Contexte: Il n’y a pas de consensus concernant la meilleure activité physique pour réduire le risque cardio-vasculaire (RCV) résultant de l'accumulation du tissu adipeux viscéral dans le syndrome métabolique (SMet). Objectif: analyser les effets de l'activité physique sur le tissu adipeux viscéral et sur le RCV chez des patients SMet. Méthodes: 100 adultes, 50-70 ans, ont été randomisés en trois groupes d’activité physique: mixte (endurance et résistance) résistance modérée + endurance modérée (re), Résistance intense + endurance modérée (Re), résistance modérée + Endurance intense (rE). Une cure de trois semaines (J0 à J20), en institution, a précédé un suivi à domicile d’une année (M12). Nous avons suivi le tissu adipeux viscéral et la composition corporelle par DXA, les paramètres du SMet, les performances en force et en endurance, et le RCV en utilisant le score de Framingham et l’épaisseur intima-média carotidienne. L’observance a été évaluée entre D20 et M12. Résultats: 78 participants (78%) ont terminé l'étude. À J20, la perte de graisse viscérale était la plus élevée pour Re (-18%, p<.0001) et plus élevée pour rE que re (-12% vs 7%, p<.0001). De même, à partir de M3, la graisse viscérale a plus pour Re et rE (p<.05) pour atteindre à M12 une perte de graisse viscérale de -21,5% (Re) et -21,1% (rE) > -13,0% (re) (p<.001). Le RCV, le SMet et les performances physiques ont été améliorées dans tous les groupes. Les principales améliorations ont été obtenues durant la cure et ont ensuite évolué en fonction de l’observance. Particulièrement entre M6 et M12, les non-observants dégradent leurs améliorations alors que les observants restent stables. La perte de tissu adipeux viscéral est corrélée aux améliorations des paramètres du SM. Conclusions: Les 3 modalités d'activité physique induisent une perte de graisse viscérale et améliorent le RCV et le SMet, mais une haute intensité en résistance entraîne une amélioration plus rapide. Une cure avec un encadrement quotidien est indispensable pour aider les patients à atteindre leurs objectifs. L’observance semble être le principal défi dans le succès du traitement du SM. / Background: Opinions differ over the type of physical activity that best limits the cardiovascular risk (CVR) resulting from visceral fat accumulation in the metabolic syndrome (MetS). Aim: To analyze the effects of physical activity on visceral fat and cardiovascular risk (CVR) in patients suffering from MetS. Methods: 100 adults, aged 50-70y, were randomized to three training groups: moderate endurance and resistance (re), dominant resistance (Re), or dominant endurance (rE). A 1-year at-home follow-up (M12) began with a 3-week residential program (Day 0 to Day 20). We measured the change in central fat and body composition by DXA, MetS parameters, fitness and CVR using the Framingham score and carotid-intima-media-thickness. Compliance was assessed between D20 and M12. Results: 78 participants (78%) completed the study. At D20, central fat loss was highest in Re (-18%, p<.0001) and higher in rE than re (-12% vs. -7%, p<.0001). Likewise, from M3, visceral fat decreased more in Re and rE than in re (p<.05) to reach at M12 a central fat loss of -21.5% (Re) and -21.1% (rE) > -13.0% (re) (p<.001). CVR, MetS parameters and fitness improved in all groups. The main improvements were obtained during the residential program and evolved thereafter depending on compliance. Non-compliers had higher values in most outcomes between M6 and M12 whereas compliers maintained improvement. Central fat loss correlated with changes in MetS parameters. Conclusions: The 3 modalities of physical activity induced central fat loss and improvements in CVR and MetS, but high-intensity-resistance resulted in a faster improvement. A residential program with daily coaching is essential to help patients achieve their aims. Compliance appears to be the main challenge in successful Mets treatment.

