Ces travaux de thèse sont focalisés sur l’étude de trois adipocytokines (adiponectine, visfatine et chémérine) chez des espèces dont les anomalies du métabolisme énergétique sont associées à des désordres de la fonction de reproduction. Nos résultats montrent des effets du régime alimentaire sur le métabolisme lipidique et glucidique et de manière moins prononcée sur les fonctions de reproduction chez la vache laitière et la poule reproductrice de souche chair. Ces effets ont en partie été associés aux profils d’expression de l’adiponectine, la visfatine et la chémérine. De plus, nous avons mis en évidence une surexpression du système chémérine/CMKLR1 dans le liquide folliculaire et dans les cellules ovariennes de patientes atteintes du syndrome des ovaires polykystiques associé ou non à une obésité. D’une part, ces découvertes révèlent la possibilité de considérer ces adipocytokines comme de potentiels biomarqueurs de l’évaluation de la croissance, de l’état d’engraissement et de fertilité dans les élevages agricoles. D’autre part, elles suggèrent une potentielle implication de la chémérine dans la régulation des fonctions ovariennes chez la femme. / This thesis is focused on the study of three adipokines (adiponectin, visfatin and chemerin) in species that develop abnormalities of energy metabolism associated with reproductive disorders. Our results have shown some diet effects on the lipid and carbohydrate metabolisms and in a less extend, on the reproductive functions in dairy cows and broiler hens. These effects were partly associated with the expression profiles of adiponectin, visfatin and chemerin. In addition, we have demonstrated overexpression of the chemerin/CMKLR1 system in follicular fluid and in ovarian cells of patients with polycystic ovarian syndrome, with or without obesity. First, these findings reveal the possibility of considering these adipokines as potential biomarkers for evaluating growth, fattening status and fertility in agricultural farms. On the other hand, they suggest a potential involvement of chemerin in the regulation of ovarian functions in women.

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Introdução: O sobrepeso e a obesidade representam um grave problema de Saúde Pública, tendo seu desenvolvimento associado à adolescência, impacto negativo na fase adulta, sobretudo, devido suas complicações metabólicas. Considerando que o caráter crônico e inflamatório de baixa intensidade presente na obesidade estimula a geração de radicais livres, torna-se relevante avaliar a relação entre as adipocitocinas e a oxidação das lipoproteínas. Objetivos: Avaliar a possível influência da obesidade sobre a LDL(-) e adipocitocinas. Material e Métodos: Foram recrutados 156 adolescentes de ambos os sexos, com faixa etária de 10 a 19 anos e regularmente matriculados em escolas públicas da cidade de São Paulo. Os adolescentes foram distribuídos em três grupos: Eutrófico, Sobrepeso e Obeso, segundo COLE et al. (2000). Após jejum (12-15h) foi coletada uma amostra de sangue e a partir do plasma realizamos as seguintes análises: perfil lipídico, glicose e insulina (kits comerciais), LDL(-) e seus auto-anticorpos (ELISA), leptina, resistina e adiponectina (ELISA). O perfil sócio-econômico e clínico dos adolescentes foi investigado por meio de questionários estruturados. Foram coletadas informações antropométricas (peso, altura, circunferência da cintura, porcentagem de gordura) e dados de consumo alimentar (3 x R24h). O consumo alimentar foi estimado por meio do programa NutWin®. As diferenças entre as variáveis qualitativas foram determinadas pelo teste c2. As variáveis quantitativas foram ajustadas pela idade por meio do General Linear Model, sendo as diferenças entre os grupos estabelecidas pelo teste post-hoc de Bonferroni (SPSS®, versão 15.0). Resultados: Dos 156 adolescentes incluídos no estudo, 76 (48,7 por cento ) foram meninos e 80 (51,3 por cento ) meninas, com idade média de 14,5 ± 2,3 anos. Os adolescentes foram distribuídos em três grupos: Eutrófico (n = 52 adolescentes; 33,3 por cento ), Sobrepeso (n = 53 adolescentes; 34,0 por cento ) e Obeso (n = 51 adolescentes; 32,7 por cento ). Estes grupos foram pareados quanto ao sexo, escolaridade da mãe, renda, maturação sexual e antecedentes familiares de doenças. Como previsto pelo critério de estratificação dos grupos, os valores médios de IMC foram diferentes entre os grupos, sendo confirmados pela CC e porcentagem de gordura. Em relação ao hábito alimentar, a análise dos dados brutos e ajustados pela energia e variabilidade intrapessoal não apresentou diferença entre 4 os grupos. As análises da glicemia de jejum, colesterol total, triacilgliceróis e LDL-C não apresentaram diferenças entre os grupos. A insulina plasmática no grupo Obeso apresentou valores superiores aos grupos Eutrófico (p< 0,001) e Sobrepeso (p< 0,001), e o índice HOMA-IR no grupo Obeso apresentou valores superiores aos grupos Eutrófico (p< 0,001) e Sobrepeso (p< 0,001), enquanto o HDL-C apresentou valores maiores no grupo Eutrófico, quando comparado ao Obeso (p=0,012). A LDL(-) e seus autoanticorpos apresentaram diferentes concentrações entre os grupos (p= 0,040; p= 0,026, respectivamente). A leptina no grupo Eutrófico apresentou valores menores que os grupos Sobrepeso (p< 0,001) e Obeso (p< 0,001), assim como o grupo Sobrepeso apresentou valores inferiores ao grupo Obeso (p< 0,001). Perfil inverso foi observado em relação à concentração de adiponectina, A resistina apresentou valores maiores no grupo Obeso (p= 0,006), que no grupo Eutrófico. A leptina apresentou correlações positivas com percentual de gordura (r= 0,540; p= 0,001), circunferência da cintura (r= 0,679; p= 0,003) e IMC (r= 0,670; p< 0,001). Em relação ao metabolismo de carboidratos, a leptina se correlacionou positivamente com a insulina (r= 0,578; p< 0,001) e o HOMA-IR (r= 0,570; p= 0,001), enquanto a adiponectina se correlacionou negativamente com insulina (r= -0,255; p= 0,001) e o HOMA-IR (r= -0,246; p=0,002). Em relação ao perfil lipídico, a leptina correlacionou-se com colesterol total (r= 0,496; p= 0,003), triacilgliceróis (r= 0,409; p= 0,016) e LDL-C (r= 0,416; p= 0,014), assim como a adiponectina correlacionou-se com LDL(-) (r= -0,428; p= 0,012) e a resistina com HDL-C (r= -0,337; p= 0,050). Portanto, os resultados obtidos demonstram que adolescentes com excesso de peso, mesmo ainda considerados clinicamente saudáveis, apresentam diversos parâmetros antropométricos e bioquímicos alterados, que sugerem a presença de um elevado número de fatores de risco cardiometabólico nessa população / Introduction: Overweight and obesity represent a serious Public Health issue. Their development associated with adolescence, generate a negative impact in adulthood, mainly because of metabolic complications. As the low and chronic inflammatory state present in obesity stimulates the generation of free radicals, it becomes relevant to assess the relationship between adipocytokines and the oxidation of lipoproteins. Objective: Evaluate the possible influence of overweight and obesity on the electronegative LDL and adipocytokines (leptin, adiponectin and resistin). Materials and Methods: Adolescents of both genders, aged 10 to 19 years old and regularly registered in public schools at the city of São Paulo were recruited for this research. They were divided into three groups: Healthy weight, Overweight and Obese, according to Cole et al. (2000), by gender and age. After fasting (12-15h) a blood sample was collected and the following tests were performed on each samples plasma: total lipid profile, glucose and insulin (commercial kits), leptin, resistin, adiponectin (ELISA), LDL(-) (ELISA) and its autoantibodies (ELISA). The socio-economic and health profiles of the adolescents were determined by structured questionnaires. Anthropometric (weight, height, waist circumference - WC, percentage of body fat) and food consumption data (3 x 24-hour recall) were collected. The 24-hour recall data was analyzed by the NutWin® software. Differences between qualitative variables were determined by c2 test. Quantitative variables were adjusted for age by means of General Linear Model, being the differences between the groups established by post-hoc Bonferroni test (SPSS ®, version 15.0). Results: Of the 156 eligible individuals, 76 (48.7 per cent ) were boys and 80 (51.3 per cent ) girls, with the average age being of 14.5 ± 2.3 years. The adolescents were divided into three groups: Healthy weight, n = 52 adolescents (33.3 per cent ), Overweight, n = 53 adolescents (34.0 per cent ) and Obese, n = 51 adolescents (32.7 per cent ). These groups were matched up by gender, mother\'s education, income, sexual maturation, and current medical history. As expected by the group inclusion criteria, there were statistical differences in BMI and this profile was confirmed by WC and body fat. Opposite profile was showed for lean body mass. In relation to food consumption, the analysis of crude data adjusted for energy and intrapersonal variability did 6 not differ between the groups. Analyses of fasting glucose, total cholesterol, triglycerides and LDL-C did not differ between the groups. There were higher levels of plasma insulin and HOMA-IR in the obese group than in the healthy weight (p <0.001; p <0.001) and the overweight (p <0.001; p < 0.001) groups. HDL-C in the healthy weight group showed increased values in comparison to Obese one (p = 0.012). The LDL (-) in plasma and its autoantibodies indicated different concentrations between the groups (p = 0.040, p= 0.026, respectively). There were lower values of leptin both in the healthy weight group in comparison with the overweight (p <0.001) and the obese (p <0.001) groups, as well as in the Overweight group in comparison with the Obese group (p <0.001). Opposite profile was observed for adiponectin levels, between the healthy weight group and the overweight (p = 0.019) and obese (p = 0.000) groups. Resistin showed higher values in the obese group (p = 0.006) than in the healthy weight group. Leptin showed positive correlations with body fat percentage (r= 0.540 and p= 0.001), waist circumference (r= 0.679 and p= 0.003) and BMI (r= 0.670 and p <0.001). In relation to carbohydrate metabolism, leptin correlated positively with insulin (r= 0.578 and p <0.001) and HOMA-IR (r= 0.570 and p= 0.001), and opposite profile was showed for adiponectin (Insulin: r= -0.255, p= 0.001; HOMA-IR: r= -0.246, p= 0.002, respectively). Regarding the lipid profile, leptin correlated with total cholesterol (r= 0.496 and p= 0.003), triglycerides (r= 0.409 and p= 0.016) and LDL-C (r= 0.416 and p= 0.014); adiponectin correlated with LDL (-) (r= -0.428, p= 0.012); and resistin with HDL-C (r= -0.337, p= 0.050). Therefore, the results show that overweight and obese adolescents, even those who are still considered clinically healthy, showed several anthropometric and biochemical changes, which suggest increased number of cardiometabolic risk factors in this population

Introdução: O sobrepeso e a obesidade representam um grave problema de Saúde Pública, tendo seu desenvolvimento associado à adolescência, impacto negativo na fase adulta, sobretudo, devido suas complicações metabólicas. Considerando que o caráter crônico e inflamatório de baixa intensidade presente na obesidade estimula a geração de radicais livres, torna-se relevante avaliar a relação entre as adipocitocinas e a oxidação das lipoproteínas. Objetivos: Avaliar a possível influência da obesidade sobre a LDL(-) e adipocitocinas. Material e Métodos: Foram recrutados 156 adolescentes de ambos os sexos, com faixa etária de 10 a 19 anos e regularmente