Orientador: Ilza Maria Urbano Monteiro / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-27T21:47:52Z (GMT). No. of bitstreams: 1 Souza_NataliaDal'Avade_D.pdf: 1420906 bytes, checksum: a2935c71ee1a1153564862074a4b592f (MD5) Previous issue date: 2015 / Resumo: INTRODUÇÃO: O ganho de peso associado ao uso de métodos contraceptivos contendo apenas progestágenos pode levar à descontinuação do uso. A avaliação da composição corporal (CC) pode auxiliar na compreensão e monitoração do ganho de peso. A mensuração da CC pela técnica de absorciometria de duplo feixe de raios-X (DEXA) permite quantificar os diferentes componentes da CC - massa gorda (MG), massa magra (MM). OBJETIVOS: Estimar a CC de mulheres na menacme e avaliar sua variação entre usuárias de acetato de medroxiprogesterona de depósito (AMPD) comparadas com usuárias de dispositivo intrauterino TCu380A (DIU TCu380A). SUJEITOS E MÉTODOS: Foram realizados dois estudos de avaliação da CC pela técnica DEXA. As participantes dos estudos foram selecionadas no Ambulatório de Planejamento Familiar do Departamento de Tocoginecologia da UNICAMP. Estudo 1: Estudo de corte transversal com 639 mulheres, entre 20 e 50 anos, divididas por faixas etárias (20-25, 26-30, 31-35, 36-40, 41-45, 46-50), no qual foi avaliado o peso corporal (kg), índice de massa corpórea (IMC kg/m2) e as variáveis de CC: MG (kg) e MM (kg), percentual de MG e de MM, índice de MG (IMG kg/m²) e índice de MM (IMM kg/m²). Estudo 2: Estudo de coorte prospectivo com acompanhamento de um ano, composto por dois grupos: 26 usuárias de AMPD como grupo-estudo e 26 usuárias de DIU TCu380A como grupo-controle , pareadas por peso (±2kg) e idade (±2 anos). Para avaliação da mudança de CC utilizaram-se variações percentuais de MG e MM e do peso (kg). A primeira avaliação foi realizada antes de se iniciar o uso do método contraceptivo e a segunda após 12 meses de uso. RESULTADOS: Estudo 1: Houve aumento absoluto de peso de 8kg (p=0,0001), 4,7kg de MG (p=0,003) e 1,9kg de MM (p=0,124) concomitante com a idade, embora não tenha ocorrido mudança significativa nos percentuais de MG e MM. O IMC(kg/m²) médio foi de 26,18(±4,6), sendo que as mulheres apresentaram sobrepeso desde a faixa etária de 26 a 30 anos e altos percentuais de gordura, atingindo valor médio de 41,6%(±7,4). O IMG médio das mulheres foi 10,5(±3,5). Estudo 2: Aos 12 meses de uso, as usuárias de AMPD tiveram aumento de peso de 1,9kg (p=0,02), resultante do ganho de 1,6kg (p=0,03) de MG. Nas usuárias de DIU TCu380A não houve alteração de peso; entretanto, houve ganho de 1,2kg de MM aos 12 meses de uso (p=0,001). O número de mulheres praticantes de atividade física aumentou neste grupo. Houve diferença significativa entre os grupos na variação do percentual de gordura central (p=0,04). CONCLUSÕES: As mulheres avaliadas apresentaram sobrepeso desde a idade jovem e ganho de peso, concomitantemente ao aumento da idade. Embora os percentuais de MG e MM não tenham se modificado, a quantidade absoluta de MG e de MM aumentou com o aumento da idade. O ganho de peso ocorrido nas usuárias de AMPD deveu-se ao ganho de MG, enquanto que as usuárias de DIU TCu380A tiveram aumento de MM e diminuição na MG abdominal / Abstract: INTRODUCTION: Weight gain associated with the use progestin-only contraceptive methods can lead women to discontinue the use. The boody composition assessment (BC) could assist to understand and to monitor weight gain. Evaluation of body composition by the technique dual-energy X-ray absorptiometry (DXA) allows to quantify the different components of CC: fat mass (FM) and lean mass (LM). OBJECTIVE: This study estimated body composition in women at reproductive age and evaluated body composition (BC) changes in users of depot medroxyprogesterone acetate (DMPA) and compared to TCu380A intrauterine device (IUD) users. SUJEITOS E MÉTODOS: It was performed two studies of BC assessment by DXA. Women of both studies were recruited at Woman Hospital of University of Campinas (Unicamp). Study 1: Cross-sectional study assessed BC of 639 women, between 20 - 50 years into age brackets (20-25, 26-30, 31-35, 36-40, 41-45, 46-50). It was evaluated weight, body mass index (BMI kg/m²), fat (FM) and lean mass (LM), percentage of fat (%FM) and lean mass (%FFM), fat mass index (FMI kg/m²) and fat-free mass index (FFMI kg/m²). Study 2: Prospective study was performed to compare body weight (BW) and BC in DMPA and IUD users at baseline and after one year of use. We enrolled 26 new DMPA users and age (± 2) and weight (± 2) matched 26 new IUD users. Weight and height were measured, BC (fat and lean mass), and physical activity was assessed at baseline and at 12 months. RESULTS: Study 1: It was an increase of 8kg of BW (p=0.0001), 4.7kg of FM (p= 0.003) of 1.9kg of LM (p= 0.124) concomitantly with increasing age, however it was no significant changes in %FM and %LM. Mean BMI (kg/m²) was 26.18 (±4.6), and women presented overweight since 26 years and elevated %FM, mean of 41.6% (±7.4). Mean FMI was (kg/m²) 10.5 (±3.5). Study 2: An increase of 1.9 kg occurred in BW (p=0.02) in DMPA users at 12 months of use, resulting from an increase in fat mass of 1.6 kg (p=.03). Weight remained stable in IUD users; however, there was an increase in lean mass of 1.2kg at 12 months of use (p=0.001). The number of women practicing physical activity increased in this group. There was a significant difference between the groups regarding the variation in the percentage of central fat (p=0.04). CONCLUSIONS: The women evaluated were overweight from the range of 26-30 years and presented weight gain concomitantly with increasing age. Although the percentage of fat and lean body mass has not changed, the absolute amount of fat and lean body mass increased with increasing age. Weight gain in the DMPA group resulted from an increase in fat mass. Weight remained stable in the IUD group; however, an increase in lean mass and a reduction in localized abdominal fat mass occurred / Doutorado / Fisiopatologia Ginecológica / Doutora em Ciências da Saúde

Atualmente, a obesidade pode ser classificada como uma pandemia. Com a clonagem do gene ob e do seu receptor, foi descoberta a leptina. Secretada principalmente pelo tecido adiposo, está diretamente correlacionada à quantidade de gordura corporal. Entretanto, diversos fatores influenciam sua expressão e síntese, tais como jejum, atividade simpática, exercício físico e alterações no balanço energético. Os efeitos do treinamento aeróbio sobre este hormônio são ainda contraditórios. Desta forma, este estudo teve como objetivo a verificação dos efeitos do treinamento aeróbio nas concentrações plasmáticas de leptina. Ratos Wistar machos foram divididos em dois grupos: treinado (T) e controle (C). Não houve diferença na ingestão energética e no gasto energético de repouso. Ratos treinados apresentaram menor peso corporal final, conteúdo de gordura corporal, insulinemia e melhora na resposta glicêmica. Houve maior expressão do mRNA da leptina no tecido adiposo visceral do que no subcutâneo nos dois grupos. Não houve, entretanto, diferença na expressão da leptina entre os grupos em ambos os depósitos. A menor concentração de leptina plasmática nos animais treinados ocorreu, principalmente, devido ao menor conteúdo de gordura corporal deste grupo. No entanto, após a correção da concentração de xiii leptina pelo conteúdo de gordura corporal, ainda foi observada diferença significativa entre os grupos, sugerindo que exista(m) outro(s) fator(es) de modulação das concentrações de leptina após o treinamento aeróbio, sendo a principal candidata a tal regulação a insulina / Obesity currently qualifies as a worldwide health epidemic. With the cloning of mouse ob gene and its receptor leptin was discovered. Leptin is expressed and secreted primarily by adipose tissue and is highly correlated to body fat mass. Nevertheless many factors can regulate leptin synthesis and expression, such as fasting, sympathetic activity, insulin, exercise and changes in energy balance. Endurance training effects on leptin are still contradictory. Therefore the aim of the present study was to verify the effects of endurance training on leptin levels. Male Wistar rats were separated in two groups: trained (T) and sedentary control (C). Energy intake and basal energy expenditure were not different between groups. Trained rats had lower final body weight, body fat mass, insulin levels and improved glycemic response. Leptin mRNA expression was higher in visceral than in subcutaneous adipose tissue in both groups. However, no difference in leptin expression between groups in either fat depot was found. Lower leptin levels in trained rats were due primarily to their lower body fat mass. Nonetheless, after correction for body fat mass leptin levels were still lower in exercised rats, suggesting that there might be other regulators of leptin levels in response to endurance training, being insulin the main candidate for such role