O objetivo do presente estudo foi comparar a composição corporal, ingestão alimentar e condição periodontal de pacientes obesos mórbidos com síndrome metabólica (SM) e sem SM, candidatos à cirurgia bariátrica. O estudo foi de caráter observacional, transversal e analítico, envolvendo pacientes com índice de massa corporal (IMC) entre 40,0 a 49,9 kg/m² e idade entre 18 e 55 anos, atendidos no ambulatório de Cirurgia Bariátrica do Hospital Amaral Carvalho (HAC), de Jaú - SP. A amostra foi constituída por 60 indivíduos, divididos em dois grupos: grupo com SM (G1-com SM = 30) e grupo sem SM (G2-sem SM = 30), os quais foram avaliados no pré-operatório da cirurgia bariátrica. As variáveis analisadas foram: idade, escolaridade, renda per capita, peso, altura, IMC, circunferência da cintura, circunferência do quadril, relação cintura-quadril, composição corporal por bioimpedância elétrica, ingestão alimentar, consumo de bebida alcoólica, índice de sangramento gengival, recessão gengival, profundidade da sondagem, índice de placa e índice de cálculo. Foram adotados os testes Qui-quadrado e teste t não pareado, para verificar a associação entre SM e o desfecho bucal (doença periodontal), seguidos de regressão linear multivariada e correlação Scatter-Plot (p<0,05). Não houve diferença significativa entre os grupos quanto à composição corporal e a ingestão alimentar. O G1-com SM apresentaram maior idade (p=0,0006) e maior número de dentes ausentes (p=0,0002). Quanto às condições periodontais, a bolsa vestibular ou lingual de 0-3mm foram mais prevalentes em G2-sem SM (p=0,0002), recessão vestibular ou lingual =0 também foram maior (p<0,0003). Concluiu-se que pacientes com SM apresentam piores condições periodontais do que os sem SM. A atenção integral à saúde destes pacientes se faz necessária através de equipe multiprofissional, com a participação do cirurgião dentista. / The aim of the present study was to compare the body composition, food intake and periodontal condition of morbidly obese patients with metabolic syndrome (MS) and without MS, candidates for bariatric surgery. The study was observational, crosssectional and analytical, involving patients with body mass index (BMI) between 40.0 and 49.9 kg / m² and aged between 18 and 55 years, attended at the ambulatory of Bariatric Surgery of the Hospital Amaral Carvalho (HAC), Jaú - SP. The sample consisted of 60 subjects, divided into two groups: group with MS (G1-with SM = 30) and group without MS (G2-without SM = 30), which were evaluated in the preoperative period of bariatric surgery. The variables analyzed were: age, education, per capita income, weight, height, BMI, waist circumference, hip circumference, waist to hip ratio, body composition by electric bio impedance, food intake, alcohol consumption and gingival bleeding index, gingival recession, probing pocket depth, plaque index and calculus index. Chi-square tests and unpaired t test were used to verify the association between MS and buccal outcome (periodontal disease), followed by multivariate linear regression and Scatter-Plot correlation (p <0.05). There was no significant difference between the groups regarding body composition and food intake. The G1-with SM showed older age (p = 0.0006) and greater number of missing teeth (p = 0.0002). As for periodontal conditions, the vestibular or lingual pouch of 0-3mm were more prevalent in G2-without SM (p = 0.0002), buccal or lingual recession = 0 were also higher (p <0.0003).It was concluded that patients with MS have worse periodontal conditions than those without MS. The integral health care of these patients is necessary through a multiprofessional team, with the participation of the dentist surgeon.