matriculados em escolas públicas da cidade de São Paulo. Os adolescentes foram distribuídos em três grupos: Eutrófico, Sobrepeso e Obeso, segundo COLE et al. (2000). Após jejum (12-15h) foi coletada uma amostra de sangue e a partir do plasma realizamos as seguintes análises: perfil lipídico, glicose e insulina (kits comerciais), LDL(-) e seus auto-anticorpos (ELISA), leptina, resistina e adiponectina (ELISA). O perfil sócio-econômico e clínico dos adolescentes foi investigado por meio de questionários estruturados. Foram coletadas informações antropométricas (peso, altura, circunferência da cintura, porcentagem de gordura) e dados de consumo alimentar (3 x R24h). O consumo alimentar foi estimado por meio do programa NutWin®. As diferenças entre as variáveis qualitativas foram determinadas pelo teste c2. As variáveis quantitativas foram ajustadas pela idade por meio do General Linear Model, sendo as diferenças entre os grupos estabelecidas pelo teste post-hoc de Bonferroni (SPSS®, versão 15.0). Resultados: Dos 156 adolescentes incluídos no estudo, 76 (48,7 por cento ) foram meninos e 80 (51,3 por cento ) meninas, com idade média de 14,5 ± 2,3 anos. Os adolescentes foram distribuídos em três grupos: Eutrófico (n = 52 adolescentes; 33,3 por cento ), Sobrepeso (n = 53 adolescentes; 34,0 por cento ) e Obeso (n = 51 adolescentes; 32,7 por cento ). Estes grupos foram pareados quanto ao sexo, escolaridade da mãe, renda, maturação sexual e antecedentes familiares de doenças. Como previsto pelo critério de estratificação dos grupos, os valores médios de IMC foram diferentes entre os grupos, sendo confirmados pela CC e porcentagem de gordura. Em relação ao hábito alimentar, a análise dos dados brutos e ajustados pela energia e variabilidade intrapessoal não apresentou diferença entre 4 os grupos. As análises da glicemia de jejum, colesterol total, triacilgliceróis e LDL-C não apresentaram diferenças entre os grupos. A insulina plasmática no grupo Obeso apresentou valores superiores aos grupos Eutrófico (p< 0,001) e Sobrepeso (p< 0,001), e o índice HOMA-IR no grupo Obeso apresentou valores superiores aos grupos Eutrófico (p< 0,001) e Sobrepeso (p< 0,001), enquanto o HDL-C apresentou valores maiores no grupo Eutrófico, quando comparado ao Obeso (p=0,012). A LDL(-) e seus autoanticorpos apresentaram diferentes concentrações entre os grupos (p= 0,040; p= 0,026, respectivamente). A leptina no grupo Eutrófico apresentou valores menores que os grupos Sobrepeso (p< 0,001) e Obeso (p< 0,001), assim como o grupo Sobrepeso apresentou valores inferiores ao grupo Obeso (p< 0,001). Perfil inverso foi observado em relação à concentração de adiponectina, A resistina apresentou valores maiores no grupo Obeso (p= 0,006), que no grupo Eutrófico. A leptina apresentou correlações positivas com percentual de gordura (r= 0,540; p= 0,001), circunferência da cintura (r= 0,679; p= 0,003) e IMC (r= 0,670; p< 0,001). Em relação ao metabolismo de carboidratos, a leptina se correlacionou positivamente com a insulina (r= 0,578; p< 0,001) e o HOMA-IR (r= 0,570; p= 0,001), enquanto a adiponectina se correlacionou negativamente com insulina (r= -0,255; p= 0,001) e o HOMA-IR (r= -0,246; p=0,002). Em relação ao perfil lipídico, a leptina correlacionou-se com colesterol total (r= 0,496; p= 0,003), triacilgliceróis (r= 0,409; p= 0,016) e LDL-C (r= 0,416; p= 0,014), assim como a adiponectina correlacionou-se com LDL(-) (r= -0,428; p= 0,012) e a resistina com HDL-C (r= -0,337; p= 0,050). Portanto, os resultados obtidos demonstram que adolescentes com excesso de peso, mesmo ainda considerados clinicamente saudáveis, apresentam diversos parâmetros antropométricos e bioquímicos alterados, que sugerem a presença de um elevado número de fatores de risco cardiometabólico nessa população / Introduction: Overweight and obesity represent a serious Public Health issue. Their development