O envelhecimento é marcado por inúmeras alterações fisiológicas, dentre as quais encontramos um aumento da gordura corporal e alterações na resposta do sistema imunológico. Muito se sabe sobre a intrínseca ligação entre o aumento de gordura e as doenças de risco e fica a questão à cerca de sua influência sobre as respostas do sistema imunológico, já que estes dois fatores encontram-se alterados no envelhecimento. Portanto, o propósito deste estudo foi investigar a interação entre a quantidade de gordura corporal e as células do sistema imunológico de ratos envelhecidos. Para isso, num primeiro estudo, foram utilizados ratos ADULTOS e ENVELHECIDOS para a caracterização das alterações encontradas no processo de envelhecimento. Numa segunda etapa, os animais ENVELHECIDOS foram submetidos a dois protocolos de emagrecimento, a restrição calórica a 50%(RC) e o exercício aeróbio (EX) (natação), durante o período de quatro a seis semanas. Assim, foi possível avaliar alguns parâmetros do metabolismo de macrófagos e linfócitos em ratos envelhecidos com diferentes quantidades de gordura corporal. No primeiro estudo, os resultados comprovaram o aumento da gordura bem como algumas alterações no sistema imunológico de ratos envelhecidos, principalmente na capacidade funcional de macrófagos. Quanto ao segundo estudo, os resultados demonstram que ambos os protocolos foram eficientes em diminuir o peso corporal, bem como a gordura, sendo que para a RC os valores alcançados foram mais evidentes. Com relação ao sistema imunológico houve um aumento da resposta fagocitária e de produção de H2O2 por macrófagos e uma alteração da capacidade proliferativa de linfócitos, em ambos os protocolos. / Ageing is marked by several kinds of physiological changes, among then we find an increase of fat mass and a decline in several aspects of the immune system. It is well understood the intrinsical connexion between the increase in body fat and the risk of related diseases and the one question that remains is about the influence over the immune system response, since these two factors are altered on the ageing process. The purpose of this study was to investigate the relationship among fat content and immune cells of the aging rats. For this, in one first study, we used ADULTS and AGEING rats to determine the changes found in the ageing process. In the second time, the AGEING rats were submitted to two protocols for weight loss (slimming), 50% of caloric restriction (CR) and aerobic exercise (swimming) (EX), for four or six weeks. In this way, we can study some parameters of macrophages and lymphocytes metabolism in ageing rats with different body fat content. In the first study, the results confirmed the fat increase as well as some changes in the immune system of the ageing rats, especially in the macrophages functional capabilities. In the second study, the results showed that both protocols decreased body fat and weight, with the best results happening with CR protocol. The immune system had an increase on the phagocytic response and H2O2 production for macrophages and alterations of the proliferative capacities of the lymphocytes, in both protocols.

Obesidade na idade adulta é um fator de risco para o desenvolvimento de demência. O aumento da prevalência de obesidade, assim como o aumento da expectativa de vida na população tornam mais importante avaliar estratégias de prevenção e tratamento que possam diminuir o risco de declínio cognitivo. Neste estudo, foi avaliado se, em idosos obesos com Comprometimento Cognitivo Leve, a perda de peso induzida por dieta poderia melhorar aspectos da cognição, e se o genótipo para apoliproteína E, perfil metabólico e marcadores inflamatórios também teriam influência. Foi realizado um ensaio clínico prospectivo, randomizado de 1:1, de 12 meses, no Ambulatório de Endocrinologia do Hospital das Clínicas da Faculdade de Medicina da USP, entre 2011 e 2013, incluindo pacientes com 60 anos ou mais, com índice de massa corporal maior ou igual a 30 kg/m2, com Comprometimento cognitivo leve. Eles foram randomizados em dois grupos, um com assistência médica convencional (grupo convencional), outro adicionalmente com reuniões de orientação alimentar (26 a 28 sessões em 12 meses), com objetivo de obter maior perda de peso (grupo intensivo). Dos 1605 voluntários foram selecionados 80 pacientes, com idade média de 68,1 ±4,9 anos, escolaridade de 8,8 ±4,6 anos, IMC 35,5±4,4kg/m2; 13 (16,3%) eram do sexo masculino, 67 (83,6%) apresentavam síndrome metabólica; 50 (62,5%) eram fisicamente ativos. Os grupos eram semelhantes quanto às características iniciais. Após 12 