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

Lookup NU author(s): Dr Ana ViñuelaORCiD

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Abstract

© 2018 The Author(s).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.

Publication metadata

Author(s): Small KS, Todorcevic M, Civelek M, El-Sayed Moustafa JS, Wang X, Simon MM, Fernandez-Tajes J, Mahajan A, Horikoshi M, Hugill A, Glastonbury CA, Quaye L, Neville MJ, Sethi S, Yon M, Pan C, Che N, Vinuela A, Tsai P-C, Nag A, Buil A, Thorleifsson G, Raghavan A, Ding Q, Morris AP, Bell JT, Thorsteinsdottir U, Stefansson K, Laakso M, Dahlman I, Arner P, Gloyn AL, Musunuru K, Lusis AJ, Cox RD, Karpe F, McCarthy MI

Publication type: Article

Publication status: Published

Journal: Nature Genetics

Year: 2018

Volume: 50

Issue: 4

Pages: 572-580

Print publication date: 01/04/2018

Online publication date: 09/04/2018

Acceptance date: 15/02/2018

ISSN (print): 1061-4036

ISSN (electronic): 1546-1718

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/s41588-018-0088-x

DOI: 10.1038/s41588-018-0088-x

PubMed id: 29632379

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