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

Laber, S., Forcisi, S., Bentley, L., Petzold, J., Moritz, F., Smirnov, K.S., 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. ORCID: 0000-0002-8805-3777, Long, H., Simon, M., Lindgren, C., Bickmore, W.A., Hauner, H., Schmitt-Kopplin, P., Claussnitzer, M. and Cox, R.D., 2021. Linking the FTO obesity rs1421085 variant circuitry to cellular, metabolic, and organismal phenotypes in vivo. Science Advances, 7 (30): eabg0108. ISSN 2375-2548

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Abstract

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.

Item Type: Journal article
Publication Title: Science Advances
Creators: Laber, S., Forcisi, S., Bentley, L., Petzold, J., Moritz, F., Smirnov, K.S., 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. and Cox, R.D.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 21 July 2021
Volume: 7
Number: 30
ISSN: 2375-2548
Identifiers:
NumberType
10.1126/sciadv.abg0108DOI
1454931Other
Rights: Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Divisions: Schools > School of Science and Technology
Record created by: Laura Ward
Date Added: 29 Jul 2021 13:52
Last Modified: 29 Jul 2021 13:52
URI: http://irep.ntu.ac.uk/id/eprint/43661

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