Por favor, use este identificador para citar o enlazar este Item:http://hdl.handle.net/20.500.12105/18959
Título
Folliculin-interacting protein FNIP2 impacts on overweight and obesity through a polymorphism in a conserved 3' untranslated region.
Autor(es)
Fernández, Lara P | Deleyto-Seldas, Nerea | Colmenarejo, Gonzalo | Sanz, Alba | Wagner, Sonia | Plata-Gómez, Ana Belén | Gómez-Patiño, Mónica | Molina, Susana | Espinosa-Salinas, Isabel | Aguilar-Aguilar, Elena | Ortega Jimenez, Sagrario CNIO | Graña Castro, Osvaldo CNIO | Loria-Kohen, Viviana | Fernández-Marcos, Pablo J | Efeyan, Alejo CNIO | Ramírez de Molina, Ana
Fecha de publicación
2022-10-31
Cita
Genome Biol . 2022;23(1):230
Idioma
Inglés
Tipo de documento
journal article
Resumen
BACKGROUND
Overweight 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.
RESULTS
We 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 increased FNIP2 mRNA 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 endogenous Fnip2 allele in mice. Primary cells derived from Fnip2 C/C mice show increased mRNA stability, and more importantly, Fnip2 C/C mice replicate the decreased adiposity and increased leanness observed in human volunteers. Finally, expression levels of FNIP2 in 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.
CONCLUSIONS
We propose that rs2291007 influences human leanness through an evolutionarily conserved modulation of FNIP2 mRNA levels.
MESH
Overweight | MicroRNAs | Humans | Animals | Mice | 3' Untranslated Regions | Thinness | Polymorphism, Single Nucleotide | RNA, Messenger | Obesity | Carrier Proteins
Versión en línea
DOI
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