associated with adolescence, generate a negative impact in adulthood, mainly because of metabolic complications. As the low and chronic inflammatory state present in obesity stimulates the generation of free radicals, it becomes relevant to assess the relationship between adipocytokines and the oxidation of lipoproteins. Objective: Evaluate the possible influence of overweight and obesity on the electronegative LDL and adipocytokines (leptin, adiponectin and resistin). Materials and Methods: Adolescents of both genders, aged 10 to 19 years old and regularly registered in public schools at the city of São Paulo were recruited for this research. They were divided into three groups: Healthy weight, Overweight and Obese, according to Cole et al. (2000), by gender and age. After fasting (12-15h) a blood sample was collected and the following tests were performed on each samples plasma: total lipid profile, glucose and insulin (commercial kits), leptin, resistin, adiponectin (ELISA), LDL(-) (ELISA) and its autoantibodies (ELISA). The socio-economic and health profiles of the adolescents were determined by structured questionnaires. Anthropometric (weight, height, waist circumference - WC, percentage of body fat) and food consumption data (3 x 24-hour recall) were collected. The 24-hour recall data was analyzed by the NutWin® software. Differences between qualitative variables were determined by c2 test. Quantitative variables were adjusted for age by means of General Linear Model, being the differences between the groups established by post-hoc Bonferroni test (SPSS ®, version 15.0). Results: Of the 156 eligible individuals, 76 (48.7 per cent ) were boys and 80 (51.3 per cent ) girls, with the average age being of 14.5 ± 2.3 years. The adolescents were divided into three groups: Healthy weight, n = 52 adolescents (33.3 per cent ), Overweight, n = 53 adolescents (34.0 per cent ) and Obese, n = 51 adolescents (32.7 per cent ). These groups were matched up by gender, mother\'s education, income, sexual maturation, and current medical history. As expected by the group inclusion criteria, there were statistical differences in BMI and this profile was confirmed by WC and body fat. Opposite profile was showed for lean body mass. In relation to food consumption, the analysis of crude data adjusted for energy and intrapersonal variability did 6 not differ between the groups. Analyses of fasting glucose, total cholesterol, triglycerides and LDL-C did not differ between the groups. There were higher levels of plasma insulin and HOMA-IR in the obese group than in the healthy weight (p <0.001; p <0.001) and the overweight (p <0.001; p < 0.001) groups. HDL-C in the healthy weight group showed increased values in comparison to Obese one (p = 0.012). The LDL (-) in plasma and its autoantibodies indicated different concentrations between the groups (p = 0.040, p= 0.026, respectively). There were lower values of leptin both in the healthy weight group in comparison with the overweight (p <0.001) and the obese (p <0.001) groups, as well as in the Overweight group in comparison with the Obese group (p <0.001). Opposite profile was observed for adiponectin levels, between the healthy weight group and the overweight (p = 0.019) and obese (p = 0.000) groups. Resistin showed higher values in the obese group (p = 0.006) than in the healthy weight group. Leptin showed positive correlations with body fat percentage (r= 0.540 and p= 0.001), waist circumference (r= 0.679 and p= 0.003) and BMI (r= 0.670 and p <0.001). In relation to carbohydrate metabolism, leptin correlated positively with insulin (r= 0.578 and p <0.001) and HOMA-IR (r= 0.570 and p= 0.001), and opposite profile was showed for adiponectin (Insulin: r= -0.255, p= 0.001; HOMA-IR: r= -0.246, p= 0.002, respectively). Regarding the lipid profile, leptin correlated with total cholesterol (r= 0.496 and p= 0.003), triglycerides (r= 0.409 and p= 0.016) and LDL-C (r= 0.416 and p= 0.014); adiponectin correlated with LDL (-) (r= -0.428, p= 0.012); and resistin with HDL-C (r= -0.337, p= 0.050). Therefore, the results show that overweight and obese adolescents, even those who are still considered clinically healthy, showed several anthropometric and biochemical changes, which suggest increased number of cardiometabolic risk factors in this population