As Distrofias Musculares Progressivas (DMP) constituem um grupo de doenças genéticas caracterizadas por uma degeneração progressiva e irreversível da musculatura esquelética. A Distrofia Muscular de Duchenne (DMD) é a forma mais comum e grave de DMP. Obedece a herança recessiva ligada ao X e é caracterizada pela ausência de distrofina na membrana das fibras musculares. Atualmente não existe nenhum tratamento efetivo para este grupo de doenças. Deste modo, este trabalho tem como objetivo principal avaliar o potencial terapêutico das células-tronco mesenquimais de tecido adiposo humano (human Adipose-derived Stem Cells - hASCs) visando à regeneração ou diminuição da degeneração muscular. Para tanto, verificamos o potencial miogênico destas células in vitro, utilizando células musculares de pacientes DMD e in vivo utilizando como modelo camundongos distróficos e cães da raça Golden Retriever portadores de distrofia muscular (GRMD - Golden Retriever Muscular Dystrophy). Demonstramos neste estudo que hASCs são capazes de restaurar a expressão de distrofina in vitro, quando co-cultivadas com células musculares de pacientes DMD. Frente a estes resultados, continuamos nossos estudos em modelos animais, in vivo, e demonstramos que as hASCs são capazes de chegar à musculatura de camundongos distróficos e de cães GRMD, quando injetadas por via venosa, e de restaurar a expressão da proteína muscular defeituosa. Foi possível observar uma melhora funcional nos camundongos injetados. Nos cães GRMD encontramos distrofina humana seis meses após a última injeção entretanto é difícil julgar se houve melhora clínica. Todos esses experimentos de xenotransplantes foram feitos sem imunosupressão e não observamos rejeição. Concluímos que o tecido adiposo é uma fonte de células-tronco com potencial para regeneração muscular in vivo. Contudo é de extrema importância repetir os experimentos em um número maior de cães GRMD e ainda investigar novas estratégias visando melhorar os resultados obtidos neste trabalho, antes de começar qualquer teste clínico. / Progressive muscular dystrophies (PMD) are a clinically and genetically heterogeneous group of disorders caused by the deficiency or abnormal muscle proteins, resulting in progressive degeneration and loss of skeletal muscle function. As effective treatments for these diseases are still unavailable, they have been widely investigated as possible candidates for stem cell therapy. Duchenne Muscular Dystrophy (DMD), a lethal X-linked disorder, is the most common and severe form of muscular dystrophies, affecting 1 in 3000 male births. Mutations in the DMD gene lead to the absence of muscle dystrophin. The aim of this study is to evaluate the therapeutic potential of human Adipose-derived Stem Cells (hASCs) for muscle regeneration. First we verified the myogenic potential of these cells in vitro co-culturing them with muscle cells from DMD patients and verifying that hASCs are able to restore dystrophin expression in vitro. Subsequently we repeated this experiment in vivo using the dystrophic mice SJL and the dystrophic golden retriever dogs (GRMD - Golden Retriever Muscular Dystrophy) as animal models. We demonstrated that the hASCs are able to reach the muscles of the dystrophic mice and the GRMD dogs when injected systemically and restore expression of absent muscle protein, without any immunosupression. We observed a functional improvement in the injected mice. We found human dystrophin in injected dogs up to 6 months after the last injection. However it is difficult to evaluate if there was clinical improvement in the GRMD dogs due to their great phenotypic variability. We conclude that the adipose tissue is a source of stem cells with potential for muscle regeneration in vivo and that human cells are not rejected even in xenotransplants without immunosuppression. However it is important to repeat the experiments on a larger number of GRMD dogs and to investigate new strategies to improve our findings before starting any clinical trial.

