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

Biomolecules

LeandroM. Castro¹  CamilaS. Dale²  Nathalia Senger²  MariaL. M. Barreto-Chaves²  LuanaA. Biondo³  MariliaC. L. Seelaender³  JoannaD. C. C. Lima³  AlexandreA. S. Teixeira³  JoséC. Rosa Neto³  NielsO. S. Camara⁴  Angela Castoldi⁴  NiltonB. Dos Santos⁵  MayaraC. F. Gewehr⁵  RenéeN. O. Da Silva⁵  AlineC. Inada⁵  RosangelaA. S. Eichler⁵  BrunaA. C. Santos⁵  AliceC. Rodrigues⁵  ElianaH. Akamine⁵  EmerS. Ferro⁵  Patrícia Reckziegel⁶  AmandaM. Cordibello⁷  FábioC. Gozzo⁷ 

[1] Biosciences Institute, São Paulo State University, 11330-900 São Vicente, SP, Brazil;Department of Anatomy, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, Brazil;Department of Cell Biology and Development, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, Brazil;Department of Immunology, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, Brazil;Department of Pharmacology, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, Brazil;Department of Pharmacology, Federal University of São Paulo, 04023-062 São Paulo, SP, Brazil;Institute of Chemistry, State University of Campinas, 13083-862 Campinas, SP, Brazil;

关键词: obesity;    insulin resistance;    diet-induced obesity;    proteasome;    proteases;    peptidases;    mass spectrometry;    peptidome;   

DOI  :  10.3390/biom10020321

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown