Back to Search Start Over

Obesity-associated variants within FTO form long-range functional connections with IRX3

Authors :
Smemo, Scott
Tena, Juan J.
Kim, Kyoung-Han
Gamazon, Eric R.
Sakabe, Noboru J.
Gomez-Marin, Carlos
Aneas, Ivy
Credidio, Flavia L.
Sobreira, Debora R.
Wasserman, Nora F.
Lee, Ju Hee
Puviindran, Vijitha
Tam, Davis
Shen, Michael
Son, Joe Eun
Vakili, Niki Alizadeh
Sung, Hoon-Ki
Naranjo, Silvia
Acemel, Rafael D.
Manzanares, Miguel
Nagy, Andras
Cox, Nancy J.
Hui, Chi-Chung
Gomez-Skarmeta, Jose Luis
Nobrega, Marcelo A.
Source :
Nature. March 20, 2014, Vol. 507 Issue 7492, p371, 17 p.
Publication Year :
2014

Abstract

Genome-wide association studies (GWAS) have reproducibly associated variants within introns of FTO with increased risk for obesity and type 2 diabetes (T2D) (1-3). Although the molecular mechanisms linking these noncoding variants with obesity are not immediately obvious, subsequent studies in mice demonstrated that FTO expression levels influence body mass and composition phenotypes (4-6). However, no direct connection between the obesity-associated variants and FTO expression or function has been made (7-9). Here we show that the obesity-associated noncoding sequences within FTO are functionally connected, at megabase distances, with the homeobox gene IRX3. The obesity-associated FTO region directly interacts with the promoters of IRX3 as well as FTO in the human, mouse and zebrafish genomes. Furthermore, long-range enhancers within this region recapitulate aspects of IRX3 expression, suggesting that the obesity-associated interval belongs to the regulatory landscape of IRX3. Consistent with this, obesity-associated single nucleotide polymorphisms are associated with expression of IRX3, but not FTO, in human brains. A direct link between IRX3expression and regulation of body mass and composition is demonstrated by a reduction in body weight of 25 to 30% in Irx3-deficient mice, primarily through the loss of fat mass and increase in basal metabolic rate with browning of white adipose tissue. Finally, hypothalamic expression of a dominant-negative form of Irx3 reproduces the metabolic phenotypes of Irx3-deficient mice. Our data suggest that IRX3is a functional long-range target of obesity-associated variants within FTO and represents a novel determinant of body mass and composition.<br />Noncoding variation in single nucleotide polymorphisms (SNPs) within a 47-kilobase (kb) region of high linkage disequilibrium in introns 1 and 2 of FTO remains the strongest genetic association with risk [...]

Details

Language :
English
ISSN :
00280836
Volume :
507
Issue :
7492
Database :
Gale General OneFile
Journal :
Nature
Publication Type :
Academic Journal
Accession number :
edsgcl.364957110