Muitos estudos têm sido conduzidos em diferentes populações visando a identificação da proporção da variância fenotípica total atribuída a efeitos genéticos. A herdabilidade de fatores de risco relacionados à Síndrome Metabólica apresenta variações entre populações, tanto por causa da diferente distribuição de fatores de risco ambientais quanto pela variação genética presente em populações distintas. O objetivo desta análise foi avaliar as influências genéticas e ambientais dos componentes da Síndrome Metabólica, usando uma análise de componentes de variância, estimando a herdabilidade destes fatores em uma amostra de extensas famílias. Nós examinamos 1.712 indivíduos de 119 famílias selecionadas randomicamente da população geral de uma cidade do Brasil. Um total de 1.666 indivíduos de 81 famílias foi usado para análises. O tamanho das famílias variou de 3 a 156 indivíduos com uma média de 21 indivíduos por família. Antes de ajustes, as herdabilidades poligênicas da pressão sistólica (PAS) e diastólica (PAD) foram de 15 e 16,4%, circunferência abdominal de 26,1%, glicemia de 32,8%, triglicérides de 25,7% e HDL-c de 31,2%. Ajuste para idade, sexo, idade2 e interação sexo x idade aumentou as estimativas de herdabilidade para todos os traços: PAS (25,9%), PAD (26,2%), circunferência abdominal (40,1%), glicemia de jejum (34,5%), triglicérides (28,8%) e HDL-c (32,0%). Quando os fatores de risco para Síndrome Metabólica foram tratados como traços discretos, utilizando pontos de corte segundo critérios do ATPIII, as estimativas de herdabilidade, após ajuste para covariáveis, foram: 24,5% para SM, 37,5% para pressão arterial, 40,6% para circunferência abdominal, 54,5% para glicemia, 25,5% para triglicérides e 37,8% para HDL-c. Em conclusão, as estimativas de herdabilidade para os traços da síndrome metabólica em uma amostra da população brasileira são altas e não significativamente diferente de outros estudos em populações mundiais / Many studies have been conducted in different populations aiming at the identification of the proportion of total phenotypic variance that is attributable to genetic effects. The heritability of Metabolic Syndrome (MS) factors is expected to differ between populations because of the different distribution of environmental risk factors, as well as the genetic make-up of different human populations. The purpose of this analysis was to evaluate genetic and environmental influences on metabolic syndrome traits, using a variance component analysis, by estimating the heritability of these traits in a sample of extended pedigrees. We examined 1,712 individuals of 119 randomly selected families from the general population of a city of Brazil. A total of 1,666 individuals of 81 families were used for analysis. Family size varied from 3 to 156 individuals with a mean of 21 subjects per family. Before adjustment, polygenic heritability of systolic (SBP) and diastolic (DBP) blood pressure were 15% and 16.4%, waist circumference 26.1%, fasting glucose 32.8%, triglycerides 25.7%, and HDL-c 31.2%. Adjustment for age, sex, age2, age and sex interaction increased polygenic heritability estimates for all traits: SBP (25.9%), DBP (26.2%), waist circumference (40.1%), fasting glucose (34.5%), triglycerides (28.8%), and HDL-c (32,0%). When the Metabolic Syndrome factors were treated as discrete traits, using ATPIII cut off, the estimates of heritability after adjusting for covariates were: 24.5% for MS, 37.5% for blood pressure, 40.6% for abdominal circumference, 54.5% for fasting glucose, 25.5% for triglycerides, and 37.8% for HDL-cholesterol. In conclusion, heritability estimates for metabolic syndrome traits in a sample of Brazilian population are high and not significantly different from other studied worldwide populations