Objetivo do estudo foi estudar a participação dos adipócitos e do fígado na inflamação e o papel da microbiota ao longo da progressão da caquexia. Para verificar o comportamento dos adipócitos e do fígado utilizamos ratos Wistar macho de 8 semanas, divididos em dois grupos: i) controle; ii) tumor. Este último foi subdividido em 2 grupos: a) 7º. e b) 14º. dia após a inoculação das células tumorais. Para avaliar o comportamento da microbiota durante o quadro de caquexia utilizamos camundongos C57Bl/6 convencional e germ free de 8-10 semanas, divididos em quatro grupos: i) Convencional controle; ii) Germ Free controle; iii) Convencional tumor; iv) Germ Free tumor. A célula tumoral usada para esse modelo foi Lewis Lung Carcinoma. Adipócitos isolados dos TAB, mesentérico, mais o fígado, mostraram que a via do inflamassoma esta ativa na fase terminal da caquexia. No modelo Germ Free, observamos que a caquexia apresenta-se é acelerada no tecido adiposo epididimal comparado aos camundongos convencionais tumor. Em conclusão, os adipócitos e o fígado desempenha papel importante no estabelecimento da inflamação, enquanto que a simbiose da microbiota parece ser essencial para combater a redução do tecido adiposo. / The goal of this study the role of adipocytes and liver inflammation and the role of microbiota along the progression of cachexia. The main aspects evaluated were increased of the inflammation, alteration in both pathways NF-kB and the inflammasome, and importance of the microbiota during progression of cachexia. To verify the behavior of adipocytes and liver I used Eight weeks-old male rats, I divided into two main groups: i) control; ii) tumor. The latter was divided into 2 groups: a) 7º. and b) 14º. day after tumor cell. To assess the microbial behavior during the development of cachexia I used C57BL/6 conventional mice and Germ Free 8-10 weeks, they were divided into four groups: i) Conventional control; ii) Germ Free control; iii) Conventional tumor; iv) Germ Free tumor. The tumor cell used in this model was Lewis Lung Carcinoma. Adipocytes isolated from TAB, mesenteric further the liver, showed that the inflammasome pathway is active in the terminal phase of cachexia. In model of Germ free mice we observed that cachexia is accelerated in epididymal adipose tissue compared to conventional tumor. In conclusion, adipocytes and liver seem to play a relevant role in the establishment of inflammation, while the microbial symbiosis seems to be essential for combating the reduction of adipose tissue.

A hipótese de que peptídeos gerados como produtos de proteólise intracelular poderiam modular cascatas de sinalização, foi originalmente proposto pelo nosso grupo. Um estudo realizado por Heimann et al. (2005) mostrou que camundongos geneticamente modificados e submetidos à dieta hiperlipídica, apresentavam uma diferença no conteúdo intracelular de peptídeos e uma melhora da resistência à insulina. Neste trabalho, investigamos o conteúdo peptídico intracelular do tecido adiposo de animais que desenvolveram obesidade e resistência à insulina, após serem submetidos à dieta cafeteria. Duas sequências peptídicas apresentaram 100% de aumento no tecido adiposo de animais submetidos à dieta cafeteria, em relação aos controles, tendo sido analisadas por ensaios de cinética enzimática, captação de glicose, western blot e cromatografia de afinidade. Os resultados obtidos corroboram os dados de Heimann et al. (2005) de que peptídeos intracelulares podem estar envolvidos na resistência à insulina, modulando o transporte de glicose no tecido adiposo. / The hypothesis that peptides generated as degradation products of intracellular proteolyses could modulate signaling pathways, was originally proposed by our group. A study by Heimann et al. (2005) showed that mice genetically modified and fed with high-fat diet, showed a difference in intracellular content of peptides and an improvement of insulin resistance. In this study, we investigated the intracellular peptide content from adipose tissue of animals that developed obesity and insulin resistance after being treated with the Western diet. Two peptide sequences showed 100% increase in adipose tissue of animals submitted to the Western diet compared to controls, and were analyzed by enzymatic assays, glucose uptake, western blot and affinity chromatography. Altogether, these results corroborate previous suggestions that intracellular peptides may be involved in insulin resistance, modulating glucose transport in adipose tissue.