Les aclipocytokines (aclipo), produites par le tissu adipeux jouent un rôle clé dans la régulation des fonctions métaboliques mais qu'en est-il pour les fonctions de reproduction? Nous montrons que la chemerine et ses récepteurs, la visfatine et la résistine sont présents dans les cellules ovariennes humaines et bovines. ln vitro nous observons que la chemerine et la résistine diminuent la stéroïdogenèse des cellules de la granulosa (CG) humaine induite par IGF-1 alors que la visfatine l'augmente. Des résultats similaires sont observés chez la vache pour la chemerine et la visfatine. Dans les deux espèces, les aclipo influencent la prolifération des CG, et les voies de signalisation AKT, MAPK-ERKl/2 et P38 ou l'AMPK. Chez le bovin, la chemerine bloque la maturation ovocytaire in vitro. Nous observons aussi dans cette espèce que la concentration plasmatique de résistine et son expression dans les aclipocytes est augmentée après vêlage lorsque la lipomobilisation est élevée. Ces travaux confirment le rôle de la résistine dans la régulation métabolique chez la vache et montrent l'importance des adipo dans les cellules ovariennes humaine et bovine. Il reste à élargir leur rôle au niveau central dans les fonctions de reproduction. / The aclipokines (aclipo ), produced by the adipose tissue play a key role in the regulation of metabolic functions, but what about for reproductive functions? We show that chemerin and its receptors, visfatin and resistin are present in human and bovine ovary cells. ln vitro we observe that chemerin and resistin decrease steroidogenesis in granulosa cells (GC) in response to IGF-1 while visfatin increases it. Similar results are observed for chemerin and visfatin in cows. In both species, chemerin, visfatin and resistin affect the proliferation of CG and signaling pathways inclucling AKT, MAPKERKl I 2 and P38 or AMPK. In cattle, chemerin blocks in vitro oocyte maturation. In this species, we also observe that the plasma resistin and its expression in aclipocytes are increased after calving when the fatty acid mobilization is high. This work confirms the role of resistin in the metabolic regulations in cow and shows the importance of aclipo in the human and bovine ovary cells. It remains to investigate their role at the central level in the reproductive functions.

Abstract The incidence of pre-eclampsia (PE) is 2–7% in different populations and in the worst cases PE may threaten the survival of both mother and newborn; its pathogenesis is not resolved. Field literature today considers PE an angiogenic disorder. Coordinated vascularization is essential for placental development. We wanted to find novel factors in the etiology of PE, and focused our attention on angiogenesis, inherited thrombophilia and folate-homocysteine metabolism. Homocysteine inhibits endothelial cell proliferation, which is closely related to angiogenesis. We performed gene expression profiling of placental tissue using microarray chips, studied the prevalence of factor V Leiden (FVL), prothrombin (F5) G20210A and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in patients with severe pregnancy complications and normal controls, compared the expression of the placental adiponectin, leptin and their receptor genes and the relationship of each to trophoblast apoptosis and further, studied the effect of folic acid fortified mineral water on plasma homocysteine concentration during pregnancy. Gene expression