meses, houve diminuição média de IMC de 1,7±1,8kg/m2 (4,9% do peso), e 85% da perda de peso foi em gordura corporal; sendo a variação semelhante entre os grupos. Para a maioria dos testes cognitivos aplicados houve melhora, sem diferença estatisticamente significativa entre os grupos. Na análise do grupo todo, a perda de peso induzida por dieta foi associada a melhora em avaliação de memória, função executiva, atenção e queixas subjetivas, tendo sido essa associação mais forte abaixo dos 70 anos e em carreadores do alelo 4 da apoliproteína E. Variação de insulinemia, HOMA-IR, triglicérides, proteína C reativa e leptina estiveram associadas à melhora em alguns testes cognitivos; risco maior de piora foi associado a níveis mais altos de pressão arterial (memória e cognição global) e de hemoglobina glicada (executivo/visuo-espacial) e de IL6 (atenção e velocidade de processamento); adiponectina mais alta diminuiu risco de piora (memória visual/verbal). Houve melhora principalmente em memória verbal, visual e memória de trabalho associadas à dieta, com relação à diminuição de consumo calórico, de carboidratos e gorduras, e sem relação com diminuição de consumo proteico. Houve melhora na avaliação funcional em relação à velocidade de marcha e força de membros inferiores e melhora na qualidade de vida associada à capacidade funcional, mostrando que a intervenção não trouxe prejuízo a essas áreas. A intervenção com restrição calórica em idosos obesos, com objetivo de promover perda de peso, foi benéfica em diversos aspectos da cognição e segura do ponto de vista funcional / Obesity in adulthood is a risk factor for developing dementia. The populational rise in obesity and life expectancy increase the importance of search for strategies for prevention and treatment to reduce the risk of cognitive decline. In this study we evaluated if in elderly obese with Mild Cognitive Impairment, weight loss induced by diet could improve aspects of cognition, and if the apolipoprotein E genotype, metabolic profile and inflammatory markers also influence these tests. A prospective, randomized clinical trial was conducted at Ambulatório de Endocrinologia do Hospital das Clínicas da Faculdade de Medicina da USP, between 2011 and 2013, including patients 60 years or older, with a body mass index greater than or equal to 30 kg/m2, with mild cognitive impairment. They were randomized into two groups and followed by 12 months, one with conventional medical care (conventional group), another with also group meetings with nutricionists (26-28 sessions over 12 months), in order to achieve greater weight loss (intensive group). Of the 1605 volunteers were selected 80 subjects, mean age 68.1 ± 4.9 years, education 8.8 ± 4.6 years, BMI 35.5 ± 4.4kg/m2; 13 were male (16.3%), 67 (83.6%) had metabolic syndrome; 50 were physically active. The groups had similar baseline characteristics. After 12 months there was a decrease in BMI of 1.7 ± 1.8 kg/m2 (4.9% of weight), and 85% weight loss was in fat; similar between groups. There was improvement for most of the cognitive tests, without difference between groups. In the analysis of the whole group, the weight loss induced by diet was associated with improvements in memory, executive function, attention and subjective complaints, though this association was strongest under 70 years of age and in carriers of the ?4 allele of apolipoprotein E. Changes in insulin, HOMA-IR, triglycerides, C-reactive protein and leptin were associated with improvement in some cognitive tests; increased risk of worsening was associated with higher blood pressure levels (memory and global cognition), HbA1c (executive / visuospatial) and IL6 (attention and processing speed); higher adiponectin decreased risk of worsening (visual memory/verbal). There was improvement in verbal, visual and working memory associated with diet, with respect to decreased caloric intake, carbohydrates and fats, and unrelated to decreased protein intake memory. There was improvement in functional assessment in relation to gait speed and lower limb strength and improvement in quality of life associated with functional capacity, showing that the intervention did not bring damage to these areas. Intervention with caloric restriction in obese elderly, in order to promote weight loss was safe and had beneficial effects in cognition