A Caquexia associada ao câncer (CC) e a Síndrome Metabólica (MetS) apresentam características comuns como inflamação e resistência à insulina. Na MetS, a resistência à insulina é compensada pela hiperinsulinemia, que pode contribuir para a resistência à insulina através do aumento da inflamação, em particular, no fígado, onde a concentração de insulina é mais elevada. Esta hipótese foi testada neste estudo. Células da linhagem humanas U937 foram diferenciadas em macrófagos e expostas à insulina, LPS e PGE2. A insulina induziu a expressão gênica de IL-1&#946; e IL-8 e potencializou a indução provocada por LPS, além de aumentar a indução de IL-1&#946; provocada por PGE2 e atenuar a inibição de TNF-&#945; causada por PGE2. Sobrenadantes de macrófagos tratados com insulina reduziram em hepatócitos a indução da glucoquinase dependente de insulina. Isso foi causado por citocinas contidas nos sobrenadantes, que ativaram ERK 1/2 e STAT3, resultando na fosforilação inibitória do substrato do receptor da insulina e a indução de SOCS3, respectivamente. MicroRNAs são protagonistas em doenças inflamatórias. Pacientes caquéticos exibiram níveis circulantes elevados dos mediadores pró-inflamatórios IL-6 e IL-8 e reduzidos do microRNA-21-5p em relação à pacientes não-caquéticos; a expressão do microRNA-21-5p correlaciona-se negativamente com níveis de IL-6. Isto indica que a hiperinsulinemia e a expressão do microRNA-21-5p diminuída podem contribuir para a inflamação e a resistência à insulina. / Cancer Cachexia (CC) and Metabolic Syndrome (MetS) share common issues as inflammation and insulin resistance. In MetS insulin resistance is compensated by hyperinsulinemia, which might contribute to insulin resistance by enhancing inflammation in particular in liver where insulin concentration is higher. This hypothesis was tested in this study. Cells of the human cell line U937 were differentiated into macrophages and exposed to insulin, LPS and PGE2. Insulin induced the gene expression of pro-inflammatory mediators like IL-1&#946; and IL-8 and enhanced the induction provoked by LPS. Insulin enhanced the induction of IL-1&#946; by PGE2 and attenuated the inhibition of TNF&#945; by PGE2. Supernatants of insulin-treated macrophages reduced insulin-dependent glucokinase induction in hepatocytes. This insulin resistance was caused by cytokines contained in the supernatants, which activated ERK1/2 and STAT3, resulting in inhibitory phosphorylation of insulin receptor substrate and induction of SOCS3, respectively. MicroRNAs are active players in inflammatory disorders. In cachectic cancer patients circulating levels of the pro-inflammatory mediators IL-6 and IL-8 were higher and microRNA-21-5p lower than in non-cachectic patients; microRNA-21-5p negatively correlated with IL-6. This indicates that hyperinsulinemia and diminished microRNA-21-5p expression might contribute to inflammation and insulin resistance.

Submitted by Rosina Valeria Lanzellotti Mattiussi Teixeira (rosina.teixeira@unisantos.br) on 2017-04-25T16:59:36Z No. of bitstreams: 1 Narriane Chaves Pereira de Holanda.pdf: 1302637 bytes, checksum: b468541773c5328d51e8317a0be8cba3 (MD5) / Made available in DSpace on 2017-04-25T16:59:36Z (GMT). No. of bitstreams: 1 Narriane Chaves Pereira de Holanda.pdf: 1302637 bytes, checksum: b468541773c5328d51e8317a0be8cba3 (MD5) Previous issue date: 2017-01-23 / Background: A relevant portion of the economically active world population is involved in some kind of night work and there are a relationship between shift work and short sleep duration. A few studies have shown the association between short sleep duration and negative consequences to the cardiometabolic health of night workers. The aim of this study was to analyze the association between shiftwork, sleep duration with metabolic syndrome risk factors in nursing personnel of a public hospital. Methods: A crosssectional study, involving nursing personnel of a children´s public hospital in João Pessoa, Brazil, was conducted. Sixty workers filled out a survey with socio-demographic, sleep (Karolinska Sleep Questionnaire), physical activity (International Physical Activity Questionnaire), Karasek's Job Demands-Control, and nutrition data (16-Food Intake Questionnaire). Body measurements and blood pressure were taken and blood was collected for glycemia, total cholesterol and portions of low-density lipoprotein and highdensity lipoprotein, triglycerides and leptin. The sample was divided into three groups according to the work shift of the participants (only morning shift, mixed - morning and night shifts, ex-night shift). To do the statistical analyzes, tests of the difference of the average of quantitative variables were done (ANOVA and Kruskal Wallis) and tests of proportion (chi-square test and Fisher exact) of quantitative variables to compare the three groups. In all tests was considered p < 0,05 as significant. The program used