profiling revealed downregulation of nine and upregulation of four genes. Interestingly, in one PE patient with cord compression during delivery the profile resembled that observed in normals. The expression level of the leptin and the adiponectin receptor 1 (ADIPOR1) genes was significantly higher in PE. No other significant expression changes were observed. The rate of apoptosis was higher in patients with PE. The FVL prevalence was 9.5%, in PE cases and 1.8% in the controls; a difference of 7.7%, (95% CI 2.0–13.4%). No statistical difference was found in other polymorphisms.. Maternal serum folate concentration increased in our intervention group, but decreased in the control group (p &lt; 0.05). The plasma homocysteine concentrations decreased more in the intervention group (p &lt; 0.001). The expression of angiogenesis-related placental genes can be altered in PE and cord compression cases. The activity of adipocytokine genes in PE may mean that they have a role in placental angiogenesis and apoptosis. Women with FVL may have an increased risk of PE. Fortified mineral water will help us to ensure that especially pregnant women achieve adequate folate intake.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

INTRODUÇÃO: Síndrome antifosfolípide está associada com aterosclerose acelerada. Embora adipocitocinas exerçam um papel fundamental na interface entre obesidade, inflamação, resistência insulínica e aterosclerose, a exata natureza e relativa contribuição das adipocitocinas, como potenciais marcadores, requer investigação na síndrome antifosfolípide primária (SAFP). OBJETIVO: Este estudo foi desenvolvido para avaliar a possível associação das adipocitocinas com síndrome metabólica (SM), inflamação e outros fatores de risco cardiovascular na SAFP. MÉTODOS: 56 pacientes com SAFP e 72 controles saudáveis pareados por sexo e idade foram incluídos. Adiponectina, leptina, visfatina, resistina, inibidor do ativador de plasminogênio-1 (PAI-1), lipoproteina (a), glicemia, insulina, VHS, PCR, ácido úrico e perfil lipídico foram dosados. SM foi definida de acordo com os critérios da Federação Internacional de Diabetes (IDF) e resistência insulínica foi estabelecida pelo índice de homeostasis model assessment (HOMA). RESULTADOS: Leptina [21,5 (12,9- 45,7) vs 12,1 (6,9-26,8) ng/mL, P=0.001] foi maior em SAFP do que em controles. Adiponectina (P=0,10), resistina (P=0,23), visfatina (P=0,68) and PAI-1 (P=0,77) não diferiu entre os grupos. Em SAFP, leptina e PAI-1 foram positivamente correlacionada com IMC (r=0,61 and 0,29), HOMA-IR (r=O,71 and 0,28) and CRP (r=0,32 and 0,36). Adiponectina foi negativamente correlacionada com IMC (r=-0,28), triglicérides (r=-0,43), HOMA-IR (r=-0,36) e positivamente correlacionada com HDL (r=0,37), aCL IgG (r=0,41), anti- 2GPI IgG (r=0,31) e anti- 2GPI IgM (r=0,38). A análise de pacientes com e sem SM revelou uma associação positiva com leptina (P=0,002) e PAI-1 (P=0,03) e uma associação negativa com adiponectina (P=0,042). No modelo de regressão linear múltipla, observamos que as variáveis que independentemente influenciam a adiponectina foram triglicérides (P<0,001), VLDL-c (P=0,002) e anti-2GPI IgG (P=0,042), leptina foram IMC (P<0,001), glicemia (P=0,046), HOMA-IR (P<0,001) e VHS (P=0,006) e PAI-1 foram PCR (P=0,013) e SM (P=0,048). CONCLUSÕES: O presente estudo demonstra que as adipocitocinas podem estar envolvidas com inflamação, resistência insulínica e SM em pacientes com SAFP / INTRODUCTION: Antiphospholipid syndrome is associated with accelerated atherosclerosis. Although adipocytokines play a key role in the interface between obesity, inflammation, insulin resistance and atherosclerosis, the exact nature and relative contribution of adipocytokines as potential markers warrant further investigation in primary antiphospholipid syndrome (PAPS). OBJECTIVE: This study was undertaken to evaluate a possible