Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK.
Nat Genet. 2018 Apr;50(4):572-580. doi: 10.1038/s41588-018-0088-x. Epub 2018 Apr 9.
Individual risk of type 2 diabetes (T2D) is modified by perturbations to the mass, distribution and function of adipose tissue. To investigate the mechanisms underlying these associations, 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, the expression of 385 genes. We demonstrate, in human cellular studies, that reduced KLF14 expression increases pre-adipocyte proliferation but disrupts lipogenesis, and in mice, that adipose tissue-specific deletion of Klf14 partially recapitulates the human phenotype of insulin resistance, dyslipidemia and T2D. We show that carriers of the KLF14 T2D risk allele shift body fat from gynoid stores to abdominal stores and display a marked increase in adipocyte cell size, and that these effects on fat distribution, and the T2D association, are female specific. The metabolic risk associated with variation at this imprinted locus depends on the sex both of the subject and of the parent from whom the risk allele derives.
个体 2 型糖尿病（T2D）的风险受脂肪组织质量、分布和功能变化的影响。为了研究这些关联的潜在机制，我们探索了与 KLF14 附近的 T2D 相关等位基因相关的分子、细胞和全身效应。我们表明，KLF14 糖尿病风险等位基因在脂肪组织中起作用，降低 KLF14 的表达，并在转录水平上调节 385 个基因的表达。我们在人类细胞研究中证明，降低 KLF14 的表达会增加前脂肪细胞的增殖，但会破坏脂肪生成，在小鼠中，脂肪组织特异性敲除 Klf14 部分再现了人类胰岛素抵抗、血脂异常和 T2D 的表型。我们表明，KLF14 T2D 风险等位基因的携带者将体脂肪从女性型储存转移到腹部储存，并表现出脂肪细胞大小的显著增加，而这种对脂肪分布的影响以及与 T2D 的关联是女性特有的。在这个印记基因座上的变异与主体和风险等位基因来源的父母的性别都有关。
