Linking the <i>FTO</i> obesity rs1421085 variant circuitry to cellular, metabolic, and organismal phenotypes in vivo
Samantha Laber, Sara Forcisi, Liz Bentley, Julia Petzold, Franco Moritz, Kirill S. Smirnov, Loubna Al Sadat, Iain Williamson, Sophie Strobel, Thomas Agnew, Shahana Sengupta, T. NICOL, Harald Grallert, Margit Heier, Julius Honecker, Joffrey Mianné, Lydia Teboul, Rebecca Dumbell, Helen Long, Michelle Simon, Cecilia M. Lindgren, Wendy A. Bickmore, Hans Hauner, Philippe Schmitt‐Kopplin, Melina Claussnitzer, Roger Cox
Abstract
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.