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Doctoral Thesis
DOI
10.11606/T.17.2018.tde-24042018-173433
Document
Author
Full name
Mariana Pinto Chaves
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
Ribeirão Preto, 2017
Supervisor
Committee
Freitas, Maria Cristina Foss de (President)
Jordao Junior, Alceu Afonso
Saad, Mario Jose Abdalla
Salles, João Eduardo Nunes
Suen, Vivian Marques Miguel
Title in Portuguese
Efeitos da suplementação do ácido graxo alfa-linolênico (ALA) no metabolismo e no estresse do retículo endoplasmático em tecido adiposo visceral de obeso grau III
Keywords in Portuguese
Ácido alfa-linolênico
Estresse do retículo endoplasmático
Leptina
Obesidade
Tecido adiposo visceral
Abstract in Portuguese
Atualmente, a obesidade é considerada uma epidemia mundial. Está associada a um estado de inflamação crônica e ativação do estresse do retículo endoplasmático (ERE), relacionados à patogênese de diversas doenças como diabetes mellitus tipo 2, doenças cardiovasculares, câncer, hipertensão, dentre outras. Nesse contexto, são necessários estudos para encontrar alternativas que melhorem o processo inflamatório. Vários estudos em humanos e animais já demostraram as propriedades anti-inflamatórias do ácido graxo ômega-3. O objetivo do nosso trabalho foi avaliar os efeitos da suplementação do ácido alfa-linolênico (ALA) no metabolismo e no estresse do retículo endoplasmático em obesos grau III. Foi conduzido um estudo prospectivo, randomizado, placebo-controlado, duplo-cego. No total, 52 pacientes foram randomizados para a suplementação com 3g/dia de ALA ou placebo, sendo 27 indivíduos do grupo ômega-3/ALA e 25 do grupo controle. Foi avaliado perfil lipídico, glicídico e inflamatório antes e após suplementação. O tecido adiposo visceral (TAV) foi coletado durante cirurgia bariátrica após suplementação. O perfil de ácidos graxos incorporados no TAV foi avaliado por cromatografia gasosa. Os genes foram avaliados através de PCR em tempo real. Não houve alteração nos níveis séricos de IL-6 (p=0,2201), TNF-? (0.7703) e PCR (p=0,57) após suplementação com ômega-3/ALA, porém observamos diminuição nos níveis séricos de Leptina (p=0.0154) e IP-10 (p=0.0410), citocinas inflamatórias, e aumento na IL-4 (p=0,0211), citocina anti-inflamatória. Foi observado incorporação significativa do ALA (p=0,0002), EPA (p<0,0001) e DHA (p=0,0005) no TAV. Avaliação molecular evidenciou um aumento da expressão gênica do XBP1 (p=0,0013), sXBP1 (p<0,0001), EIF2-? (p=0,0063) e da chaperona CCT4 (p=0,0001) e diminuição na expressão gênica da leptina (p=0,0410). Podemos concluir que o ALA pode modular o ERE através da via da IRE1/XBP, levando ao aumento das chaperonas (CCT4), o que pode demonstrar um potencial terapêutico do ALA em pacientes obesos.
Title in English
Alpha-linolenic acid supplementation effects on endoplasmic reticulum stress in visceral adipose tissue from morbid obese patients
Keywords in English
Alpha-linolenic acid
Endoplasmic reticulum stress
Leptin
Obesity
Visceral adipose tissue
Abstract in English
Currently, obesity is considered a worldwide epidemic. It is associated with chronic inflammation and stress activation of the endoplasmic reticulum (ERE), related to the pathogenesis of various diseases such as type 2 diabetes mellitus, cardiovascular diseases, cancer, hypertension, among others. In this context, studies are needed to find alternatives that improve the inflammatory process. Several studies in humans and animals have already demonstrated the anti-inflammatory properties of omega-3 fatty acid. The objective of our study was to evaluate the effects of alpha-linolenic acid (ALA) supplementation on the metabolism and stress of the endoplasmic reticulum in obese patients. A prospective, randomized, placebo-controlled, double-blind study was conducted. In total, 52 patients were randomized to supplementation with 3 g / day of ALA or placebo, 27 individuals from the omega-3 / ALA group and 25 from the control group. Lipid, glycidic and inflammatory profile were evaluated before and after supplementation. Visceral adipose tissue (TAV) was collected during bariatric surgery after supplementation. The fatty acid profile incorporated in the TAV was evaluated by gas chromatography. Genes were evaluated by real-time PCR. There was no change in serum levels of IL-6 (p = 0.2201), TNF-? (0.7703) and CRP (p = 0.57) after supplementation with ALA, but we observed a decrease in serum Leptin levels (P = 0.0154) and IP-10 (p = 0.0410), inflammatory cytokines, and increase in IL-4 (p = 0.0211), anti-inflammatory cytokine. Significant incorporation of ALA (p = 0.0002), EPA (p <0.0001) and DHA (p = 0.0005) into the TAV was observed. Molecular evaluation showed an increase in the gene expression of XBP1 (p = 0.0013), sXBP1 (p <0.0001), EIF2-? (p = 0.0063), GADD34 (p=0,0117) and CCT4 chaperone (p = 0.0001), decrease in the gene expression of leptin (p = 0.0410) and ATF-6 (p=0,0305) and a tendency to decrease the gene expression of CHOP. We can conclude that ALA can modulate ERE through the IRE1 / XBP, PERK and ATF-6 pathways, leading to increased chaperones (CCT4), which may demonstrate a therapeutic potential of ALA in obese patients.
 
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Publishing Date
2018-07-13
 
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