was the STATA 12.0 (Stata corp, Texas, USA). The ethical questions involving people were respected. Results: The participants average age was 39.8 years old (SD=10.5 years old). The prevalence of the metabolic syndrome in the studied population was 32%, however, there was no significant differences among the groups. Also, there were no significant differences among the studied groups regarding to socio-demographic, physical activity, food patterns, health characteristics, and job demands-control categories. Nevertheless, the group of morning and night workers reported sleep less (p<0.01), and showed a higher sleep debt (p<0.01) than the other groups in workdays. In addition, the higher proportion of workers with hypertriglyceridemia (TG ¿ 200 mg/dl; p=0.03) and diastolic arterial hypertension (DAP ¿ 90 mmHg; p=0.01) was observed in the morning and night shift group. Conclusion: The prevalence of metabolic syndrome in the studied population was above the general population. Although no differences were observed among the groups, the one which includes night shift showed more sleep disturbances than the others, and higher prevalence of two out of three risk factors to the metabolic syndrome diagnosis. The relationship between MS and shift work should be investigated in the light of work activity. / Introdução: Importante parcela da população mundial economicamente ativa está envolvida em algum tipo de trabalho noturno. Este tipo de trabalho promove dessincronização do ciclo virgília-sono e prejuízo do sono destes trabalhadores; e vários estudos observacionais têm demonstrado a associação entre sono de curta duração e consequências negativas para a sáude cardiometabólica. Objetivo: Analisar a relação entre o trabalho turno de trabalho, sono de curta duração e síndrome metabólica em uma equipe de enfermagem. Métodos: Tratou-se de um estudo epidemiológico do tipo transversal envolvendo funcionárias da enfermagem de um hospital infantil, situado na cidade de João Pessoa-PB. Sessenta profissionais responderam questões sociodemográficas e questionários validados internacionalmente sobre sono (Questionário Karolinska), prática de atividade física (IPAQ-SF), binômio demanda-trabalho (Job Scale, versão curta) e nutrição (16-FIQ). Foram aferidas medidas antropométricas, da pressão arterial e realizada coleta de sangue para avaliação bioquímica da glicemia de jejum, colesterol total e frações, triglicerídeos e leptina. Para as análises estatísticas foram realizados testes de diferença de médias das variáveis quantitativas (ANOVA e Kruskal Wallis), assim como testes de proporções (qui-quadrado e exato de Fisher) das variáveis qualitativas para comparar os três grupos. Em todos os testes foi considerado significante o valor de ¿p¿ menor que 0,05. O programa utilizado foi o STATA 12.0 (Stata corp, Texas, USA). As questões éticas de pesquisa envolvendo seres humanos foram devidamente respeitadas. Resultados: A amostra foi dividida em três grupos, de acordo com o turno de trabalho exercido pelas participantes (diurno, misto - diurno e noturno, e ex-noturno). A idade média das participantes foi 39,8 anos (DP=10,5 anos), variando de 26 a 66 anos. A prevalência da síndrome metabólica na população estudada foi de 32%, estando acima da média da população geral. Entretanto, não houve diferença significativa entre os grupos estudados. Não houve diferença significativa entre os grupos estudados quanto às características sociodemográficas, de saúde, prática de atividade física, padrão alimentar e categorias de demanda e controle no ambiente de trabalho. As trabalhadoras diurnas e noturnas relataram dormir menos (p<0,01) e apresentaram um maior débito de sono (p<0,01), quando comparadas às trabalhadoras diurnas e ex-noturnas. Além disso, este grupo apresentou mais hipertrigliceridemia franca (TG ¿ 200 mg/dl) (p=0,03) e hipertensão arterial diastólica (PAD ¿ 90 mmHg) (p=0,01). Conclusão: A prevalência de síndrome metabólica na população estudada foi maior que a da população geral. Embora nenhuma diferença tenha sido observada entre os grupos, o grupo que incluiu trabalhadoras noturnas apresentou mais distúrbios do sono, além de uma maior prevalência de dois de três fatores de risco para o diagnóstico de síndrome metabólica.

Abstract available through http://www.fasebj.org/doi/abs/10.1096/fasebj.31.1_supplement.1037.5.

