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Doctoral Thesis
DOI
10.11606/T.42.2014.tde-13082014-140429
Document
Author
Full name
Diogo Manuel Lopes de Paiva Cavalcanti
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2014
Supervisor
Committee
Ferro, Emer Suavinho (President)
Camargo, Antonio Carlos Martins de
Ortis, Fernanda
Rioli, Vanessa
Tersariol, Ivarne Luis dos Santos
Title in Portuguese
Caracterização fenotípica de camundongos knockout para neurolisina.
Keywords in Portuguese
Gliconeogênese
Insulina
Metabolismo de glicose
Neurolisina
Peptídeos
Peptídeos intracelulares
Abstract in Portuguese
A oligopeptidase neurolina (E.C.3.4.24.16; nln ) foi identificado pela primeira vez em membranas sinápticas de cérebro de ratos como sendo capaz de participar no metabolismo de peptídeos bioativos, como neurotensina e bradicinina. Recentemente, foi sugerido que a ausência de Nln pode melhorar a sensibilidade a insulina. Aqui, nós mostrado que camundongos knockout para Nln (KO) são mais tolrerantes à glicose, sensíveis à insulina e apresentam maior gliconeogênese. Os animais KO apresentou um aumento na expressão de mRNA de vários genes relacionados com a gliconeogênese no fígado. A semiquantificação de peptídeos intracelulares revelou um aumento em peptídeos intracelulares específicos no gastrocnêmio e tecido adiposo epididimal, que estão envolvidos com o aumento da tolerância a glicose e maior sensibilidade à insulina nos animais KO. Esses resultados sugerem fortemente a nova possibilidade de que Nln é uma enzima chave no metabolismo energético e pode ser um novo alvo terapêutico para melhorar a captação de glicose e sensibilidade a insulina.
Title in English
Phenotype characterization of neurolysin knockout mice.
Keywords in English
Gluconeogenesis
Glucose metabolism
Insulin
Intracellular peptides
Neurolysin
Peptides
Abstract in English
The oligopeptidase neurolysin (EC 3.4.24.16; Nln) was first identified in rat brain synaptic membranes and shown to ubiquitously participate in the catabolism of bioactive peptides such as neurotensin and bradykinin. Recently, it was suggested that Nln reduction could improve insulin sensitivity. Here, we have shown that Nln knockout mice (KO) have increased glucose tolerance, insulin sensitivity and gluconeogenesis. KO mice have increased liver mRNA for several genes related to gluconeogenesis. Isotopic label semi-quantitative peptidomic analysis suggests increase in specific intracellular peptides in gastrocnemius and epididymal adipose tissue, which likely is involved with the increased glucose tolerance and insulin sensitivity in the KO mice. These results suggest the exciting new possibility that Nln is a key enzyme for energy metabolism and could be a novel therapeutic target to improve glucose uptake and insulin sensitivity.
 
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Publishing Date
2014-08-14
 
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