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BACKGROUND: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. METHODS: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. FINDINGS: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. INTERPRETATION: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.

Original publication

DOI

10.1016/j.ebiom.2019.05.047

Type

Journal article

Journal

EBioMedicine

Publication Date

06/2019

Volume

44

Pages

467 - 475

Addresses

Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK.

Keywords

Adipose Tissue, Cell Line, Extracellular Matrix, Adipocytes, Humans, MicroRNAs, Gene Expression Profiling, Signal Transduction, Gene Expression Regulation, RNA Interference, Polymorphism, Single Nucleotide, Alleles, Quantitative Trait Loci, Adult, Middle Aged, Female, Male, Adiposity, Transcriptome