The Relevance of Thimet Oligopeptidase in the Regulation of Energy Metabolism and Diet-Induced Obesity
Autor(a) principal: | |
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Data de Publicação: | 2020 |
Outros Autores: | , , , , , , , , , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.3390/biom10020321 http://hdl.handle.net/11449/196726 |
Resumo: | Thimet oligopeptidase (EC 3.4.24.15; EP24.15; THOP1) is a potential therapeutic target, as it plays key biological functions in processing biologically functional peptides. The structural conformation of THOP1 provides a unique restriction regarding substrate size, in that it only hydrolyzes peptides (optimally, those ranging from eight to 12 amino acids) and not proteins. The proteasome activity of hydrolyzing proteins releases a large number of intracellular peptides, providing THOP1 substrates within cells. The present study aimed to investigate the possible function of THOP1 in the development of diet-induced obesity (DIO) and insulin resistance by utilizing a murine model of hyperlipidic DIO with both C57BL6 wild-type (WT) and THOP1 null (THOP1(-/-)) mice. After 24 weeks of being fed a hyperlipidic diet (HD), THOP1(-/-) and WT mice ingested similar chow and calories; however, the THOP1(-/-) mice gained 75% less body weight and showed neither insulin resistance nor non-alcoholic fatty liver steatosis when compared to WT mice. THOP1(-/-) mice had increased adrenergic-stimulated adipose tissue lipolysis as well as a balanced level of expression of genes and microRNAs associated with energy metabolism, adipogenesis, or inflammation. Altogether, these differences converge to a healthy phenotype of THOP1(-/-) fed a HD. The molecular mechanism that links THOP1 to energy metabolism is suggested herein to involve intracellular peptides, of which the relative levels were identified to change in the adipose tissue of WT and THOP1(-/-) mice. Intracellular peptides were observed by molecular modeling to interact with both pre-miR-143 and pre-miR-222, suggesting a possible novel regulatory mechanism for gene expression. Therefore, we successfully demonstrated the previously anticipated relevance of THOP1 in energy metabolism regulation. It was suggested that intracellular peptides were responsible for mediating the phenotypic differences that are described herein by a yet unknown mechanism of action. |
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The Relevance of Thimet Oligopeptidase in the Regulation of Energy Metabolism and Diet-Induced Obesityobesityinsulin resistancediet-induced obesityproteasomeproteasespeptidasesmass spectrometrypeptidomeThimet oligopeptidase (EC 3.4.24.15; EP24.15; THOP1) is a potential therapeutic target, as it plays key biological functions in processing biologically functional peptides. The structural conformation of THOP1 provides a unique restriction regarding substrate size, in that it only hydrolyzes peptides (optimally, those ranging from eight to 12 amino acids) and not proteins. The proteasome activity of hydrolyzing proteins releases a large number of intracellular peptides, providing THOP1 substrates within cells. The present study aimed to investigate the possible function of THOP1 in the development of diet-induced obesity (DIO) and insulin resistance by utilizing a murine model of hyperlipidic DIO with both C57BL6 wild-type (WT) and THOP1 null (THOP1(-/-)) mice. After 24 weeks of being fed a hyperlipidic diet (HD), THOP1(-/-) and WT mice ingested similar chow and calories; however, the THOP1(-/-) mice gained 75% less body weight and showed neither insulin resistance nor non-alcoholic fatty liver steatosis when compared to WT mice. THOP1(-/-) mice had increased adrenergic-stimulated adipose tissue lipolysis as well as a balanced level of expression of genes and microRNAs associated with energy metabolism, adipogenesis, or inflammation. Altogether, these differences converge to a healthy phenotype of THOP1(-/-) fed a HD. The molecular mechanism that links THOP1 to energy metabolism is suggested herein to involve intracellular peptides, of which the relative levels were identified to change in the adipose tissue of WT and THOP1(-/-) mice. Intracellular peptides were observed by molecular modeling to interact with both pre-miR-143 and pre-miR-222, suggesting a possible novel regulatory mechanism for gene expression. Therefore, we successfully demonstrated the previously anticipated relevance of THOP1 in energy metabolism regulation. It was suggested that intracellular peptides were responsible for mediating the phenotypic differences that are described herein by a yet unknown mechanism of action.