Folliculin-interacting protein FNIP2 impacts on overweight and obesity through a polymorphism in a conserved 3′ untranslated region

Abstract

AbstractBackgroundOverweight and obesity are defined by an anomalous or excessive fat accumulation that may compromise health. To find single-nucleotide polymorphisms (SNPs) influencing metabolic phenotypes associated with the obesity state, we analyze multiple anthropometric and clinical parameters in a cohort of 790 healthy volunteers and study potential associations with 48 manually curated SNPs, in metabolic genes functionally associated with the mechanistic target of rapamycin (mTOR) pathway.ResultsWe identify and validate rs2291007 within a conserved region in the 3′UTR of folliculin-interacting protein FNIP2 that correlates with multiple leanness parameters. The T-to-C variant represents the major allele in Europeans and disrupts an ancestral target sequence of the miRNA miR-181b-5p, thus resulting in increasedFNIP2mRNA levels in cancer cell lines and in peripheral blood from carriers of the C allele. Because the miRNA binding site is conserved across vertebrates, we engineered the T-to-C substitution in the endogenousFnip2allele in mice. Primary cells derived fromFnip2C/C mice show increased mRNA stability, and more importantly,Fnip2C/C mice replicate the decreased adiposity and increased leanness observed in human volunteers. Finally, expression levels ofFNIP2in both human samples and mice negatively associate with leanness parameters, and moreover, are the most important contributor in a multifactorial model of body mass index prediction.ConclusionsWe propose that rs2291007 influences human leanness through an evolutionarily conserved modulation ofFNIP2mRNA levels.Graphical Abstract