The Relevance of Thimet Oligopeptidase in the Regulation of Energy Metabolism and Diet-Induced Obesity

Autor(es):Mostrar menos -

Gewehr, Mayara C. F. ^[1] ; Teixeira, Alexandre A. S. ^[2] ; Santos, Bruna A. C. ^[1] ; Biondo, Luana A. ^[2] ; Gozzo, Fabio C. ^[3] ; Cordibello, Amanda M. ^[3] ; Eichler, Rosangela A. S. ^[1] ; Reckziegel, Patricia ^[4] ; Da Silva, Renee N. O. ^[1] ; Dos Santos, Nilton B. ^[1] ; Camara, Niels O. S. ^[5] ; Castoldi, Angela ^[5] ; Barreto-Chaves, Maria L. M. ^[6] ; Dale, Camila S. ^[6] ; Senger, Nathalia ^[6] ; Lima, Joanna D. C. C. ^[2] ; Seelaender, Marilia C. L. ^[2] ; Inada, Aline C. ^[1] ; Akamine, Eliana H. ^[1] ; Castro, Leandro M. ^[7] ; Rodrigues, Alice C. ^[1] ; Rosa Neto, Jose C. ^[2] ; Ferro, Emer S. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Biomed Sci Inst, Dept Pharmacol, BR-05508900 Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Biomed Sci Inst, Dept Cell Biol & Dev, BR-05508900 Sao Paulo, SP - Brazil

^[3] Univ Estadual Campinas, Inst Chem, BR-13083862 Campinas, SP - Brazil

^[4] Univ Fed Sao Paulo, Dept Pharmacol, BR-04023062 Sao Paulo, SP - Brazil

^[5] Univ Sao Paulo, Biomed Sci Inst, Dept Immunol, BR-05508900 Sao Paulo, SP - Brazil

^[6] Univ Sao Paulo, Biomed Sci Inst, Dept Anat, BR-05508900 Sao Paulo, SP - Brazil

^[7] Sao Paulo State Univ, Biosci Inst, BR-11330900 Sao Vicente, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: BIOMOLECULES; v. 10, n. 2 FEB 2020.
• Citações Web of Science: 0

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. (AU)

• Processo FAPESP: 14/17264-3 - Novas fronteiras em proteômica estrutural: caracterizando estruturas de proteínas e complexos proteicos por espectrometria de massas
• Beneficiário: Fabio Cesar Gozzo
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 16/04000-3 - Farmacologia de oligopeptidases e peptídeos intracelulares
• Beneficiário: Emer Suavinho Ferro
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 04/04933-2 - Biologia celular molecular de oligopeptidases
• Beneficiário: Emer Suavinho Ferro
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 15/20657-0 - Avaliação do potencial uso farmacológico da hemopressina (HP) no tratamento da obesidade
• Beneficiário: Patrícia Reckziegel
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado