The Relevance of Thimet Oligopeptidase in the Regulation of Energy Metabolism and Diet-Induced Obesity
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 peptide...
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2020-02-01
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| author | Mayara C. F. Gewehr Alexandre A. S. Teixeira Bruna A. C. Santos Luana A. Biondo Fábio C. Gozzo Amanda M. Cordibello Rosangela A. S. Eichler Patrícia Reckziegel Renée N. O. Da Silva Nilton B. Dos Santos Niels O. S. Camara Angela Castoldi Maria L. M. Barreto-Chaves Camila S. Dale Nathalia Senger Joanna D. C. C. Lima Marilia C. L. Seelaender Aline C. Inada Eliana H. Akamine Leandro M. Castro Alice C. Rodrigues José C. Rosa Neto Emer S. Ferro |
| author_facet | Mayara C. F. Gewehr Alexandre A. S. Teixeira Bruna A. C. Santos Luana A. Biondo Fábio C. Gozzo Amanda M. Cordibello Rosangela A. S. Eichler Patrícia Reckziegel Renée N. O. Da Silva Nilton B. Dos Santos Niels O. S. Camara Angela Castoldi Maria L. M. Barreto-Chaves Camila S. Dale Nathalia Senger Joanna D. C. C. Lima Marilia C. L. Seelaender Aline C. Inada Eliana H. Akamine Leandro M. Castro Alice C. Rodrigues José C. Rosa Neto Emer S. Ferro |
| author_sort | Mayara C. F. Gewehr |
| collection | DOAJ |
| 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<sup>−/−</sup>) mice. After 24 weeks of being fed a hyperlipidic diet (HD), THOP1<sup>−/−</sup> and WT mice ingested similar chow and calories; however, the THOP1<sup>−/−</sup> mice gained 75% less body weight and showed neither insulin resistance nor non-alcoholic fatty liver steatosis when compared to WT mice. THOP1<sup>−/−</sup> 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<sup>−/−</sup> 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<sup>−/−</sup> 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. |
| first_indexed | 2024-04-13T05:57:09Z |
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| spelling | doaj.art-cd23c3a4fd914795937480a86869742c2022-12-22T02:59:36ZengMDPI AGBiomolecules2218-273X2020-02-0110232110.3390/biom10020321biom10020321The Relevance of Thimet Oligopeptidase in the Regulation of Energy Metabolism and Diet-Induced ObesityMayara C. F. Gewehr0Alexandre A. S. Teixeira1Bruna A. C. Santos2Luana A. Biondo3Fábio C. Gozzo4Amanda M. Cordibello5Rosangela A. S. Eichler6Patrícia Reckziegel7Renée N. O. Da Silva8Nilton B. Dos Santos9Niels O. S. Camara10Angela Castoldi11Maria L. M. Barreto-Chaves12Camila S. Dale13Nathalia Senger14Joanna D. C. C. Lima15Marilia C. L. Seelaender16Aline C. Inada17Eliana H. Akamine18Leandro M. Castro19Alice C. Rodrigues20José C. Rosa Neto21Emer S. Ferro22Department of Pharmacology, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, BrazilDepartment of Cell Biology and Development, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, BrazilDepartment of Pharmacology, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, BrazilDepartment of Cell Biology and Development, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, BrazilInstitute of Chemistry, State University of Campinas, 13083-862 Campinas, SP, BrazilInstitute of Chemistry, State University of Campinas, 13083-862 Campinas, SP, BrazilDepartment of Pharmacology, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, BrazilDepartment of Pharmacology, Federal University of São Paulo, 04023-062 São Paulo, SP, BrazilDepartment of Pharmacology, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, BrazilDepartment of Pharmacology, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, BrazilDepartment of Immunology, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, BrazilDepartment of Immunology, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, BrazilDepartment of Anatomy, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, BrazilDepartment of Anatomy, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, BrazilDepartment of Anatomy, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, BrazilDepartment of Cell Biology and Development, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, BrazilDepartment of Cell Biology and Development, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, BrazilDepartment of Pharmacology, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, BrazilDepartment of Pharmacology, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, BrazilBiosciences Institute, São Paulo State University, 11330-900 São Vicente, SP, BrazilDepartment of Pharmacology, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, BrazilDepartment of Cell Biology and Development, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, BrazilDepartment of Pharmacology, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, BrazilThimet 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<sup>−/−</sup>) mice. After 24 weeks of being fed a hyperlipidic diet (HD), THOP1<sup>−/−</sup> and WT mice ingested similar chow and calories; however, the THOP1<sup>−/−</sup> mice gained 75% less body weight and showed neither insulin resistance nor non-alcoholic fatty liver steatosis when compared to WT mice. THOP1<sup>−/−</sup> 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<sup>−/−</sup> 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<sup>−/−</sup> 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.https://www.mdpi.com/2218-273X/10/2/321obesityinsulin resistancediet-induced obesityproteasomeproteasespeptidasesmass spectrometrypeptidome |
| spellingShingle | Mayara C. F. Gewehr Alexandre A. S. Teixeira Bruna A. C. Santos Luana A. Biondo Fábio C. Gozzo Amanda M. Cordibello Rosangela A. S. Eichler Patrícia Reckziegel Renée N. O. Da Silva Nilton B. Dos Santos Niels O. S. Camara Angela Castoldi Maria L. M. Barreto-Chaves Camila S. Dale Nathalia Senger Joanna D. C. C. Lima Marilia C. L. Seelaender Aline C. Inada Eliana H. Akamine Leandro M. Castro Alice C. Rodrigues José C. Rosa Neto Emer S. Ferro The Relevance of Thimet Oligopeptidase in the Regulation of Energy Metabolism and Diet-Induced Obesity Biomolecules obesity insulin resistance diet-induced obesity proteasome proteases peptidases mass spectrometry peptidome |
| title | 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_short | The Relevance of Thimet Oligopeptidase in the Regulation of Energy Metabolism and Diet-Induced Obesity |
| title_sort | relevance of thimet oligopeptidase in the regulation of energy metabolism and diet induced obesity |
| topic | obesity insulin resistance diet-induced obesity proteasome proteases peptidases mass spectrometry peptidome |
| url | https://www.mdpi.com/2218-273X/10/2/321 |
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