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Univ Sao Paulo, Biomed Sci Inst, Dept Pharmacol, BR-05508900 Sao Paulo, SP, BrazilUniv Sao Paulo, Biomed Sci Inst, Dept Cell Biol & Dev, BR-05508900 Sao Paulo, SP, BrazilUniv Estadual Campinas, Inst Chem, BR-13083862 Campinas, SP, BrazilUniv Fed Sao Paulo, Dept Pharmacol, BR-04023062 Sao Paulo, SP, BrazilUniv Sao Paulo, Biomed Sci Inst, Dept Immunol, BR-05508900 Sao Paulo, SP, BrazilUniv Sao Paulo, Biomed Sci Inst, Dept Anat, BR-05508900 Sao Paulo, SP, BrazilSao Paulo State Univ, Biosci Inst, BR-11330900 Sao Vicente, SP, BrazilSao Paulo State Univ, Biosci Inst, BR-11330900 Sao Vicente, SP, BrazilFAPESP: 2004/04933-2FAPESP: 2014/17264-3FAPESP: 2015/20657-0FAPESP: 2016/04000-3CNPq: 445363/2014-2CNPq: 400944/2014-6CNPq: 302809/2016-3MdpiUniversidade de São Paulo (USP)Universidade Estadual de Campinas (UNICAMP)Universidade Federal de São Paulo (UNIFESP)Universidade Estadual Paulista (Unesp)Gewehr, Mayara C. F.Teixeira, Alexandre A. S.Santos, Bruna A. C.Biondo, Luana A.Gozzo, Fabio C.Cordibello, Amanda M.Eichler, Rosangela A. S.Reckziegel, PatriciaDa Silva, Renee N. O.Dos Santos, Nilton B.Camara, Niels O. S.Castoldi, AngelaBarreto-Chaves, Maria L. M.Dale, Camila S.Senger, NathaliaLima, Joanna D. C. C.Seelaender, Marilia C. L.Inada, Aline C.Akamine, Eliana H.Castro, Leandro M. [UNESP]Rodrigues, Alice C.Rosa Neto, Jose C.Ferro, Emer S.2020-12-10T19:54:17Z2020-12-10T19:54:17Z2020-02-01info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article40http://dx.doi.org/10.3390/biom10020321Biomolecules. Basel: Mdpi, v. 10, n. 2, 40 p., 2020.http://hdl.handle.net/11449/19672610.3390/biom10020321WOS:000522138500047Web of Sciencereponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengBiomoleculesinfo:eu-repo/semantics/openAccess2021-10-23T09:34:10Zoai:repositorio.unesp.br:11449/196726Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462021-10-23T09:34:10Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
The Relevance of Thimet Oligopeptidase in the Regulation of Energy Metabolism and Diet-Induced Obesity |
title |
The Relevance of Thimet Oligopeptidase in the Regulation of Energy Metabolism and Diet-Induced Obesity |
spellingShingle |
The Relevance of Thimet Oligopeptidase in the Regulation of Energy Metabolism and Diet-Induced Obesity Gewehr, Mayara C. F. obesity insulin resistance diet-induced obesity proteasome proteases peptidases mass spectrometry peptidome |
title_short |
The Relevance of Thimet Oligopeptidase in the Regulation of Energy Metabolism and Diet-Induced Obesity |
title_full |
The Relevance of Thimet Oligopeptidase in the Regulation of Energy Metabolism and Diet-Induced Obesity |
title_fullStr |
The Relevance of Thimet Oligopeptidase in the Regulation of Energy Metabolism and Diet-Induced Obesity |
title_full_unstemmed |
The Relevance of Thimet Oligopeptidase in the Regulation of Energy Metabolism and Diet-Induced Obesity |
title_sort |
The Relevance of Thimet Oligopeptidase in the Regulation of Energy Metabolism and Diet-Induced Obesity |
author |
Gewehr, Mayara C. F. |
author_facet |
Gewehr, Mayara C. F. Teixeira, Alexandre A. S. Santos, Bruna A. C. Biondo, Luana A. Gozzo, Fabio C. Cordibello, Amanda M. Eichler, Rosangela A. S. Reckziegel, Patricia Da Silva, Renee N. O. Dos Santos, Nilton B. Camara, Niels O. S. Castoldi, Angela Barreto-Chaves, Maria L. M. Dale, Camila S. Senger, Nathalia Lima, Joanna D. C. C. Seelaender, Marilia C. L. Inada, Aline C. Akamine, Eliana H. Castro, Leandro M. [UNESP] Rodrigues, Alice C. Rosa Neto, Jose C. Ferro, Emer S. |
author_role |
author |
author2 |
