Regulatory variants at KLF14 influence type 2 diabetes risk via a female-specific effect on adipocyte size and body composition.
Regulatory variants at KLF14 influence type 2 diabetes risk via a female-specific effect on adipocyte size and body composition.
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DOI：
10.1038/s41588-018-0088-x
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发表时间：
2018-04
期刊：
影响因子：
30.8
通讯作者：
McCarthy MI
中科院分区：
文献类型：
--
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
2型糖尿病（T2D）的个体风险是由脂肪量、分布和功能的扰动而改变的。为了研究相关机制，我们探索了KLF14附近t2d相关等位基因的分子、细胞和全身效应。我们发现KLF14糖尿病风险等位基因在脂肪组织中降低KLF14的表达，并在反式中调节385个基因的表达。我们证明，在人类细胞研究中，KLF14表达的减少增加了脂肪前细胞增殖，但破坏了脂肪生成，并且，在小鼠中，KLF14的脂肪特异性缺失部分再现了人类胰岛素抵抗、血脂异常和T2D的表型。我们发现KLF14 T2D风险等位基因携带者将身体脂肪从雌性转移到腹部储存，并显示脂肪细胞大小显着增加：这些对脂肪分布的影响以及与T2D的关联是女性特有的。与该基因座变异相关的代谢风险取决于受试者的性别和该风险等位基因的亲本。
Individual risk of type 2 diabetes (T2D) is modified by perturbations of adipose mass, distribution and function. To investigate mechanisms responsible, we explored the molecular, cellular, and whole-body effects of T2D-associated alleles near KLF14. We show that KLF14 diabetes-risk alleles act in adipose tissue to reduce KLF14 expression, and modulate, in trans, expression of 385 genes. We demonstrate that, in human cellular studies, reduced KLF14 expression increases pre-adipocyte proliferation but disrupts lipogenesis, and, in mice, adipose-specific deletion of Klf14 partially recapitulates the human phenotype of insulin resistance, dyslipidemia and T2D. We show that KLF14 T2D risk-allele carriers shift body fat from gynoid to abdominal stores, and display a marked increase in adipocyte cell size: these effects on fat distribution, and the T2D-association, are female-specific. Metabolic risk associated with variation at this imprinted locus depends on both the sex of the subject, and of the parent from whom the risk-allele derives.
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影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
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影响因子：
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作者：
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影响因子：
30.8
作者：
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通讯作者：
Knight, Julian C.
影响因子：
4.5
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通讯作者：
ENGAGE Consortium
影响因子：
7.7
作者：
Keildson S;Fadista J;Ladenvall C;Hedman ÅK;Elgzyri T;Small KS;Grundberg E;Nica AC;Glass D;Richards JB;Barrett A;Nisbet J;Zheng HF;Rönn T;Ström K;Eriksson KF;Prokopenko I;MAGIC Consortium;DIAGRAM Consortium;MuTHER Consortium;Spector TD;Dermitzakis ET;Deloukas P;McCarthy MI;Rung J;Groop L;Franks PW;Lindgren CM;Hansson O
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