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 an...

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Published in:Science advances 2021-07, Vol.7 (30)
Main Authors: Laber, Samantha, Forcisi, Sara, Bentley, Liz, Petzold, Julia, Moritz, Franco, Smirnov, Kirill S, Al Sadat, Loubna, Williamson, Iain, Strobel, Sophie, Agnew, Thomas, Sengupta, Shahana, Nicol, Tom, Grallert, Harald, Heier, Margit, Honecker, Julius, Mianne, Joffrey, Teboul, Lydia, Dumbell, Rebecca, Long, Helen, Simon, Michelle, Lindgren, Cecilia, Bickmore, Wendy A, Hauner, Hans, Schmitt-Kopplin, Philippe, Claussnitzer, Melina, Cox, Roger D
Format: Article
Language:English
Subjects:
Adipocytes - metabolism
Alpha-Ketoglutarate-Dependent Dioxygenase FTO - genetics
Alpha-Ketoglutarate-Dependent Dioxygenase FTO - metabolism
Animals
Diet, High-Fat - adverse effects
Genetics
Life Sciences
Male
Mice
Obesity - genetics
Obesity - metabolism
Phenotype
Polymorphism, Single Nucleotide
SciAdv r-articles
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Summary: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 and 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.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.abg0108