A caquexia é um síndrome para neoplástica que interfere na morfologia e fisiologia do tecido adiposo. O objetivo do presente estudo foi avaliar os efeitos do treinamento de força e da suplementação de tributirina sobre os parâmetros da caquexia em animais inoculados com células do tumor de Walker 256. Ratos Wistar (n=7) foram randomizados em grupos experimentais: Controle (CT), Tumor (TB), Tumor tratado com tributirina (TBTrib), Treinado com Tumor (TFTB) e Tumor Treinado e suplementado com tributirina (TFTBTrib). Os parâmetros: peso tumoral, peso total carregado, quantidades de glicogênio, perfil plasmático, quantidades de citocinas, histologia do tecido adiposo foram analisados. Os grupos TBTrib e TFTBTrib tiveram menores quantidades de massa tumoral quando comparado com o grupo TB. O glicogênio muscular de TFTB e TFTBTrib estavam 37% e 35% maiores comparados com TB. As proteínas musculares aumentaram 48% e 50% para os grupos TFTB e TFTBTrib, sendo diferentes comparados com os grupos CT e TB. Se observou melhor balanço de IL-10/TNF-a nos grupos TFTB e TFTBTrib, sendo que a secção transversa diminuiu nos grupos TB e TBTrib. Se propõe que o treinamento de força e a suplementação de tributirina podem ser usados em trabalhos futuros com humanos. / Cachexia is a syndrome to neoplastic interfering in the morphology and physiology of adipose tissue. The aim of this study was to evaluate the effects of strength training and supplementation of tributyrin on the parameters of cachexia in animals inoculated with tumor cells of Walker 256 . Wistar rats (n = 7) were randomized into experimental groups : control (CT) , tumor (TB) , tumor treated with tributyrin (TBTrib) Trained with Tumor (TFTB) and Tumor Trained and supplemented with tributyrin (TFTBTrib). The parameters : tumor weight , total weight loaded amounts of glycogen , plasma levels , amounts of cytokines, histology of adipose tissue were analized. The TBTrib and TFTBTrib groups have smaller amounts of tumor mass compared to TB group. Muscle glycogen and TFTB TFTBTrib were 37% and 35% when compared to BD. The muscle proteins were 48% and 50%, respectively for TFTB and TFTBTrib groups being different when compared with TB and TC groups. Better balance was observed in groups IL-10/TNF-a TFTB and TFTBTrib , and the cross-section decreased in the groups TBTrib and TB. Proposes that resistance exercise and tributyrin supplementation can be used in future studies with humans.