Les lymphomes à grandes cellules anaplasiques ou ALCL (Anaplastic Large-Cell Lymphoma) sont des cancers appartenant à la famille des lymphomes de type non-Hodgkin. La majorité des ALCL est issue d'une translocation t(2;5)(p23;q35) donnant lieu à la formation d'une protéine de fusion appelée NPM-ALK. A ce jour, peu d'inhibiteurs présentent de bonnes activités contre cette protéine chimérique. L'obésité représente un problème socio-médical d'envergure, à la fois pour ses effets directs et indirects ; le surpoids étant un facteur primaire dans de nombreuses maladies, tout particulièrement les diabètes, les accidents cardiovasculaires, le cancer, etc. A contrario, une restriction calorique (RC) est associée à des bénéfices importants en terme de santé. A l'issue de plusieurs criblages, un inhibiteur au motif 2-acylaminothiazole a montré une activité anticancéreuse sur ALK mais également la faculté de mimer la restriction calorique chez C. Elegans. Par conséquent, les travaux de recherche réalisés lors de cette thèse ont concerné la synthèse d'inhibiteurs comportant le squelette 2-acylaminothiazole. Les chromatographies d'affinité effectuées sur deux de nos inhibiteurs ont permis l'identification de cibles principales potentielles dans le cadre de la restriction calorique et des cibles secondaires possibles pour NPM-ALK. Ensuite, la présence d'un atome de brome sur le cycle aromatique a mené à la formation de liaisons C(sp2)-C(sp2), C(sp2)-C(sp) et C(sp2)- N, en utilisant les couplages catalysés par le palladium. Les différentes méthodes de modulation chimique ont conduit à mettre en place une librairie de 134 molécules. Certains d'entres eux et plus précisément ceux possédant un atome de silicium ont démontré une très bonne activité contre ALK et son mutant L1196M. Enfin, des résultats préliminaires ont également été obtenus sur le sujet de la restriction calorique avec quatre composés montrant une réduction du taux de lipides chez C. Elegans / Anaplastic Large-Cell Lymphoma (ALCL) is a type of cancer belonging to the non-Hodgkin family. The majority of ALCL arises from a translocation t(2;5) (p23;35) which leads to the formation of a fusion protein called NPM-ALK. Nowadays, few molecules are known to inhibit the activity of this chimeric protein. Obesity is a major socio-medical problem, for both direct and indirect effects, overweight is a primary factor in many diseases, especially diabetes, cardiovascular events, cancer, etc... In contrast, caloric restriction (CR) is associated with significant benefits in terms of health. After several screenings, one inhibitor based on a 2-acylaminothiazol scaffold showed anticancer activity on the protein ALK but also the ability to mimic caloric restriction in C. Elegans. The aim of this PhD was to develop the synthesis of new inhibitors including the 2-acylaminothiazol scaffold. The affinity chromatography performed on two of our inhibitors was used to identify potential major cellular targets in the process of caloric restriction and secondary cellular targets for NPM-ALK. Then, the presence of a bromo group on the aromatic ring allowed the formation of C(sp2)-C(sp2), C(sp2)- C(sp) and C(sp2)-N bonds, using palladium-catalyzed couplings. The different chemical methodologies afforded the synthesis of a library of 134 molecules. Some of them especially with a silicon atom demonstrated very good inhibitory activity and high selectivity against NPM-ALK and L1196M-NPM-ALK. Finally, preliminary results were also obtained on the subject of calorie restriction with four compounds showing a reduction of lipids in C. Elegans

Dans les cellules somatotropes, la liaison du facteur de libération de l’hormone de croissance (GHRH) à son récepteur (GHRH-R) stimule la synthèse et la sécrétion de l’hormone de croissance (GH) ainsi que la prolifération cellulaire. Chez les mammifères, le vieillissement est caractérisé par une diminution de la sécrétion de GH, liée à une perte de sensibilité des somatotropes au GHRH. Chez le rat âgé, des modifications de niveaux d'ARNm du GHRH-R et une diminution d'affinité et de capacité de liaison du GHRH sont rapportés. Au cours du vieillissement, une augmentation des niveaux de glucose et d’acides gras libres sérique suggère qu’une gluco- ou lipotoxicité puisse contribuer au dysfonctionnement de la fonction somatotrope. À ce jour, la restriction calorique modérée de longue durée (RCMLD) constitue l’intervention la plus efficace pour prévenir ou retarder les détériorations liées à l’âge. Des études ont montré des effets bénéfiques de la RCMLD sur l’axe somatotrope au cours du vieillissement via un maintien des paramètres de liaison du GHRH-R. Compte tenu de l’importance de cet axe, la compréhension des mécanismes menant à la somatopause ainsi que ceux associés aux effets bénéfiques de la RCMLD s’avère importante. Les objectifs principaux de la présente thèse étaient : 1) de