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 - Publisher Copyright:
© 2018 The Author(s).
PY - 2018/4/1
Y1 - 2018/4/1
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 - http://www.scopus.com/inward/record.url?scp=85045303087&partnerID=8YFLogxK
U2 - 10.1038/s41588-018-0088-x
DO - 10.1038/s41588-018-0088-x
M3 - 文章
C2 - 29632379
AN - SCOPUS:85045303087
SN - 1061-4036
VL - 50
SP - 572
EP - 580
JO - Nature Genetics
JF - Nature Genetics
IS - 4
ER -
