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Master's Dissertation
DOI
10.11606/D.42.2019.tde-04122018-151945
Document
Author
Full name
Thais Barabba Auricino
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2018
Supervisor
Committee
Lotfi, Claudimara Ferini Pacicco (President)
Caperuto, Luciana Chagas
Frazão, Renata
Nunes, Maria Tereza
Title in Portuguese
Estudo da ação dos peptídeos n-terminal da POMC no córtex adrenal de camundongos Pomc knockout induzidos por tamoxifeno.
Keywords in Portuguese
Camundongos CrePomcflox/flox
Eixo HPA
Peptídeos N-terminal POMC
Suprarrenal
Abstract in Portuguese
O ACTH é considerado o principal fator atuante no desenvolvimento, na manutenção e na esteroidogênese da glândula adrenal. No entanto, existem evidências que peptídeos N-Pomc, derivados do processamento da Proopiomelanocortina (POMC), possam atuar na manutenção do córtex adrenal, embora ainda não seja conhecida sua importância e mesmo quais são os peptídeos que atuam na suprarrenal. Nesse trabalho tivemos como objetivo avaliar os efeitos de peptídeos sintéticos de 28 aminoácidos derivados do N-Pomc (N-PomcCys, N-PomcMet e N-PomcSer) na morfologia e função da suprarrenal de camundongos, cujo gene Pomc foi condicionalmente silenciado com Tamoxifeno (Tmx). Foram obtidos animais machos adultos (CrePomcfloxflox) com um sistema "knock-out" condicional Cre-Lox induzível por Tmx, que foram tratados através de minibombas osmóticas por 21 dias com os peptídeos ou com salina, e como controle animais Pomcfloxflox não tratados. Foram analisados: 1) dados metabólicos; 2) a concentração de ACTH e de corticosterona plasmáticos; 3) a morfologia e a reconstrução anatômica da adrenal; 4) a capacidade funcional através da coloração com Oil Red O (ORO) e 5) a capacidade de proliferação através da expressão da proteína PCNA. A caracterização dos animais CrePomcfloxflox + Tmx após o silenciamento mostrou a redução de 60% da concentração de ACTH plasmático e esses animais apresentaram 1) redução do gasto energético, aumento da ingestão de alimentos e ganho de peso corpóreo; 2) alteração significante a área ou o volume das adrenais; 3) redução da produção de gotículas lipídicas e 4) redução do número de núcleos positivos para a proteína PCNA. Esses animais silenciados para a Pomc e tratados com os peptídeos N POMCCys e N-POMCMet apresentaram 1) aumento da corticosterona plasmática e apenas o N-POMCCys aumentou o ACTH plasmático; 2) aumento de núcleos marcados para PCNA. Concluímos, que os camundongos Cre Pomcflox/flox silenciados para a Pomc com o Tamoxifeno apresentaram alterações metabólicas, morfológicas e fisiológicas. A análise do efeito biológico dos peptídeos N-POMC mostrou ação desses peptídeos na função e na manutenção do córtex adrenal.
Title in English
Study of the action of the N-terminal peptides of the POMC in the adrenal cortex of tamoxifen-induced knockout Pomc mice.
Keywords in English
Adrenal
HPA axis
Mice CrePomcfloxflox
N-terminal POMC peptides
Abstract in English
ACTH is considered the main active factor in the development, maintenance and steroidogenesis of the adrenal gland. However, there is evidence that N-Pomc peptides, derived from the processing of Proopiomelanocortina (POMC), may play a role in the maintenance of the adrenal cortex, although their importance is not yet known. In this work we aimed to evaluate the effects of synthetic peptides of 28 amino acids derived from N-Pomc (N-PomcCys, N-PomcMet e N-PomcSer) on the morphology and function of the adrenal cortex of mice whose Pomc gene was conditionally silenced with Tamoxifen (Tmx). Adult males (CrePomcfloxflox) were obtained with a Tmx inducible Cre-Lox conditional knock-out system, which were treated by osmotic minipumps for 21 days with the peptides or with saline, and as control untreated Pomcfloxfloxanimals. We analyzed: 1) metabolic data; 2) plasma ACTH and corticosterone concentration; 3) the morphology and the anatomical reconstruction of the adrenal; 4) functional capacity through staining with Oil Red O (ORO) and 5) the ability to proliferate through expression of PCNA protein. The characterization of the CrePomcfloxflox + Tmx animals after silencing showed a 60% reduction in plasma ACTH concentration and these animals presented 1) reduction of energy expenditure, increased food intake and body weight gain; 2) significant alteration of adrenal area or volume; 3) reduction of the production of lipid droplets and 4) reduction of the number of nuclei positive for the PCNA protein. These animals that were silenced to Pomc and treated with peptides N-PomcCys, N-PomcMet had 1) increase in plasma corticosterone and only N-POMCCys increased plasma ACTH; 2) increase of nuclei marked for PCNA. We conclude that CrePomcflox/flox mice silenced for Pomc with Tamoxifen presented metabolic, morphological and physiological alterations. The analysis of the biological effect of N-POMC peptides showed the action of these peptides on the function and maintenance of the adrenal cortex.
 
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Release Date
2020-12-03
Publishing Date
2019-01-04
 
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