déterminer les effets de la RCMLD chez le rat, sur le GHRH-R hypophysaire et la sensibilité des somatotropes au GHRH, 2) d’identifier les mécanismes associés à la somatopause et aux effets bénéfiques de la RCMLD, et 3) de préciser les effets d’une gluco-ou lipotoxicité sur l’axe somatotrope de rats et leur implication dans la somatopause. Des rats de 8 mois ont été soumis à une restriction calorique de 40% jusqu’à l’âge de 18-20 mois et ont été comparés à des rats jeunes et âgés nourris ad libitum. Cette étude a permis de mettre en évidence des effets bénéfiques de la RCMLD sur la régulation et la fonctionnalité du GHRH-R et de proposer que le glucose et les acides gras libres (AGL) circulants soient impliqués dans le vieillissement de la somatotrope. Une étude de micro-puce à ADN à permis d’identifier des gènes associés à des mécanismes de protection et de réparation des dommages cellulaires mis en place dans l’hypophyse antérieure au cours du vieillissement et par la RCMLD. Finalement, les effets d’un stress gluco- ou lipotoxique sur la fonction somatotrope ont été étudiés chez des rats de 2 et 6 mois, infusés 72 h avec une solution de glucose ou d’Intralipides, mimant les niveaux circulants de glucose et d’AGL retrouvés chez le rat âgé. Les résultats obtenus montrent que la glucotoxicité affecte la régulation de certains gènes de la somatotrope, dont le GHRH-R, et suggèrent que la capacité de réponse à ce type de stress est altérée. Les mécanismes par lesquels la glucotoxicité exerce ces effets pourraient inclure la génération de stress oxydant. L’ensemble de ces résultats proposent de nouvelles pistes mécanistiques qui pourraient contribuer au retardement de la somatopause et, ultimement, à l’élaboration de nouvelles stratégies d’intervention nutritionnelles ou pharmacologiques ciblant les mêmes voies que la RCMLD, avec une efficacité similaire ou supérieure. / In somatotroph cells, growth hormone-releasing hormone (GHRH) binding to its receptor (GHRH-R) stimulates growth hormone (GH) secretion and cell proliferation. In mammals, aging is characterized by a decrease of GH, associated with a decline of GHRH somatotroph sensitivity. In the aged rat, changes in GHRH-R mRNA levels and decrease of GHRH affinity and capacity were reported. In the course of aging, significant increase of glucose and free fatty acid (FFA) serum levels are observed, suggesting that gluco- or lipotoxicity could contribute to somatotroph dysfunction. Up to now, long-term moderate caloric restriction (LTMCR) has been the most efficient intervention to prevent or delay age-related deteriorations. Studies have shown beneficial effects of LTMCR on somatotroph axis during aging, through the maintenance of GHRH-R binding parameters. Knowing the importance of this axis, an understanding of the mechanisms associated with the effects of somatopause and benefits of LTMCR is important. Therefore, the main objectives of this thesis were: 1) to determine the effects of LTMCR on rat pituitary GHRH-R and somatotroph sensitivity to GHRH, 2) to identify the mechanisms associated to somatopause and the beneficial effects of LTMCR and 3) to specify the effect of gluco- or lipotoxicity on the rat somatotroph axis and their implications in somatopause. Eight-month-old rats were submitted to a 40% LTMCR until the age of 18 to 20-months and where compared to young and old rats fed ad libitum (AL). This study highlighted beneficial effects of LTMCR on GHRH-R regulation and functionality and suggested that high circulating levels of glucose and FFA could be involved in somatotroph aging. A microarray study was also performed, allowing the identification of genes associated to cellular protection and damage repair mechanisms regulated by aging and LTMCR in the anterior pituitary. Finally, effects of a gluco- or lipotoxic stress on the somatotroph function was assessed in 2- and 6-month-old rats submitted to a 72-h glucose and/or Intralipid infusion, to mimic the levels of glucose and FFA found in aged rats. The results showed that glucotoxicity affects the regulation of specific genes in the somatotroph, such as the GHRH-R gene, and suggest that the response capacity against this type of stress is altered with age very early on. Mechanisms by which glucotoxicity exerts these effects might include oxidative stress production. Altogether, these results proposed novel mechanisms that could contribute to delay somatopause and, ultimately, to the development of new nutritional or pharmacologic interventions targeting the same pathways as LTMCR, with a similar or greater efficiency.

No description available.

