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

TY - JOUR

T1 - Regulatory variants at KLF14 influence type 2 diabetes risk via a female-specific effect on adipocyte size and body composition

AU - Small, Kerrin S.

AU - Todorčević, Marijana

AU - Civelek, Mete

AU - El-Sayed Moustafa, Julia S.

AU - Wang, Xiao

AU - Simon, Michelle M.

AU - Fernandez-Tajes, Juan

AU - Mahajan, Anubha

AU - Horikoshi, Momoko

AU - Hugill, Alison

AU - Glastonbury, Craig A

AU - Quaye, Lydia

AU - Neville, Matt J.

AU - Sethi, Siddharth

AU - Yon, Marianne

AU - Pan, Calvin

AU - Che, Nam

AU - Viñuela, Ana

AU - Tsai, Pei-Chien

AU - Nag, Abhishek

AU - Buil, Alfonso

AU - Thorleifsson, Gudmar

AU - Raghavan, Avanthi

AU - Ding, Qiurong

AU - Morris, Andrew P.

AU - Bell, Jordana T.

AU - Thorsteinsdottir, Unnur

AU - Stefansson, Kari

AU - Laakso, Markku

AU - Dahlman, Ingrid

AU - Arner, Peter

AU - Gloyn, Anna L.

AU - Musunuru, Kiran

AU - Lusis, Aldons J.

AU - Cox, Roger D.

AU - Karpe, Fredrik

AU - McCarthy, Mark I.

N1 - Copyright © 2018 Nature America Inc., part of Springer Nature. All rights reserved

PY - 2018/4

Y1 - 2018/4

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85045303087

U2 - 10.1038/s41588-018-0088-x

DO - 10.1038/s41588-018-0088-x

M3 - Article

SN - 1061-4036

VL - 50

SP - 572

EP - 580

JO - Nature Genetics

JF - Nature Genetics

IS - 4

ER -