Mammalian Genetics Unit, MRC Harwell Institute, Oxfordshire OX11 0RD, UK.
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
Sci Adv. 2021 Jul 21;7(30). doi: 10.1126/sciadv.abg0108. Print 2021 Jul.
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.
FTO 中的变异与肥胖的关联最强；然而，这些非编码变异如何在机制上影响全身生理学仍然不清楚。我们在小鼠中设计了 rs1421085 保守顺式调控模块 (CRM) 的缺失，并在体内证实 CRM 调节脂肪细胞中的 和 基因表达和线粒体功能。CRM 以脂肪组织依赖性的方式影响分子和细胞表型，并影响与肥胖相关的机体表型，包括减少高脂肪饮食诱导的体重增加、减少全身脂肪量和减少皮肤脂肪厚度。最后，我们将 CRM 与雄性类固醇模式的遗传决定因素联系起来，这种关联依赖于营养挑战，在小鼠和人类中是保守的。总的来说，我们的数据在分子、细胞、代谢和机体水平上建立了 rs1421085 调节回路的跨物种保守性，揭示了该变异作用以前未知的上下文依赖性。