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No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) manuela_ortega_marques_rodrigues.pdf: 2356674 bytes, checksum: e576d7cb84dd67e4068acfffffe22e9f (MD5) Previous issue date: 2017 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico (CNPq) / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior (CAPES) / Funda??o de Amparo ? Pesquisa do Estado de Minas Gerais (FAPEMIG) / A expans?o do tecido adiposo branco na obesidade leva ? express?o alterada de prote?nas em seus adip?citos, bem como a infiltra??o de c?lulas do sistema imune, especialmente macr?fagos, cujas secre??es levam ao desenvolvimento da inflama??o cr?nica de baixo grau, a qual ? considerada subjacente ao desenvolvimento de in?meras comorbidades. Dentre as formas de tratamento da obesidade, dietas de restri??o cal?rica (RC) nutricionalmente balanceadas induzem a perda de peso e melhorias em marcadores sist?micos da inflama??o, mas os efeitos diretos no tecido adiposo visceral ainda s?o controversos. No entanto, existe uma lacuna sobre qual o impacto dessas dietas na inflama??o local, mesmo em condi??es de sobrecarga lip?dica. Assim, o objetivo deste estudo foi avaliar os efeitos da perda de peso corporal induzida por dieta hipolip?dica ad libitum e pela restri??o cal?rica com dieta hiperlip?dica na inflama??o do tecido adiposo visceral de camundongos obesos. Para tal, inicialmente, camundongos C57BL/6 com 12 semanas de idade, machos, foram divididos em dois grupos: LF ? alimentados com dieta controle hipolip?dica ? do ingl?s low fat (10% das calorias, fonte ?leo de soja, rica em ?cidos graxos poli-insaturados); e HF ? alimentados com dieta controle hiperlip?dica ? do ingl?s high fat (60% calorias, fonte banha de porco, rica em ?cidos graxos saturados) para indu??o da obesidade. Ap?s oito semanas, seis animais de cada grupo foram eutanasiados para verifica??o da adiposidade visceral e estado inflamat?rio (dosagens de prote?na C reativa ? PCR s?rica e hep?tica). Em seguida, os animais HF foram aleatoriamente divididos em tr?s grupos HF ? continuaram recebendo dieta HF; LFAL ? submetidos ao emagrecimento pela substitui??o da dieta HF pela LF e acesso livre (ad libitum) e RHF ? submetidos ao emagrecimento por receberem quantidades restritas em calorias da dieta HF para atingir o mesmo peso corporal dos animais LFAL. A partir deste momento, esses grupos foram alimentados, juntamente com os animais LF, por mais sete semanas. Ao final, foram avaliados o ganho/perda de peso corporal, a adiposidade, as concentra??es s?ricas e hep?ticas de PCR, e as concentra??es de leptina, adiponectina, e das citocinas IL-6, TNF e MCP-1 no tecido adiposo retroperitoneal, al?m da morfologia dos adip?citos e a presen?a de infiltrados inflamat?rios no tecido adiposo retroperitoneal. Ao final da fase de indu??o da obesidade, os animais HF estavam obesos e inflamados. Ao final da fase de indu??o da perda de peso, os grupos LFAL e RHF tiveram pesos corporais semelhantes, menores que o HF e se igualaram ao LF. No entanto, houve maior dificuldade em perder peso pelo grupo RHF em compara??o ao LFAL, dado pelas diferen?as significativas entre os deltas de perda de peso, que foram menores para RHF e pelos coeficientes de efici?ncia energ?tica, que foram maiores para o grupo RHF. Os animais LFAL retornaram a adiposidade e a hipertrofia dos adip?citos viscerais a valores semelhantes ao grupo LF. Isto provavelmente foi o que levou ? menor concentra??o de leptina com concomitante aumento da adiponectina e menor infiltra??o de c?lulas inflamat?rias neste tecido, igualando-se tamb?m ao LF. Em consequ?ncia, houve menor concentra??o tecidual de citocinas pr?-inflamat?rias, al?m de menor concentra??o hep?tica e circulante de PCR. J? para os animais RHF, houve apenas atenua??o da adiposidade e da hipertrofia dos adip?citos retroperitoneais. Isso foi suficiente para restabelecer a concentra??o local de leptina a n?veis semelhantes ao grupo LF, embora n?o tenha elevado a concentra??o de adiponectina. Al?m disso, a infiltra??o de c?lulas inflamat?rias menteve-se tamb?m elevada. N?o houve redu??o da concentra??o de citocinas pr?-inflamat?rias, ? exce??o da IL-6, que reduziu levemente. A concentra??o hep?tica de PCR foi atenuada, o que n?o refletiu na concentra??o s?rica dessa prote?na. Concluiu-se que a restri??o cal?rica com dieta hiperlip?dica foi menos eficiente em promover a perda de peso e de adiposidade e n?o melhorou a inflama??o do tecido adiposo visceral, comparada com a dieta hipolip?dica ad libitum. Inferiuse que a ingest?o de dieta com sobrecarga de lip?deos (60% das calorias) e de ?cidos graxos saturados foi mais determinante da inflama??o local do que a restri??o cal?rica per se. / Disserta??o (Mestrado) ? Programa Multic?ntrico de P?s-gradua??o em Ci?ncias Fisiol?gicas, Universidade Federal dos Vales do Jequitinhonha e Mucuri, 2017. / The expansion of white adipose tissue in obesity leads to altered protein expression in its adipocytes, as well as the infiltration of immune cells, especially macrophages, whose secretions lead to the development of chronic low-grade inflammation, which underlies the development of several comorbidities. Among treatments, caloric restriction (CR) nutritionally balanced diets induce weight loss and ameliorates inflammation systemic markers, but adipose tissue effects are still controversial. Moreover, there is a gap on the impact of these diets on local inflammation, even under lipid overload. Thus, the aim of this study was to evaluate effects of body weight loss induced by a low fat ad libitum diet and a CR in a high fat diet in the visceral adipose tissue inflammation of obese mice. Firstly, 12 weeks of age male C57BL/6 mice were divided into two groups: LF - fed a control low fat diet (10% calories, source soybean oil, high in polyunsaturated fatty acids); and HF - fed a control high fat diet (60% calories, source lard, high in saturated fatty acids) for obesity induction. After eight weeks, six animals from each group were euthanized to verify visceral adiposity and inflammatory status (serum and hepatic C-reactive protein-CRP). Then, HF animals were randomly divided into three groups: HF ? keept at HF diet; LFAL - a weight loss group that was switched from HF to LF and maintained on it ad libitum; RHF - a weight loss group that received restricted amounts of HF to maintain the same body weight as LFAL. Thereafter, these groups were fed, along with the LF animals, for another seven weeks. At end, body weight gain / loss, adiposity, serum and hepatic CRP concentrations, and adipose retroperitoneal tissue concentrations of leptin, adiponectin, IL-6, TNF and MCP-1 were evaluated, as well as adypocite morphology and the presence of inflammatory infiltrates in the retroperitoneal adipose tissue. Obesity was induced, since HF animals had higher weights, adiposity and were inflamed. At the end of the weight loss period, both LFAL and RHF had similar body weight, lower than HF and equal to LF. However, it was more dificcult to loose wheight by the RHF group compared to LFAL, since weight loss deltas were lower for RHF and energy efficiency ratios were higher for RHF group. LFAL animals returned visceral adiposity and retroperitoneal adipocyte hypertrophy similarly to the LF group. Also, there was a lower leptin level with concomitant increase of adiponectin and less infiltration of inflammatory cells in this tissue, also matching to LF. Still, there was a lower tissue concentration of proinflammatory cytokines, and a lower hepatic and serum CRP. For RHF animals, there was only an attenuation in adiposity and visceral adipocyte hypertrophy, although it was sufficient to restore local leptin concentration similarly to LF. However, this regimen was not able to elevate the adiponectin concentration. In addition, the inflammatory cells infiltration was highly elevated. There was no reduction in proinflammatory cytokines concentration, despite IL-6, which was reduced slightly. Hepatic CRP concentration was attenuated, which did not reflect in its serum concentrations. In mice with diet-induced obesity, the weight loss by means a CR in a high fat diet was less effective in promoting wheight and adiposity losses and it did not improve visceral adipose tissue inflammation. It can be inferred that a lipid overload (60% from calories) as well as a saturated fatty acid surplus from the high fat diet were more determinant of local inflammation than caloric restriction per se.

Obesidade na idade adulta é um fator de risco para o desenvolvimento de demência. O aumento da prevalência de obesidade, assim como o aumento da expectativa de vida na população tornam mais importante avaliar estratégias de prevenção e tratamento que possam diminuir o risco de declínio cognitivo. Neste estudo, foi avaliado se, em idosos obesos com Comprometimento Cognitivo Leve, a perda de peso induzida por dieta poderia melhorar aspectos da cognição, e se o genótipo para apoliproteína E, perfil metabólico e marcadores inflamatórios também teriam influência. Foi realizado um ensaio clínico prospectivo, randomizado de 1:1, de 12 meses, no Ambulatório de Endocrinologia do Hospital das Clínicas da Faculdade de Medicina da USP, entre 2011 e 2013, incluindo pacientes com 60 anos ou mais, com índice de massa corporal maior ou igual a 30 kg/m2, com Comprometimento cognitivo leve. Eles foram randomizados em dois grupos, um com assistência médica convencional (grupo convencional), outro adicionalmente com reuniões de orientação alimentar (26 a 28 sessões em 12 meses), com objetivo de obter maior perda de peso (grupo intensivo). Dos 1605 voluntários foram selecionados 80 pacientes, com idade média de 68,1 ±4,9 anos, escolaridade de 8,8 ±4,6 anos, IMC 35,5±4,4kg/m2; 13 (16,3%) eram do sexo masculino, 67 (83,6%) apresentavam síndrome metabólica; 50 (62,5%) eram fisicamente ativos. Os grupos eram semelhantes quanto às características iniciais. Após 12 meses, houve diminuição média de IMC de 1,7±1,8kg/m2 (4,9% do peso), e 85% da perda de peso foi em gordura corporal; sendo a variação semelhante entre os grupos. Para a maioria dos testes cognitivos aplicados houve melhora, sem diferença estatisticamente significativa entre os grupos. Na análise do grupo todo, a perda de peso induzida por dieta foi associada a melhora em avaliação de memória, função executiva, atenção e queixas subjetivas, tendo sido essa associação mais forte abaixo dos 70 anos e em carreadores