Format

Send to

Choose Destination
Nat Genet. 2018 Apr;50(4):572-580. doi: 10.1038/s41588-018-0088-x. Epub 2018 Apr 9.

Regulatory variants at KLF14 influence type 2 diabetes risk via a female-specific effect on adipocyte size and body composition.

Author information

1
Department of Twin Research and Genetic Epidemiology, King's College London, London, UK. kerrin.small@kcl.ac.uk.
2
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK.
3
Center for Public Health Genomics, Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA.
4
Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
5
Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
6
Cardiovascular Institute, Department of Medicine, Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
7
Biocomputing, Medical Research Council Harwell Institute, Oxford, UK.
8
Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
9
Genetics of Type 2 Diabetes, Medical Research Council Harwell Institute, Oxford, UK.
10
Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK.
11
Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
12
Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
13
deCODE Genetics, Reykjavik, Iceland.
14
Harvard Medical School, Boston, MA, USA.
15
CAS Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, PR China.
16
Department of Biostatistics, University of Liverpool, Liverpool, UK.
17
Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
18
Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
19
Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden.
20
Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
21
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK. mark.mccarthy@drl.ox.ac.uk.
22
Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK. mark.mccarthy@drl.ox.ac.uk.
23
Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK. mark.mccarthy@drl.ox.ac.uk.

Abstract

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.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center