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

Autor: Gewehr MCF; Department of Pharmacology, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, Brazil., Teixeira AAS; Department of Cell Biology and Development, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, Brazil., Santos BAC; Department of Pharmacology, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, Brazil., Biondo LA; Department of Cell Biology and Development, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, Brazil., Gozzo FC; Institute of Chemistry, State University of Campinas, 13083-862 Campinas, SP, Brazil., Cordibello AM; Institute of Chemistry, State University of Campinas, 13083-862 Campinas, SP, Brazil., Eichler RAS; Department of Pharmacology, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, Brazil., Reckziegel P; Department of Pharmacology, Federal University of São Paulo, 04023-062 São Paulo, SP, Brazil., Da Silva RNO; Department of Pharmacology, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, Brazil., Dos Santos NB; Department of Pharmacology, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, Brazil., Camara NOS; Department of Immunology, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, Brazil., Castoldi A; Department of Immunology, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, Brazil., Barreto-Chaves MLM; Department of Anatomy, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, Brazil., Dale CS; Department of Anatomy, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, Brazil., Senger N; Department of Anatomy, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, Brazil., Lima JDCC; Department of Cell Biology and Development, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, Brazil., Seelaender MCL; Department of Cell Biology and Development, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, Brazil., Inada AC; Department of Pharmacology, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, Brazil., Akamine EH; Department of Pharmacology, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, Brazil., Castro LM; Biosciences Institute, São Paulo State University, 11330-900 São Vicente, SP, Brazil., Rodrigues AC; Department of Pharmacology, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, Brazil., Neto JCR; Department of Cell Biology and Development, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, Brazil., Ferro ES; Department of Pharmacology, Biomedical Sciences Institute, University of São Paulo, 05508-900 São Paulo, SP, Brazil.
Jazyk: angličtina
Zdroj: Biomolecules [Biomolecules] 2020 Feb 17; Vol. 10 (2). Date of Electronic Publication: 2020 Feb 17.
DOI: 10.3390/biom10020321
Abstrakt: 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 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.
Competing Interests: The authors declare no conflict of interest.
Databáze: MEDLINE
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