Linking the FTO obesity rs1421085 variant circuitry to cellular, metabolic, and organismal phenotypes in vivo
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 Ir...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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American Association for the Advancement of Science
2021
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| _version_ | 1797100245166850048 |
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| author | Laber, S Forcisi, S Bentley, L Petzold, J Moritz, F Smirnov, KS 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, WA Hauner, H Schmitt-Kopplin, P Claussnitzer, M Cox, RD |
| author_facet | Laber, S Forcisi, S Bentley, L Petzold, J Moritz, F Smirnov, KS 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, WA Hauner, H Schmitt-Kopplin, P Claussnitzer, M Cox, RD |
| author_sort | Laber, S |
| collection | OXFORD |
| description | 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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| first_indexed | 2024-03-07T05:34:57Z |
| format | Journal article |
| id | oxford-uuid:e394a69b-42e3-4e81-893c-450708bda3eb |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T05:34:57Z |
| publishDate | 2021 |
| publisher | American Association for the Advancement of Science |
| record_format | dspace |
| spelling | oxford-uuid:e394a69b-42e3-4e81-893c-450708bda3eb2022-03-27T10:10:14ZLinking the FTO obesity rs1421085 variant circuitry to cellular, metabolic, and organismal phenotypes in vivoJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:e394a69b-42e3-4e81-893c-450708bda3ebEnglishSymplectic ElementsAmerican Association for the Advancement of Science2021Laber, SForcisi, SBentley, LPetzold, JMoritz, FSmirnov, KSAl Sadat, LWilliamson, IStrobel, SAgnew, TSengupta, SNicol, TGrallert, HHeier, MHonecker, JMianne, JTeboul, LDumbell, RLong, HSimon, MLindgren, CBickmore, WAHauner, HSchmitt-Kopplin, PClaussnitzer, MCox, RDVariants 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. |
| spellingShingle | Laber, S Forcisi, S Bentley, L Petzold, J Moritz, F Smirnov, KS 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, WA Hauner, H Schmitt-Kopplin, P Claussnitzer, M Cox, RD Linking the FTO obesity rs1421085 variant circuitry to cellular, metabolic, and organismal phenotypes in vivo |
| title | Linking the FTO obesity rs1421085 variant circuitry to cellular, metabolic, and organismal phenotypes in vivo |
| title_full | Linking the FTO obesity rs1421085 variant circuitry to cellular, metabolic, and organismal phenotypes in vivo |
| title_fullStr | Linking the FTO obesity rs1421085 variant circuitry to cellular, metabolic, and organismal phenotypes in vivo |
| title_full_unstemmed | Linking the FTO obesity rs1421085 variant circuitry to cellular, metabolic, and organismal phenotypes in vivo |
| title_short | Linking the FTO obesity rs1421085 variant circuitry to cellular, metabolic, and organismal phenotypes in vivo |
| title_sort | linking the fto obesity rs1421085 variant circuitry to cellular metabolic and organismal phenotypes in vivo |
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