Samantha Laber, Sara Forcisi, Liz Bentley, Julia Petzold, Franco Moritz, Kirill S Smirnov, Loubna Al Sadat, Iain Williamson, Sophie Strobel, Thomas Agnew, Shahana Sengupta, Tom Nicol, Harald Grallert, Margit Heier, Julius Honecker, Joffrey Mianne, Lydia Teboul, Rebecca Dumbell, Helen Long, Michelle Simon, Cecilia Lindgren, Wendy A Bickmore, Hans Hauner, Philippe Schmitt-Kopplin, Melina Claussnitzer, Roger D Cox
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...
July 2021: Science Advances