A sepse é uma disfunção orgânica causada por uma resposta do hospedeiro à infecção desregulada, com risco de morte. Quando o tratamento da sepse não é efetivo, o quadro pode progredir para hipotensão severa. O tecido adiposo perivascular (perivascular adipose tissue - PVAT) é reconhecido como um elemento regulador na biologia vascular, com implicações na fisiopatologia de doenças cardiovasculares. No entanto, em relação à sepse, pouco se sabe acerca dos efeitos desta sobre a ação modulatória que o PVAT exerce no tônus vascular. Dessa maneira a hipótese do presente trabalho foi a de que a sepse poderia aumentar o efeito anti-contrátil do PVAT. Portanto, o objetivo do trabalho foi avaliar o efeito da sepse experimental na ação modulatória que o PVAT exerce sobre tônus vascular e os possíveis mecanismos envolvidos nessa resposta. Para isso foram utilizados ratos Wistar Hannover com idade entre 60 e 70 dias (270 a 300g). Os ratos foram distribuídos aleatoriamente em 2 grupos: 1) Grupo Sham: foi realizada apenas uma laparotomia sem os procedimentos de ligadura e punção do ceco; 2) Grupo CLP (Cecal Ligation and Puncture) : a sepse letal foi induzida utilizando o modelo CLP no qual foi realizada uma laparotomia para exposição do ceco, onde foi feito uma ligadura e 20 punções intermediárias entre a ligadura e a ponta do ceco com agulha de calibre 18 gauge (G). Os animais foram anestesiados com quetamina/xilasina (80/10 mg/kg, i.p.) e mortos 6 h após a indução da sepse. A aorta torácica foi coletada para realização das análises bioquímicas e funcionais. A sepse letal reduziu a taxa de sobrevida, a pressão arterial média (PAM), não alterou os níveis de leucócitos e neutrófilos, mas aumentou a contagem de bactérias no sangue e no lavado peritoneal, aumentou os níveis plasmáticos de nitrato, uréia e CK-MB. A sepse diminuiu a contração induzida pela fenilefrina e serotonina nas aortas PVAT(-)/Endo(+) ou Endo (-) do grupo CLP, quando comparada ao Sham. Porém nas artérias PVAT(+)/Endo(+) ou Endo (-), o CLP induziu redução mais pronunciada da contração induzida tanto pela fenilefrina, quanto pela serotonina. O aumento do efeito anti-contrátil do PVAT na condição séptica não foi encontrado nas artérias após a incubação com L-NAME, 7-nitroindazol, 1400W, A779, carboxy-PTIO, ODQ, apamina, RO11384552 e indometacina. Tiron, catalase, 4-aminopiridina, glibenclamida e caribdotoxina não alteraram a contração induzida pela fenilefrina no grupo CLP. A sepse aumentou a concentração de H2O2 na aorta, mas não afetou a concentração no PVAT. Aumento dos níveis de ânion superóxido (O2-) e prostaglandina (PG)I2 foram detectados tanto na aorta, quanto no PVAT do grupo CLP. A sepse não alterou os níveis de PGE2 ou angiotensina (1-7) na aorta ou PVAT. Portanto, a sepse letal induzida por CLP aumenta a ação anti-contrátil do PVAT por um mecanismo que envolve a produção de NO pelas enzimas iNOS e nNOS, a participação de canais para KCa de baixa condutância e ativação da enzima guanilato ciclase solúvel. Além disso, sugere-se o envolvimento da PGI2 e angiotensina (1-7) na hiporresponsividade vascular mediada pelo PVAT durante a sepse / Sepsis is an organic dysfunction caused by an unregulated host response to lifethreatening infection. When treatment of sepsis is ineffective, the condition may progress to severe hypotension that is drug-irresponsive. Perivascular adipose tissue (PVAT) is recognized as a regulatory element in vascular biology that is implicated in the pathophysiology of cardiovascular diseases. However, little is known about the effects of sepsis in the modulatory action of PVAT. Thus, the hypothesis of the present study was that sepsis could increase the anti-contractile effect of PVAT. Therefore, the objective of the study was to evaluate the effect of experimental (lethal) sepsis in the modulatory action that PVAT exerts on vascular tone and the possible mechanisms underlying this response. With this purpose, male Wistar Hannover rats (250-300g) were divided in 2 groups: 1) Sham: the cecum was exteriorized without ligation and puncture; 2) CLP: lethal sepsis was induced using the cecal ligation and puncture (CLP) model. The thoracic aorta was isolated 6 h after sepsis for functional and biochemical assays. Lethal sepsis reduced survival rate, mean arterial pressure (MAP), did not alter leukocytes and neutrophils migration, but increased bacterial count in the blood and peritoneal cavity, increased plasma levels of nitrate, urea and CK-MB. We found that in aortas PVAT(-)/Endo(+) or Endo(-), sepsis