Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK.
Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK; NIHR Oxford Biomedical Research Centre, OUH Trust, Oxford OX3 7LE, UK.
EBioMedicine. 2019 Jun;44:467-475. doi: 10.1016/j.ebiom.2019.05.047. Epub 2019 May 28.
Abdominal fat mass is associated with metabolic risk whilst gluteal femoral fat is paradoxically protective. MicroRNAs are known to be necessary for adipose tissue formation and function but their role in regulating human fat distribution remains largely unexplored.
An initial microarray screen of abdominal subcutaneous and gluteal adipose tissue, with validatory qPCR, identified microRNA-196a as being strongly differentially expressed between gluteal and abdominal subcutaneous adipose tissue.
We found that rs11614913, a SNP within pre-miR-196a-2 at the HOXC locus, is an eQTL for miR-196a expression in abdominal subcutaneous adipose tissue (ASAT). Observations in large cohorts showed that rs11614913 increased waist-to-hip ratio, which was driven specifically by an expansion in ASAT. In further experiments, rs11614913 was associated with adipocyte size. Functional studies and transcriptomic profiling of miR-196a knock-down pre-adipocytes revealed a role for miR-196a in regulating pre-adipocyte proliferation and extracellular matrix pathways.
These data identify a role for miR-196a in regulating human body fat distribution. FUND: This work was supported by the Medical Research Council and Novo Nordisk UK Research Foundation (G1001959) and Swedish Research Council. We acknowledge the OBB-NIHR Oxford Biomedical Research Centre and the British Heart Foundation (BHF) (RG/17/1/32663). Work performed at the MRC Epidemiology Unit was funded by the United Kingdom's Medical Research Council through grants MC_UU_12015/1, MC_PC_13046, MC_PC_13048 and MR/L00002/1.
腹部脂肪量与代谢风险相关，而臀股脂肪量则具有保护作用，这令人感到矛盾。已知 microRNA 对于脂肪组织的形成和功能是必要的，但它们在调节人体脂肪分布中的作用在很大程度上仍未得到探索。
我们对腹部皮下和臀股脂肪组织进行了初步的 microRNA 芯片筛选，并进行了 qPCR 验证，结果发现 microRNA-196a 在臀股和腹部皮下脂肪组织之间的表达存在显著差异。
我们发现，HOXC 基因座上 pre-miR-196a-2 内的 rs11614913 是腹部皮下脂肪组织（ASAT）中 miR-196a 表达的 eQTL。在大型队列中的观察结果表明，rs11614913 增加了腰围与臀围之比，这主要是由于 ASAT 的扩张所致。在进一步的实验中，rs11614913 与脂肪细胞大小有关。miR-196a 敲低前脂肪细胞的功能研究和转录组谱分析显示，miR-196a 在调节前脂肪细胞增殖和细胞外基质途径中起作用。
这些数据表明，miR-196a 在调节人体脂肪分布中发挥作用。
这项工作得到了英国医学研究理事会和诺和诺德英国研究基金会（G1001959）以及瑞典研究理事会的支持。我们感谢 OBB-NIHR 牛津生物医学研究中心和英国心脏基金会（BHF）（RG/17/1/32663）。在 MRC 流行病学组开展的工作得到了英国医学研究理事会通过以下拨款的支持：MC_UU_12015/1、MC_PC_13046、MC_PC_13048 和 MR/L00002/1。
