The role of adipocyte KLF14 in Metabolic Syndrome

脂肪细胞 KLF14 在代谢综合征中的作用

• 批准号: 10391464
• 负责人: Mete Civelek
• 金额: $ 47.99万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-25 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10391464
• 关键词: Adipocytes; Adipose tissue; Auxins; Binding; Binding Sites; Biological; Biopsy; Blood Glucose; Body fat; CRISPR/Cas technology; Cardiovascular Diseases; Cell Line; Central obesity; ChIP-seq; Chromosomes; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Consensus; Data; Data Set; Depressed mood; Development; Diabetes Mellitus; Diagnosis; Disease; Endothelial Cells; Epidemic; Epitopes; Family; Female; Gene Expression; Genes; Genetic; Genetic Recombination; Genetic Transcription; Genetic study; Growth; Heritability; High Density Lipoproteins; Human; Human Genetics; Hypertension; In Vitro; Incidence; Individual; Insulin; Insulin Resistance; Laboratories; Life Style; Lipids; Lipolysis; Liver; Maps; Measurement; Measures; Metabolic; Metabolic syndrome; Metabolism; Molecular; Mus; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Participant; Pathology; Pathway interactions; Plant Growth Regulators; Plasma; Prevention; Process; Risk; Risk Factors; Role; Running; Serum; Signal Transduction; Testing; Therapeutic; Tissues; Transcript; Transcription Initiation Site; Transgenic Mice; Triglycerides; Whole Blood; Woman; abdominal fat; adipocyte differentiation; base; cardiometabolism; cohort; diabetes pathogenesis; differential expression; disorder prevention; epidemiology study; genetic variant; genome editing; genome wide association study; genomic locus; glucose tolerance; glucose uptake; improved; insulin tolerance; islet; lipid biosynthesis; male; member; men; metabolic phenotype; metabolic profile; monocyte; novel; overexpression; pleiotropism; programs; public health relevance; response; risk variant; sex; subcutaneous; trait; transcription factor; transcription factor USF; trend

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.

项目摘要 代谢综合征（MetSyn）是一组代谢状况，这些状况一起发生并促进代谢。 心血管疾病（CVD）和2型糖尿病的发展。虽然定义的各种标准 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（HDL）水平降低，血糖水平升高和高血压。 MetSyn的发病率预计将增加，因为肥胖已成为一种世界性的流行病。这种增加 可能会产生有害影响，实际上可能会逆转美国CVD下降的趋势。遗传力 MetSyn的单个组分的估计值在40%至70%之间变化，表明 遗传成分与疾病病理学的联系最近的全基因组关联研究（GWAS）发现， 超过600个与肥胖、糖尿病、CVD和心脏代谢特征相关的基因组位点。然而，在这方面， 大多数潜在的基因和这些基因座如何促成疾病过程的相关机制 仍然未知。染色体7q32.3处的2型糖尿病GWAS信号之一具有多效性作用， 它还与血清HDL水平和身体脂肪分布有关。基因变异的影响 女性比男性更强壮该信号映射到45kb的重组区间，从3kb延伸到45kb。 转录因子KLF14的上游。利用皮下脂肪组织的基因表达数据 从男性代谢综合征（METSIM）队列的参与者中收集的活检，我们表明， KLF14可能是该基因座的顺式效应基因，并揭示它是一个主要的反式调节程序， 脂肪组织表达。我们的研究结果表明，KLF14的低表达与 对人体有害的代谢特征。因此，我们假设诱导KLF14丰度和 导致其在脂肪细胞中的靶点的变化将导致有益的代谢谱。为了验证这一 假设，该提案概述了一种多层次的方法来定义KLF 14的转录目标， 脂肪细胞，调节KLF14表达对脂肪细胞功能的影响，并探讨 在转基因小鼠中脂肪细胞特异性诱导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，以分析KLF14的作用 基因表达和代谢表型。

项目成果

Adipocyte-Specific Modulation of KLF14 Expression in Mice Leads to Sex-Dependent Impacts on Adiposity and Lipid Metabolism.

小鼠中 KLF14 表达的脂肪细胞特异性调节会对肥胖和脂质代谢产生性别依赖性影响。

• DOI: 10.2337/db21-0674
• 发表时间: 2022
• 期刊: Diabetes
• 影响因子: 7.7
• 作者: Yang,Qianyi;Hinkle,Jameson;Reed,JordanN;Aherrahrou,Redouane;Xu,Zhiwen;Harris,ThurlE;Stephenson,ErinJ;Musunuru,Kiran;Keller,SusannaR;Civelek,Mete
• 通讯作者: Civelek,Mete

Genes in human obesity loci are causal obesity genes in C. elegans.

• DOI: 10.1371/journal.pgen.1009736
• 发表时间: 2021-09
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Ke W;Reed JN;Yang C;Higgason N;Rayyan L;Wählby C;Carpenter AE;Civelek M;O'Rourke EJ
• 通讯作者: O'Rourke EJ