decreased the contraction induced by phenylephrine or serotonin, when compared to sham. In PVAT(+)/Endo(+) or Endo (-) arteries sepsis induced a more pronounced reduction of phenylephrine-induced contraction. Sepsis-induced increase of anti-contractile action of PVAT was not found after incubation of arteries with L-NAME, 7-nitroindazole, 1400W, A779, carboxyPTIO , ODQ, apamin, indomethacin and RO1138452. Tiron, catalase, charybdotoxin, 4- aminopyridine and glibenclamide did not alter phenylephrine-induced contraction in the CLP group. Sepsis increased H2O2 concentration in the aorta, but did not affect H2O2 concentration in PVAT. Increased levels of superoxide anion (O2-) and prostaglandin (PG) I2 were detected in both aorta and PVAT. Sepsis did not alter the levels of PGE2 or angiotensin (1-7) in the aorta or PVAT. Conclusion: Lethal sepsis increases the anticontractile action of PVAT by a mechanism that involves the production of nitric oxide (NO) by iNOS and nNOS, the participation of calcium-dependent K+ channel of low conductance and activation of the enzyme soluble guanylate cyclase. Angiotensin (1-7) and PGI2 also contribute to the increased anti-contractile effect displayed by PVAT during sepsis. Financial Support: CAPES

Les traitements antirétroviraux (TARV) actuels ne parviennent pas à éradiquer totalement le virus de l'immunodéficience humaine (VIH) de l’organisme, le virus reste présent dans des sites anatomiques ou cellulaires appelés "réservoirs". Cette persistance virale se traduit aussi par une inflammation chronique à bas-bruit, responsable de la majorité des comorbidités associées au VIH.L'objectif de mon travail de thèse est d'étudier le rôle du tissu adipeux infecté en tant que facteur d'inflammation et site de persistance virale. Le tissu adipeux est un organe endocrine, doué de propriétés immunologiques claires dans lequel on trouve les cibles principales du VIH: les LTCD4 et les macrophages. Nous avons analysé l'impact de l'infection SIV sur les profils d'activation et différenciation des lymphocytes T et macrophages du tissu adipeux sous cutané (SCAT) et le tissu graisseux mésentérique (VAT) prélevé au niveau du grand omentum de macaques cynomolgus. Nous avons démontré une activation du tissu adipeux: recrutement des macrophages, profil plus inflammatoire des macrophages, recrutement massif de LTCD8, et une plus forte proportion de LT activés. Parallèlement, nous avons détecté la présence du virus SIV (détection d'ARN et d'ADN viral) dans les fractions stroma-vasculaires du tissu adipeux et dans les fractions triées de lymphocytes T et macrophages chez les macaques infectés. Nous avons aussi démontré la présence du VIH au niveau du tissu adipeux des patients infectés et traités (Damouche et al PlosPathogens 2015). Ces résultats identifient pour la première fois le tissu adipeux comme un site réservoir du VIH.Nous avons ensuite évalué si le tissu adipeux présente des propriétés intrinsèques favorisant la persistance du VIH en nous concentrant sur les lymphocytes T CD4. Cette étude a été menée chez des patients infectés par le VIH et sous TARV efficace et des sujets non infectés. Nous avons observés une augmentation dans la proportion des Ly Treg chez les patients infectés par rapport aux sujets sains. Aucun changement majeur dans les pourcentages des fractions Th1 et Th17, au sein des Ly T CD4 chez les patients infectés par le VIH et sous ART n’a été observé. De même, le pourcentage de lymphocytes T CD4 mémoires « résidant » n'a pas été affecté par l’infection. Collectivement, ces résultats suggèrent que les cellules T CD4 du tissu adipeux n'ont pas subi d’importantes altérations dans le profil de différenciation et d’activation malgré la persistance virale. Nous avons aussi évalué le profil immuno-modulateur pouvant contribuer à l'activation limitée intervenant dans le tissu adipeux. Nous avons observé un pourcentage élevé de cellules exprimant PD-1 parmi les cellules T CD4 mémoire résistante aux tissus adipeux chez les patients infectés par le VIH et non infectés, suggérant un rôle immuno-modulateur des cellules T CD4 du TA. Cette forte expression de PD-1 à la surface des cellules T CD4, intrinsèque au tissu adipeux pourrait contribuer à la persistance virale. / The current antiretroviral treatments (ART) do not completely eradicate the human immunodeficiency virus (HIV) from the body, the virus remains present in anatomical or cellular sites called "reservoirs". This viral persistence also results in chronic low-grade inflammation, responsible for the