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

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 c...

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Autores: 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, Graña Castro, Osvaldo, Loria-Kohen, Viviana, Fernández-Marcos, Pablo J, Efeyan, Alejo, Ramírez de Molina, Ana
Tipo de documento: artigo
Data de publicação:2022
País:España
Recursos:Instituto de Salud Carlos III (ISCIII)
Repositório:Repisalud
Idioma:inglês
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/18959
Acesso em linha:http://hdl.handle.net/20.500.12105/18959
Access Level:Acceso aberto
Palavra-chave:Overweight
MicroRNAs
Humans
Animals
Mice
3' Untranslated Regions
Thinness
Polymorphism, Single Nucleotide
RNA, Messenger
Obesity
Carrier Proteins
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spelling Folliculin-interacting protein FNIP2 impacts on overweight and obesity through a polymorphism in a conserved 3' untranslated region.Fernández, Lara PDeleyto-Seldas, NereaColmenarejo, GonzaloSanz, AlbaWagner, SoniaPlata-Gómez, Ana BelénGómez-Patiño, MónicaMolina, SusanaEspinosa-Salinas, IsabelAguilar-Aguilar, ElenaOrtega Jimenez, SagrarioGraña Castro, OsvaldoLoria-Kohen, VivianaFernández-Marcos, Pablo JEfeyan, AlejoRamírez de Molina, AnaOverweightMicroRNAsHumansAnimalsMice3' Untranslated RegionsThinnessPolymorphism, Single NucleotideRNA, MessengerObesityCarrier ProteinsBACKGROUND 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.BMJ Publishing GroupFundación Ramón ArecesComunidad de Madrid (España)Ministerio de Ciencia e Innovación (España)Unión Europea. Comisión Europea. H202020242024-03-1420222022-10-3120222022-10-31journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfapplication/vnd.openxmlformats-officedocument.presentationml.presentationhttp://hdl.handle.net/20.500.12105/18959reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)InglésengEuropean Commission http://dx.doi.org/10.13039/501100000780 Horizon 2020 Framework Programme 638891open accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/189592026-06-12T12:43:37Z
dc.title.none.fl_str_mv Folliculin-interacting protein FNIP2 impacts on overweight and obesity through a polymorphism in a conserved 3' untranslated region.
title Folliculin-interacting protein FNIP2 impacts on overweight and obesity through a polymorphism in a conserved 3' untranslated region.
spellingShingle Folliculin-interacting protein FNIP2 impacts on overweight and obesity through a polymorphism in a conserved 3' untranslated region.
Fernández, Lara P
Overweight
MicroRNAs
Humans
Animals
Mice
3' Untranslated Regions
Thinness
Polymorphism, Single Nucleotide
RNA, Messenger
Obesity
Carrier Proteins
title_short Folliculin-interacting protein FNIP2 impacts on overweight and obesity through a polymorphism in a conserved 3' untranslated region.
title_full Folliculin-interacting protein FNIP2 impacts on overweight and obesity through a polymorphism in a conserved 3' untranslated region.
title_fullStr Folliculin-interacting protein FNIP2 impacts on overweight and obesity through a polymorphism in a conserved 3' untranslated region.
title_full_unstemmed Folliculin-interacting protein FNIP2 impacts on overweight and obesity through a polymorphism in a conserved 3' untranslated region.
title_sort Folliculin-interacting protein FNIP2 impacts on overweight and obesity through a polymorphism in a conserved 3' untranslated region.
dc.creator.none.fl_str_mv 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
Graña Castro, Osvaldo
Loria-Kohen, Viviana
Fernández-Marcos, Pablo J
Efeyan, Alejo
Ramírez de Molina, Ana
author Fernández, Lara P
author_facet 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
Graña Castro, Osvaldo
Loria-Kohen, Viviana
Fernández-Marcos, Pablo J
Efeyan, Alejo
Ramírez de Molina, Ana
author_role author
author2 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
Graña Castro, Osvaldo
Loria-Kohen, Viviana
Fernández-Marcos, Pablo J
Efeyan, Alejo
Ramírez de Molina, Ana
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Fundación Ramón Areces
Comunidad de Madrid (España)
Ministerio de Ciencia e Innovación (España)
Unión Europea. Comisión Europea. H2020
dc.subject.none.fl_str_mv Overweight
MicroRNAs
Humans
Animals
Mice
3' Untranslated Regions
Thinness
Polymorphism, Single Nucleotide
RNA, Messenger
Obesity
Carrier Proteins
topic Overweight
MicroRNAs
Humans
Animals
Mice
3' Untranslated Regions
Thinness
Polymorphism, Single Nucleotide
RNA, Messenger
Obesity
Carrier Proteins
description 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.
publishDate 2022
dc.date.none.fl_str_mv 2022
2022-10-31
2022
2022-10-31
2024
2024-03-14
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12105/18959
url http://hdl.handle.net/20.500.12105/18959
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv European Commission http://dx.doi.org/10.13039/501100000780 Horizon 2020 Framework Programme 638891
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 Internacional
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 Internacional
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/vnd.openxmlformats-officedocument.presentationml.presentation
dc.publisher.none.fl_str_mv BMJ Publishing Group
publisher.none.fl_str_mv BMJ Publishing Group
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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