Abstract available through http://www.fasebj.org/doi/abs/10.1096/fasebj.31.1_supplement.1037.5.

L’acide trans-palmitoléique (C16:1 n-7 trans, TPA) est considéré comme un marqueur de la consommation de produits laitiers. D’une part, la consommation de produits laitiers est associée à un moindre risque de syndrome métabolique. D’autre part, de forts taux circulants de TPA sont épidémiologiquement associés à un moindre risque de diabète de type 2. Les bénéfices de la consommation de produits laitiers peuvent-ils en partie être expliqués par le TPA ? À ce jour cependant, aucune étude de supplémentation en TPA n’existe pour confirmer ces associations, et les doutes sur l’origine formelle du TPA ne sont pas levés. Dans ce travail, nous montrons (1) que le TPA provient de la rétro-conversion endogène de l’acide trans vaccénique (C18:1 n-7 trans, TVA) alimentaire chez l’Homme, (2) que le TPA et le TVA sont apportés exclusivement par la matière grasse de ruminants (lait et viande de ruminants) en France, (3) la possibilité d’obtenir du TPA pur en quantités suffisantes pour mener des études nutritionnelles et (4) que la supplémentation en TPA pur chez la souris dans un contexte de mise en place de syndrome métabolique empêche la mise en place de certaines dysfonctions métaboliques. Dans l’ensemble, ces résultats montrent que le TPA, acide gras spécifique de la matière grasse laitière, peut expliquer en partie l’association épidémiologique entre consommation élevée de produits laitiers et moindre risque de syndrome métabolique. / Trans-palmitoleic acid (trans-C16:1 n-7, TPA) is usually considered as a biomarker of dairy fat consumption. On the one hand, dairy product consumption is associated with lower risk of metabolic syndrome. On the other hand, high circulating levels of TPA in humans are epidemiologically associated with lower risk of type 2 diabetes. Could benefits of dairy products consumption rely in part on TPA? So far, there is no nutritional study involving TPA to confirm such observational associations, and doubts remain as regards to the formal origin of TPA. In this work, we demonstrate (1) that TPA arises from the endogenous retro-conversion of dietary trans-vaccenic acid (trans-C18:1 n-7, TVA) in humans, (2) that both TPA and TVA intakes are exclusively ensured by ruminant products (milk and meat) consumption, (3) the ability to get pure TPA in enough amounts to carry out reliable nutritional studies and (4) that pure TPA supplementation on mice fed an obesogenic diet prevents from several metabolic dysfunctions. Taken together, our results demonstrate that the dairy fatty acid TPA may explain part of the epidemiological association between high consumption of dairy products and lower risk of metabolic syndrome.

Le vieillissement musculaire (sarcopénie) conduit inéluctablement à une perte d'autonomie, et à une moindre capacité à lutter contre les agressions métaboliques. Or, les mécanismes mis en jeu sont complexes et restent mal connus. Ainsi, au cours de cette thèse, une étude protéomique comparative a été développée afin d'identifier de nouveaux biomarqueurs potentiels de la sarcopénie chez la femme âgée post-ménopausée, et 73 protéines exprimées différentiellement dans le muscle âga ont été identifiées. En plus des altérations du muscle squelettique, l'âge est connu comme étant un facteur favorisant l'apparition du syndrome métabolique (SM), facteur de risque pour les maladies cardiovasculaires et le diabète de type II. Cependant, les effets du SM sur le muscle squelettique des personnes âgées sont peu décrits dans la littérature. Des marquages immunohistologiques ont été réalisés à partir de biopsies du muscle vastus lateralis provenant de personnes jeunes (25 ans) et âgées avec ou sans SM (75 ans), afin de décrire les altérations structurales et fonctionnelles du muscle squelettique liées à l'âge et au MS. Les résultats montrent une atrophie des fibres de type II ayant une déformation accrue lors du vieillissement. Chez les personnes âgées atteintes de SM, l'aire des fibres est augmentée par rapport aux personnes âgées contrôles, et une forte diminution de l'activité cytochrome c