2026-06-08T00:03:52Zhttps://docta.ucm.es/rest/oai/request
oai:docta.ucm.es:20.500.14352/1040952025-03-18T12:56:36Zcom_20.500.14352_14col_20.500.14352_15
Docta Complutense author Fernández, Lara P. author Deleyto-Seldas, Nerea author Colmenarejo, Gonzalo author Sanz, Alba author Wagner, Sonia author Plata-Gómez, Ana Belén author Gómez-Patiño, Mónica author Molina, Susana author Espinosa-Salinas, Isabel author Aguilar-Aguilar, Elena author Ortega, Sagrario author Graña-Castro, Osvaldo author Loria Kohen, Viviana Constanza author Fernández-Marcos, Pablo J. author Efeyan, Alejo author Ramírez de Molina, Ana 2024-05-16T11:09:05Z 2024-05-16T11:09:05Z 2022-10-31 Fernández LP, Deleyto-Seldas N, Colmenarejo G, Sanz A, Wagner S, Plata-Gómez AB, Gómez-Patiño M, Molina S, Espinosa-Salinas I, Aguilar-Aguilar E, Ortega S, Graña-Castro O, Loria-Kohen V, Fernández-Marcos PJ, Efeyan A, Ramírez de Molina A. Folliculin-interacting protein FNIP2 impacts on overweight and obesity through a polymorphism in a conserved 3' untranslated region. Genome Biol. 2022 Oct 31;23(1):230. 1474-760X 10.1186/s13059-022-02798-5 https://hdl.handle.net/20.500.14352/104095 https://genomebiology.biomedcentral.com/articles/10.1186/s13059-022-02798-5 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. eng Folliculin-interacting protein FNIP2 impacts on overweight and obesity through a polymorphism in a conserved 3′ untranslated region journal article 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URL https://docta.ucm.es/bitstreams/3e2c5e8c-bb20-4596-84b2-32f23d3a7cc5/download File MD5 a533c6d11da0a41ec4c2bf06aca54faa 521726 application/pdf Fernandez L et al 2022.pdf URL https://docta.ucm.es/bitstreams/a0943933-f25a-4579-9ac4-e34ee650b11a/download File MD5 261ec4e23a48ace66a1611a16acf6c7c 78435 text/plain Fernandez L et al 2022.pdf.txt