Abstract
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.
Highlights
The FTO locus has been reproducibly associated with body mass index (BMI) in humans across diverse ethnicities [1,2,3]
The FTO locus is linked to multiple obesity-related phenotypes through common variant association studies including BMI, fat mass–related traits, and basal metabolic rate, and is considered the strongest genetic risk locus for obesity in humans
We established a chain of causation in human preadipocytes in vitro in which the rs1421085 C allele was an active enhancer resulting in increased IRX3/5, decreased mitochondrial function, and increased lipid accumulation
Summary
The FTO locus has been reproducibly associated with body mass index (BMI) in humans across diverse ethnicities [1,2,3]. Like the vast majority of trait-associated variants identified by genome-wide efforts, BMI-associated variants at the FTO locus map to the noncoding genome, which is still poorly characterized. Genome-wide association study (GWAS) loci characteristically contain dozens of statistically significant variants in high linkage disequilibrium (LD), with regulatory variants often acting at distances up to a megabase (Mb), implicating multiple potential effector genes. These confounding factors pose a major challenge when translating genetic associations to mechanisms and therapeutic hypotheses. Multiple variants and tissues, including both adipose and brain, have been implicated in mediating risk at the FTO locus, pointing toward multiorgan and multivariant mechanisms [4, 6,7,8,9]
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