oxydase a été observée. De plus, le vieillissement et plus particulièrement le SM sont associés à une forte accumulation de lipides intramusculaires. Enfin, alors que peu de différences ont été observées chez les personnes âgées contrôles, le contenu en capillaire est fortement altéré chez les individus atteints de SM. Par la suite, une étude protéomique comparative a permis d'identifier 42 biomarqueurs potentiellement impliqués dans le vieillissement musculaire et/ou dans le syndrome métabolique. L'ensemble des résultats obtenus au cours de cette thèse devrait permettre d'améliorer notre compréhension des facteurs impliqués dans le développement de la sarcopénie, et pourrait permettre d'identifier à la fois de nouvelles voies de régulation et suggérer des cibles thérapeutiques potentielles. / Muscle aging (sarcopenia) contributes to both loss of autonomy and decreased capacity to prevent metabolic aggressions, but the mechanisms involved are complex and remain unclear. Therefore in this thesis, we have undertaken a top-down differential proteomic approach to reveal novel potential biomarkers of sarcopenia, and 73 differentially expressed proteins were identified. In addition to alterations of skeletal muscle, aging favors metabolic syndrome (MS), a risk factor for cardiovascular disease and type II diabetes. However, the effects of MS on skeletal muscle in old individuals have poorly been investigated. Immunohistochemical studies were performed with vastus lateralis muscle biopsies from young (25 years) and old (75 years) men with and without MS, to reveal the importance of age-dependent and MS-associated modifications on fiber-type characteristics. An atrophy of type-II fibers and altered fiber shape characterized muscle aging in lean healthy men. In contrast, increased cross sectional area of fibers, and reduced cytochrome c oxidase activity in all fiber types characterized MS, even in active elderly men. Moreover, aging and particularly MS were associated with accumulation of intramyocellular lipid droplets. Finally, while few differences were observed in lean healthy men, the capillary supply was strongly altered in old men with MS. Thereafter, a differential proteomic approach identified 42 potential biomarkers implicated in muscle aging and/or in metabolic syndrome. Overall the results obtained in this thesis may improve our understanding of the factors influencing sarcopenia, and may both identify new regulatory pathways and provide potential therapeutical targets.

L’obésité est un état physiopathologique d’origine multifactorielle caractérisé par une accumulation excessive de tissu adipeux (TA). Elle est associée à une augmentation du risque de développer une insulino-résistance (IR), un syndrome métabolique et, à terme, un diabète de type 2. L’altération des fonctions du TA au cours de l’obésité joue un rôle central dans l’apparition des troubles métaboliques, tels qu’une accumulation ectopique de graisse et une IR périphérique, notamment dans le muscle. Dans ce contexte, la qualité des apports énergétiques et plus précisément en lipides pourrait jouer un rôle important dans l’adaptation des tissus au cours de l’obésité. Ainsi le palmitate (PAL), un acide gras saturé (AGS) est pro-lipogénique, pro-inflammatoire et lipotoxique, ce qui favorise l’apparition d’une IR. Les acides gras polyinsaturés oméga-3 (3) auraient des effets antagonistes au PAL et donc potentiellement protecteurs vis-à-vis des perturbations métaboliques associées à l’obésité. Parmi les 3, les effets spécifiques des trois principaux acides gras alimentaires, les acides alpha-linolénique (ALA), éicosapentaénoïque (EPA) et docosahexaénoïque (DHA), ont été très peu décrits.L’objectif principal de ce travail de thèse a été d’étudier les effets propres de l’ALA, de l’EPA et du DHA sur les altérations métaboliques induites en situation d’obésité. Des explorations mécanistiques ont été réalisées sur les cellules musculaires C2C12 dans lesquelles l’IR a été induite par le PAL et sur des adipocytes 3T3-L1 pour étudier l’impact des AGPI 3 sur la différenciation adipocytaire. Les effets des AGPI 3 ont ensuite été étudiés in vivo, en