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
PY - 2018
Y1 - 2018
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.
KW - Adipocytes/pathology
KW - Alleles
KW - Animals
KW - Body Composition/genetics
KW - Body Fat Distribution
KW - Cell Size
KW - Diabetes Mellitus, Type 2/genetics
KW - Enhancer Elements, Genetic
KW - Female
KW - Gene Expression
KW - Genome-Wide Association Study
KW - Genomic Imprinting
KW - Humans
KW - Kruppel-Like Transcription Factors/deficiency
KW - Lipogenesis/genetics
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Phenotype
KW - Risk Factors
KW - Sex Characteristics
KW - Sp Transcription Factors/genetics
U2 - 10.1038/s41588-018-0088-x
DO - 10.1038/s41588-018-0088-x
M3 - Article
C2 - 29632379
SN - 1061-4036
VL - 50
SP - 572
EP - 580
JO - Nature Genetics
JF - Nature Genetics
IS - 4
ER -
