MicroRNA-196a links human body fat distribution to adipose tissue extracellular matrix compositionResearch in context
Catriona Hilton,
Matt J. Neville,
Laura B.L. Wittemans,
Marijana Todorcevic,
Katherine E. Pinnick,
Sara L. Pulit,
Jian'an Luan,
Agné Kulyté,
Ingrid Dahlman,
Nicholas J. Wareham,
Luca A. Lotta,
Peter Arner,
Cecilia M. Lindgren,
Claudia Langenberg,
Fredrik Karpe
Affiliations
Catriona Hilton
Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK
Matt J. Neville
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; Corresponding author at: Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK.
Laura B.L. Wittemans
Wellcome Trust Centre for Human Genetics, Oxford University, Oxford OX3 7BN, UK; Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge CB2 0QQ, UK
Marijana Todorcevic
Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK
Katherine E. Pinnick
Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK
Sara L. Pulit
Big Data Institute, University of Oxford, Oxford OX3 7FZ, UK; Wellcome Trust Centre for Human Genetics, Oxford University, Oxford OX3 7BN, UK; Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands
Jian'an Luan
Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge CB2 0QQ, UK
Agné Kulyté
Department of Medicine (H7), Karolinska Institutet at Karolinska University Hospital - Huddinge, 141 86 Stockholm, Sweden
Ingrid Dahlman
Department of Medicine (H7), Karolinska Institutet at Karolinska University Hospital - Huddinge, 141 86 Stockholm, Sweden
Nicholas J. Wareham
Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge CB2 0QQ, UK
Luca A. Lotta
Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge CB2 0QQ, UK
Peter Arner
Department of Medicine (H7), Karolinska Institutet at Karolinska University Hospital - Huddinge, 141 86 Stockholm, Sweden
Cecilia M. Lindgren
Big Data Institute, University of Oxford, Oxford OX3 7FZ, UK; Wellcome Trust Centre for Human Genetics, Oxford University, Oxford OX3 7BN, UK
Claudia Langenberg
Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge CB2 0QQ, UK
Fredrik Karpe
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; Corresponding author at: Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK.
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. Keywords: Abdominal, Adipocyte, Body fat distribution, Gluteal, Human adipose tissue, MicroRNA