supplémentant des souris C57BL/6 sauvages ou déficientes en leptine (ob/ob) lors de la consommation d’un régime obésogène riche en lipides et en sucrose (mimant un régime occidental).Dans les cellules musculaires C2C12, les trois 3 co-incubés avec le PAL ont induit de façon comparable une diminution du contenu en composés lipotoxiques et une amélioration de la captation du glucose, mais seuls l’EPA et le DHA ont restauré la -oxydation du PAL et l’activation de la voie de signalisation de l’insuline. De plus, l’EPA et le DHA ont eu un effet protecteur supérieur à l’ALA vis-à-vis de l’inflammation induite par le PAL. Dans le modèle in vivo, seul la supplémentation en EPA a amélioré l’homéostasie du glucose en comparaison avec les supplémentations en ALA et en DHA. Alors que l’EPA a réduit la prise de masse grasse, le DHA a induit une hypertrophie des cellules adipeuses associée à une augmentation de la sécrétion de leptine et une baisse de la sécrétion d’adiponectine. Dans un modèle d’adipocytes 3T3-L1 en culture, le DHA a accéléré la différenciation des préadipocytes en comparaison avec l’ALA et l’EPA, pouvant expliquer son effet hypertrophique in vivo.En conclusion et dans nos conditions expérimentales, les 3 ALA, EPA et DHA ont bien des effets communs sur le métabolisme lipidique et glucidique in vitro mais également des effets propres qui ont permis de montrer qu’une supplémentation nutritionnelle en EPA serait plus intéressante pour limiter l’IR in vivo par rapport au DHA ou à l’ALA. Le DHA a quant à lui favorisé l’hypertrophie du TA, perturbant ainsi la sécrétion des adipokines participant à la régulation de la sensibilité à l’insuline des tissus périphériques, comme le muscle squelettique. / Obesity is characterized by an excess of adipose tissue (AT) mass and may be caused by multiple factors. It is associated with an increased risk of the development of insulin-resistance (IR) and metabolic syndrome, leading to type 2 diabetes. The impairment of lipid storage in the AT play a central role in obesity-associated disorders, as it leads to ectopic lipid accumulation and peripheral IR notably in muscles. In this context, the quality of dietary lipids may play a role in the regulation of AT and muscle metabolisms. In fact, palmitic acid (PAL), a saturated fatty acid (SFA) induces lipogenesis, inflammation and lipotoxicity favoring IR in many tissues. On the contrary, omega-3 polyunsaturated fatty acids (3) have protective effect against obesity-associated disorders. Among them, linolenic (ALA), eicosapentaenoic (EPA) and docosahexaenoic (DHA) specific effects remained partially described.This work aimed at exploring the specific effects of 3 on metabolic disorders and the development of obesity. Mechanisms were studied in C2C12 muscle cells during PAL-induced IR and in 3T3-L1 adipocytes to determine the impact of 3 on adipocyte differentiation. In vivo, the effects of 3 were investigated by supplementating C57BL/6 wild-type or leptin-deficient (ob/ob) mice with ALA, EPA or DHA during a high fat / high sucrose diet (mimicking a western diet).In C2C12 muscle cells, co-incubation of 3 with PAL induced a similar decrease in the content of lipotoxic compound and improved glucose uptake, whereas only EPA and DHA restored -oxidation and insulin signaling activation. Furthermore, EPA and DHA were more potent to reduce PAL-induced inflammation compared to ALA. In mice, only EPA improved whole body glucose homeostasis compared to ALA and DHA. While EPA reduced body fat gain, DHA induced hypertrophy in AT, increased leptin secretion and decreased those of adiponectine. In cultured 3T3-L1 adipocytes, preadipocyte differentiation was also induced by DHA compared to ALA and EPA and might explain the hypertrophy observed in mice.In conclusion and in our experimental conditions, ALA, EPA and DHA have common effects on in vitro lipid and glucose metabolism but also specific effects, demonstrating that EPA would be more interesting to limit IR in vivo compared to DHA or ALA. DHA favored hypertrophy of AT and disturbance of adipokine secretion involved in peripheral regulation of insulin sensitivity, notably in muscle.