do alelo 4 da apoliproteína E. Variação de insulinemia, HOMA-IR, triglicérides, proteína C reativa e leptina estiveram associadas à melhora em alguns testes cognitivos; risco maior de piora foi associado a níveis mais altos de pressão arterial (memória e cognição global) e de hemoglobina glicada (executivo/visuo-espacial) e de IL6 (atenção e velocidade de processamento); adiponectina mais alta diminuiu risco de piora (memória visual/verbal). Houve melhora principalmente em memória verbal, visual e memória de trabalho associadas à dieta, com relação à diminuição de consumo calórico, de carboidratos e gorduras, e sem relação com diminuição de consumo proteico. Houve melhora na avaliação funcional em relação à velocidade de marcha e força de membros inferiores e melhora na qualidade de vida associada à capacidade funcional, mostrando que a intervenção não trouxe prejuízo a essas áreas. A intervenção com restrição calórica em idosos obesos, com objetivo de promover perda de peso, foi benéfica em diversos aspectos da cognição e segura do ponto de vista funcional / Obesity in adulthood is a risk factor for developing dementia. The populational rise in obesity and life expectancy increase the importance of search for strategies for prevention and treatment to reduce the risk of cognitive decline. In this study we evaluated if in elderly obese with Mild Cognitive Impairment, weight loss induced by diet could improve aspects of cognition, and if the apolipoprotein E genotype, metabolic profile and inflammatory markers also influence these tests. A prospective, randomized clinical trial was conducted at Ambulatório de Endocrinologia do Hospital das Clínicas da Faculdade de Medicina da USP, between 2011 and 2013, including patients 60 years or older, with a body mass index greater than or equal to 30 kg/m2, with mild cognitive impairment. They were randomized into two groups and followed by 12 months, one with conventional medical care (conventional group), another with also group meetings with nutricionists (26-28 sessions over 12 months), in order to achieve greater weight loss (intensive group). Of the 1605 volunteers were selected 80 subjects, mean age 68.1 ± 4.9 years, education 8.8 ± 4.6 years, BMI 35.5 ± 4.4kg/m2; 13 were male (16.3%), 67 (83.6%) had metabolic syndrome; 50 were physically active. The groups had similar baseline characteristics. After 12 months there was a decrease in BMI of 1.7 ± 1.8 kg/m2 (4.9% of weight), and 85% weight loss was in fat; similar between groups. There was improvement for most of the cognitive tests, without difference between groups. In the analysis of the whole group, the weight loss induced by diet was associated with improvements in memory, executive function, attention and subjective complaints, though this association was strongest under 70 years of age and in carriers of the ?4 allele of apolipoprotein E. Changes in insulin, HOMA-IR, triglycerides, C-reactive protein and leptin were associated with improvement in some cognitive tests; increased risk of worsening was associated with higher blood pressure levels (memory and global cognition), HbA1c (executive / visuospatial) and IL6 (attention and processing speed); higher adiponectin decreased risk of worsening (visual memory/verbal). There was improvement in verbal, visual and working memory associated with diet, with respect to decreased caloric intake, carbohydrates and fats, and unrelated to decreased protein intake memory. There was improvement in functional assessment in relation to gait speed and lower limb strength and improvement in quality of life associated with functional capacity, showing that the intervention did not bring damage to these areas. Intervention with caloric restriction in obese elderly, in order to promote weight loss was safe and had beneficial effects in cognition

Afin de se maintenir au sein d'un environnement changeant, les individus doivent mettre en place une réponse adéquate. Il est connu que les animaux ont la capacité d'ajuster leur comportement à leur environnement. Cette plasticité comportementale, permet une réponse adaptée et relativement rapide aux variations de l'environnement, maximisant ainsi les chances de survie et de transmission des gènes. Elle met en jeu des processus cérébraux couteux en énergie rendant ces adaptations particulièrement sensibles à des changements alimentaires. Le but de cette thèse a été de mieux comprendre les facteurs qui contraignent ces réponses chez une espèce à laquelle s'applique une forte pression de sélection. Pour ce faire, nous avons étudié les réponses comportementales d'un primate malgache, le microcèbe gris (Microcebus murinus) soumis à des changements dans la quantité ou la qualité des ressources alimentaires disponibles. La première partie de ce travail s'est intéressée aux effets à court terme d'une restriction alimentaire sans malnutrition. Cette partie comprenait deux études. La première s'intéressant aux effets d'une restriction alimentaire à 60% sans malnutrition sur la plasticité comportementale innée via l’étude de l'horloge biologique. Les résultats de cette étude montrent une diminution de la capacité à se resynchroniser après un décalage horaire en lien avec la perte de poids. Ainsi, les