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

Autor: Mayara C. F. Gewehr, Maria Luiza Morais Barreto-Chaves, Eliana Hiromi Akamine, Bruna A.C. Santos, Nilton Barreto dos Santos, Niels Olsen Saraiva Camara, Aline C Inada, Angela Castoldi, Emer S. Ferro, Joanna Darck Carola Correia Lima, Amanda M Cordibello, Fabio C. Gozzo, Leandro M. Castro, Alexandre Abilio de Souza Teixeira, Marilia Seelaender, Camila Squarzoni Dale, José Cesar Rosa Neto, Nathalia Senger, Luana A Biondo, Renée de Nazaré Oliveira da Silva, Alice Cristina Rodrigues, Patrícia Reckziegel, Rosangela Aparecida dos Santos Eichler
Přispěvatelé: Universidade de São Paulo (USP), Universidade Estadual de Campinas (UNICAMP), Universidade Federal de São Paulo (UNIFESP), Universidade Estadual Paulista (Unesp)
Rok vydání: 2020
Předmět:
Zdroj: Biomolecules
Web of Science
Repositório Institucional da UNESP
Universidade Estadual Paulista (UNESP)
instacron:UNESP
Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual)
Universidade de São Paulo (USP)
instacron:USP
Volume 10
Issue 2
Biomolecules, Vol 10, Iss 2, p 321 (2020)
ISSN: 2218-273X
Popis: 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&minus
/&minus
) mice. After 24 weeks of being fed a hyperlipidic diet (HD), THOP1&minus
and WT mice ingested similar chow and calories
however, the THOP1&minus
mice gained 75% less body weight and showed neither insulin resistance nor non-alcoholic fatty liver steatosis when compared to WT mice. THOP1&minus
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&minus
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&minus
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 unanticipated 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
Databáze: OpenAIRE
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