majority of HIV-associated comorbidities.The objective of my thesis work is to study the role of infected adipose tissue as an inflammatory factor and site of viral persistence. Adipose tissue is an endocrine organ with clear immunological properties in which the main targets of HIV are found: CD4 T lymphocytes and macrophages. We analyzed the impact of the simian immunodeficiency virus (SIV) infection on the activation and differentiation profiles of T lymphocytes and macrophages of subcutaneous adipose tissue (SCAT) and mesenteric adipose tissue (VAT) from the large omentum of cynomolgus macaques. We have demonstrated an activation of adipose tissue: macrophage recruitment, macrophage inflammatory profile, massive recruitment of LTCD8, and a higher proportion of activated T lymphocytes. At the same time, we detected the presence of the SIV virus (detection of RNA and viral DNA) in the stroma-vascular fractions of the adipose tissue and in the sorted fractions of T lymphocytes and macrophages in the infected macaques. We also demonstrated the presence of HIV in the adipose tissue of infected and treated patients (Damouche et al PlosPathogens 2015). These results identify for the first time adipose tissue as an HIV reservoir site.We then evaluated whether adipose tissue exhibits intrinsic properties that promote persistence of HIV by focusing on CD4 T lymphocytes. This study was conducted in HIV-infected patients under effective HAART and non-infected subjects. We found no major changes in the percentages of Th1, Th17 fractions within Ly T CD4 in HIV-infected patients and ART, but an increased in the proportion of Treg cells was observed in infected patients compared to healthy subjects. The percentage of "resident" CD4 T cell lymphocytes was not affected by infection. Collectively, these results suggest that CD4 T cells of adipose tissue have not undergone significant alterations in the differentiation and activation profile despite viral persistence. We also evaluated the immuno-modulatory profile that may contribute to limited activation in adipose tissue. We observed a high percentage of cells expressing PD-1 among the CD4 T cells resistant to adipose tissue in HIV-infected and uninfected patients, suggesting an immunomodulatory role of CD4 T cells of TA. This strong expression of PD-1 on the surface of CD4 T cells, intrinsic to adipose tissue, could contribute to viral persistence.

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Twenty-two young men and women of the 49thMilitary Police Brigade of the California National Guard were participants of our nutrition education and health assessment program. The California National Guard has expressed concern of unsatisfactory physical and nutritional status of their personnel related to a nutrition knowledge deficit as evidenced by preliminary data of insufficient dietary intake and poor nutrition knowledge assessment scores. Our program was designed to implement a nutrition intervention including education and evaluate its effectiveness in reducing Metabolic Syndrome (MetS) risk factors, improving body composition, and providing educational lessons intended to alter lifestyle. Baseline data was quantified and analyzed for statistical significance. Participants reported consuming less than average daily recommended calories and variable macronutrient % of recommended values (%Recommended). DXA analysis revealed high %Body Fat (BF), positively correlated with high values of Visceral Adipose Tissue (VAT) in both sexes. Statistical analyses identify HDL cholesterol (HDL-C) and waist circumference as significant predictive variables of VAT, after adjusting for age and sex. Follow-up data from two participants was collected but excluded from statistical analysis due to small sample size. Exploratory (stepwise regression) analysis considering several predictive variables reveals HDL-C is the most significant predictor of VAT (p=0.0011), when waist circumference is excluded from the model, after correcting for age and sex. Waist circumference was excluded with the consideration that waist may be a surrogate measure for VAT. HDL-C seems to be the variable most strongly associated with VAT and HDL-C explains 67% of the variability of VAT (RSquared=0.6741) in the fit model after correcting for age and sex. While the impact of high HDL-C on improved body composition and reduction of cardiometabolic risk factors is well supported by literature, the significance of HDL-C on VAT deposition presented in our findings provokes continued research.