individus perdant le plus de poids sont le moins à même de se resynchroniser sur les cycles lumineux après un décalage horaire de 6 heures. La seconde s'intéressait aux effets d'une restriction alimentaire de 40% sans malnutrition sur la plasticité comportementale acquise et montre une diminution de la capacité d'apprentissage des individus restreints après 19 jours de traitement alimentaire sans influence sur la mémoire à long terme. La moindre capacité d’apprentissage chez les individus en restriction calorique est corrélée à la perte de poids, les individus perdant le plus de poids étant les moins performants. Dans une seconde partie j’ai étudié l'effet de modifications qualitatives de l'alimentation à travers une supplémentation à long terme des individus en acides gras polyinsaturés n-3. Cette partie m’a permis de mettre en évidence une amélioration des performances d'apprentissage chez les individus supplémentés après 18 mois de traitement alimentaire accompagnée d'une diminution de l'anxiété et d'une augmentation de la neurogenèse adulte dans trois zones cérébrales.Ces travaux démontrent que les variations nutritionnelles, qu’elles soient quantitatives ou qualitatives sont capables d’influencer les différentes formes de plasticités comportementales et donc les grandes fonctions cérébrales et constituent ainsi un paramètre clé dans l’adaptation et la survie des individus. / In order to survive in a changing environment, individuals have to express an appropriate response. It is known that animals have the ability to adjust their behaviour to their environment. This behavioural plasticity allows a quick and adapted response to environmental variations, maximizing the individual'ssurvival and gene transmission. This plasticity relies on costly brain processes making these adaptations particularly dependent of food availability and maybe quality.This thesis project aimed at better understanding the constraints of these responses in a species under a strong selection pressure. To investigate this problematic, we studied the behavioural responses of a small Malagasy primate, the grey mouse lemur (Microcebus murinus), to both quantitative and qualitative changes in food resources. The first part of this work investigated the effect of a short-term caloric restriction without malnutrition over two studies. In the first one, we studied the effects of a 60% caloric restriction without malnutrition on innate behavioural plasticity via the study of the biological clock. The results show a decrease in the ability to resynchronize on a light/dark cycle following a time-shift. This difficulty to resynchronize was linked to body mass loss, the individuals loosing the more weight being the one unable to resynchronize after the 6-hours time shift. In the second study, we investigated the effect of a 40% caloric restriction without malnutrition on acquired behavioural plasticity. This study show a decrease in learning abilities of the restricted individuals after 19 days of dietary treatment and no influence on long term memory. This decrease in learning abilities was also linked with body mass loss, with the individuals loosing the more weight being the one with the worst success rate during this task. The second part focused on the effects of a qualitative variation in food supply via a long-term supplementation with n-3 polyunsaturated fatty acids. This part allowed us to show an increase in learning abilities associated with increased neurogenesis in three brain zones for supplemented animals after 18 month of treatment as well as a decrease of their anxiety level.This thesis work show that both quantitative and qualitative nutritional variations are able to influence different forms of behavioural plasticity and their cerebral basis and are of particular importance in the adaptation and survival of individuals.

In cardiology, there are different conditions associated with the release of free radicals in some forms of hypoxia, such as ventilatory hypoxia or reduced perfusion. The role of free radicals during hypoxia in cardiology is the key point of our interest. In presented thesis, we have focused on hypoxia-induced pulmonary vasoconstriction and acute myocardial ischemia. Hypoxic pulmonary vasoconstriction (HPV), an important physiological mechanism, is regulated by changes in the production of and interactions among reactive oxygen species (ROS). There is controversy, however, over whether HPV is mediated by an increase or a decrease in ROS production. Also, the role of nitric oxide (NO) in HPV remains unclear. Our results indicate that inhibition of HPV by the superoxide dismutase mimetic tempol does not depend on either NO production or a decrease in basal vascular tone. The effect of three-day fasting on cardiac ischemic tolerance was investigated in another experimental model. Short-term fasting conclusively decreases ROS production. Three-day fasting effectively protected rat hearts against major endpoints of acute ischemia-reperfusion injury. It prevented severe ventricular arrhythmias and reduced the extent of myocardial infarction. These beneficial effects can be linked to altered mitochondrial redox...

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