比男性更强壮。该信号映射到45kb的重组间隔，从3kb扩展 转录因子KLF14的上游。使用皮下脂肪组织的基因表达数据 从男性代谢综合征(METSIM)队列参与者那里收集的活组织检查显示， KLF14可能是该基因座的顺式效应基因，并显示它是一种主要的反式调节程序 脂肪组织表达。我们的结果表明，KLF14的低表达与 人体有害的新陈代谢特征。因此，我们假设KLF14丰度的诱导和 其在脂肪细胞中靶标的变化将导致有益的新陈代谢。为了测试这一点 假设，这一建议概述了一种多层次的方法来定义KLF14的转录靶点 脂肪细胞，KLF14表达的调节对脂肪细胞功能的影响，并探讨KLF14的表达 脂肪细胞特异性诱导转基因小鼠KLF14表达的治疗益处。我们将使用 原代脂肪细胞、脂肪细胞系、原代组织和转基因小鼠的研究 基因表达和代谢表型。

PROJECT SUMMARY Metabolic syndrome (MetSyn) is a group of metabolic conditions that occur together and promote the development of cardiovascular disease (CVD) and type 2 diabetes. Although various criteria for defining MetSyn exist, disease conditions include abdominal obesity, insulin resistance, elevated serum triglyceride levels, depressed serum high-density lipoprotein (HDL) levels, elevated blood glucose levels and hypertension. The incidence of MetSyn is predicted to increase as obesity has become a worldwide epidemic. This increase may have detrimental effects and may actually reverse the trend of decreasing CVD in the US. Heritability estimates for individual components of MetSyn vary between 40% to 70%, suggesting a strong contribution of genetic components to disease pathology. Recent genome-wide association studies (GWAS) have identified over 600 genomic loci that are associated with obesity, diabetes, CVD and cardiometabolic traits. However, most of the underlying genes and the related mechanisms of how these loci contribute to the disease process remain unknown. One of the Type 2 Diabetes GWAS signals at chromosome 7q32.3 has pleiotropic effects as it is also associated with serum HDL levels and body fat distribution. The effects of the genetic variants appear to be stronger in females than in males. This signal maps to a 45kb recombination interval, extending from 3kb upstream of the transcription factor KLF14. Using gene expression data from subcutaneous adipose tissue biopsies collected from participants of the Metabolic Syndrome in Men (METSIM) cohort, we showed that KLF14 is the likely cis-effector gene for this locus and revealed it to be a master trans-regulator of a program of adipose tissue expression. Our results indicated that lower expression of KLF14 was associated with detrimental metabolic profiles in humans. Therefore, we hypothesized that induction of KLF14 abundance and resulting changes in its targets in adipocytes would result in a beneficial metabolic profile. To test this hypothesis, this proposal outlines a multilayered approach to define the trancriptional targets of KLF14 in adipocytes, the impact of the modulation of KLF14 expression on adipocyte function, and explore the therapeutic benefits of adipocyte-specific induction of KLF14 expression in transgenic mice. We will use primary adipocytes, adipocyte cell lines, primary tissues, and transgenic mice to dissect the effects of KLF14 on gene expression and metabolic phenotypes.