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Laber, S.* ; Forcisi, S. ; Bentley, L.* ; Petzold, J.* ; Moritz, F. ; Smirnov, K. ; Al Sadat, L.* ; Williamson, I.* ; Strobel, S.* ; Agnew, T.* ; Sengupta, S.* ; Nicol, T.* ; Grallert, H. ; Heier, M. ; Honecker, J.* ; Mianne, J.* ; Teboul, L.* ; Dumbell, R.* ; Long, H.* ; Simon, M.* ; Lindgren, C.* ; Bickmore, W.A.* ; Hauner, H.* ; Schmitt-Kopplin, P. ; Claussnitzer, M.* ; Cox, R.D.*

Linking the FTO obesity rs1421085 variant circuitry to cellular, metabolic, and organismal phenotypes in vivo.

Sci. Adv. 7:eabg0108 (2021)
Publ. Version/Full Text DOI
Open Access Gold
Creative Commons Lizenzvertrag
Variants in FTO have the strongest association with obesity; however, it is still unclear how those noncoding variants mechanistically affect whole-body physiology. We engineered a deletion of the rs1421085 conserved cis-regulatory module (CRM) in mice and confirmed in vivo that the CRM modulates Irx3 and Irx5 gene expression and mitochondrial function in adipocytes. The CRM affects molecular and cellular phenotypes in an adipose depot-dependent manner and affects organismal phenotypes that are relevant for obesity, including decreased high-fat diet-induced weight gain, decreased whole-body fat mass, and decreased skin fat thickness. Last, we connected the CRM to a genetically determined effect on steroid patterns in males that was dependent on nutritional challenge and conserved across mice and humans. Together, our data establish cross-species conservation of the rs1421085 regulatory circuitry at the molecular, cellular, metabolic, and organismal level, revealing previously unknown contextual dependence of the variant's action.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Body-mass Index; Rare Variants; Food-intake; Gene; Mouse; Range; Signatures; Domains; Dietary
ISSN (print) / ISBN 2375-2548
e-ISSN 2375-2548
Quellenangaben Volume: 7, Issue: 30, Pages: , Article Number: eabg0108 Supplement: ,
Publisher American Association for the Advancement of Science (AAAS)
Publishing Place Washington, DC [u.a.]
Reviewing status Peer reviewed
Grants State of Bavaria
Novo Nordisk Postdoctoral Research Fellowship
Next Generation Award of the Broad Institute of MIT and Harvard
German Center for Diabetes Research (DZD)
UK Medical Research Council
MRC University Unit programme
Li Ka Shing Foundation
WT-SSI/John Fell funds
National Institute for Health Research Oxford Biomedical Research Centre
Helmholtz Zentrum Munchen-German Research Center for Environmental Health - German Federal Ministry of Education and Research (BMBF)
MRC PhD studentship