Teixeira, Alexandre A. S. Santos, Bruna A. C. Biondo, Luana A. Gozzo, Fabio C. Cordibello, Amanda M. Eichler, Rosangela A. S. Reckziegel, Patricia Da Silva, Renee N. O. Dos Santos, Nilton B. Camara, Niels O. S. Castoldi, Angela Barreto-Chaves, Maria L. M. Dale, Camila S. Senger, Nathalia Lima, Joanna D. C. C. Seelaender, Marilia C. L. Inada, Aline C. Akamine, Eliana H. Castro, Leandro M. [UNESP] Rodrigues, Alice C. Rosa Neto, Jose C. Ferro, Emer S. |
author2_role |
author author author author author author author author author author author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade de São Paulo (USP) Universidade Estadual de Campinas (UNICAMP) Universidade Federal de São Paulo (UNIFESP) Universidade Estadual Paulista (Unesp) |
dc.contributor.author.fl_str_mv |
Gewehr, Mayara C. F. Teixeira, Alexandre A. S. Santos, Bruna A. C. Biondo, Luana A. Gozzo, Fabio C. Cordibello, Amanda M. Eichler, Rosangela A. S. Reckziegel, Patricia Da Silva, Renee N. O. Dos Santos, Nilton B. Camara, Niels O. S. Castoldi, Angela Barreto-Chaves, Maria L. M. Dale, Camila S. Senger, Nathalia Lima, Joanna D. C. C. Seelaender, Marilia C. L. Inada, Aline C. Akamine, Eliana H. Castro, Leandro M. [UNESP] Rodrigues, Alice C. Rosa Neto, Jose C. Ferro, Emer S. |
dc.subject.por.fl_str_mv |
obesity insulin resistance diet-induced obesity proteasome proteases peptidases mass spectrometry peptidome |
topic |
obesity insulin resistance diet-induced obesity proteasome proteases peptidases mass spectrometry peptidome |
description |
Thimet oligopeptidase (EC 3.4.24.15; EP24.15; THOP1) is a potential therapeutic target, as it plays key biological functions in processing biologically functional peptides. The structural conformation of THOP1 provides a unique restriction regarding substrate size, in that it only hydrolyzes peptides (optimally, those ranging from eight to 12 amino acids) and not proteins. The proteasome activity of hydrolyzing proteins releases a large number of intracellular peptides, providing THOP1 substrates within cells. The present study aimed to investigate the possible function of THOP1 in the development of diet-induced obesity (DIO) and insulin resistance by utilizing a murine model of hyperlipidic DIO with both C57BL6 wild-type (WT) and THOP1 null (THOP1(-/-)) mice. After 24 weeks of being fed a hyperlipidic diet (HD), THOP1(-/-) and WT mice ingested similar chow and calories; however, the THOP1(-/-) mice gained 75% less body weight and showed neither insulin resistance nor non-alcoholic fatty liver steatosis when compared to WT mice. THOP1(-/-) mice had increased adrenergic-stimulated adipose tissue lipolysis as well as a balanced level of expression of genes and microRNAs associated with energy metabolism, adipogenesis, or inflammation. Altogether, these differences converge to a healthy phenotype of THOP1(-/-) fed a HD. The molecular mechanism that links THOP1 to energy metabolism is suggested herein to involve intracellular peptides, of which the relative levels were identified to change in the adipose tissue of WT and THOP1(-/-) mice. Intracellular peptides were observed by molecular modeling to interact with both pre-miR-143 and pre-miR-222, suggesting a possible novel regulatory mechanism for gene expression. Therefore, we successfully demonstrated the previously anticipated relevance of THOP1 in energy metabolism regulation. It was suggested that intracellular peptides were responsible for mediating the phenotypic differences that are described herein by a yet unknown mechanism of action. |
publishDate |
2020 |
dc.date.none.fl_str_mv |
2020-12-10T19:54:17Z 2020-12-10T19:54:17Z 2020-02-01 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://dx.doi.org/10.3390/biom10020321 Biomolecules. Basel: Mdpi, v. 10, n. 2, 40 p., 2020. http://hdl.handle.net/11449/196726 10.3390/biom10020321 WOS:000522138500047 |
url |
http://dx.doi.org/10.3390/biom10020321 http://hdl.handle.net/11449/196726 |
identifier_str_mv |
Biomolecules. Basel: Mdpi, v. 10, n. 2, 40 p., 2020. 10.3390/biom10020321 WOS:000522138500047 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Biomolecules |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
40 |
dc.publisher.none.fl_str_mv |
Mdpi |
publisher.none.fl_str_mv |
Mdpi |
dc.source.none.fl_str_mv |
Web of Science reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
|
_version_ |
1799964728088330240 |