association of adipocytokines with metabolic syndrome (MetS), inflammation and other cardiovascular risk factors in PAPS. METHODS: Fifty-six PAPS patients and 72 age- and gender-matched healthy controls were included. Sera samples were tested for adiponectin, leptin, visfatin, resistin, plasminogen activator inhibitor-1 (PAI-1), lipoprotein (a), glucose, insulin, ESR, CRP, uric acid and lipid profiles. MetS was defined according to the guidelines of the International Diabetes Federation (IDF) and insulin resistance was established using the homeostasis model assessment (HOMA) index. RESULTS: Concentrations of leptin [21.5 (12.1-45.7) vs 12.1 (6.9-26.8) ng/mL, P=0.001] were higher in PAPS than in controls. Concentrations of adiponectin (P=0.10), resistin (P=0.23), visfatin (P=0.68) and PAI-1 (P=0.77) did not differ between patients and controls. In PAPS, leptin and PAI-1 levels were positively correlated with BMI (r=0.61 and 0.29), HOMA-IR (r=0.71 and 0.28) and CRP (r=0.32 and 0.36). Adiponectin was negatively correlated with BMI (r=-0.28), triglycerides (r=-0.43) and HOMA-IR index (r=-0.36) and positively correlated with HDL (r=0.37), aCL IgG (r=0.41), anti- 2GPI IgG (r=0.31) and anti- 2GPI IgM (r=0.38). Further analysis of patients with and without MetS revealed a positive association of the syndrome with leptin (P=0.002) and PAI-1 (P=0.03) and a negative association with adiponectin (P=0.042). In the multiple linear regression model, we observed that the variables that independently influence the adiponectin were triglycerides (P<0.001), VLDL-C (P=0.002) and anti-2GPI IgG (P=0.042), leptin were BMI (P<0.001), glucose (P=0.046), HOMA-IR (P <0.001) and ESR (P=0.006) and PAI-1 were CRP (P=0.013) and MetS (P=0.048). CONCLUSION: The findings of the present study provide evidence that adipocytokines may be involved in inflammation, insulin resistance and metabolic syndrome of PAPS patients

Analisar a associação recíproca entre fatores de risco cardiometabólico, níveis de adipocitocinas (leptina e adiponectina de alto peso molecular), endocanabinoides (anandamida [AEA] e 2-araquidonoilglicerol [2-AG]), compostos canabimiméticos (N-oleoiletanolamina [OEA] e N-palmitoiletanolamina [PEA]) e polimorfismos em genes codificadores de componentes do sistema endocanabinoide (enzima de degradação de endocanabinoides FAAH [gene FAAH] e receptor endocanabinoide CB1 [gene CNR1]) e do receptor PPAR-&#945; [gene PPARA], em indivíduos com diferentes graus de adiposidade. Duzentos indivíduos, entre 18 e 60 anos, com diferentes graus de índice de massa corporal (IMC) compuseram a amostra, dividida em dois grupos: cem eutróficos (IMC < 25 kg/m2) e 100 obesos (IMC &#8805; 30 kg/m2), com 50 homens e 50 mulheres em cada grupo. Os obesos ficaram assim distribuídos: grau 1, com IMC < 35 kg/m2 (n=54), 27 homens e 27 mulheres; grau 2, com IMC < 40 kg/m2 (n=32), 16 homens e 16 mulheres e grau 3, com IMC &#8805; 40 kg/m2 (n=14), 7 homens e 7 mulheres. Todos os indivíduos foram recrutados entre funcionários, estudantes e residentes do Hospital Universitário Pedro Ernesto, bem como voluntários do quadro da Polícia Militar do Estado do Rio de Janeiro e selecionados com base em amostra de conveniência. Todos foram avaliados por parâmetros antropométricos, determinação da pressão arterial, análises laboratoriais e genotipagem, para determinar seu perfil metabólico, níveis de endocanabinoides e adipocitocinas e rastreamento dos polimorfismos FAAH 385C>A, CNR1 3813A>G e PPARA 484C>G. Foram excluídos do estudo aqueles com história de comorbidades crônicas, doenças inflamatórias agudas, dependência de drogas de qualquer natureza e em uso de medicação nos dez dias anteriores à entrada no estudo. A atividade inflamatória, avaliada pela proteína C reativa ultrassensível (PCRUS), acompanhou o grau de resistência insulínica. Os níveis de PEA se associaram negativamente com a adiposidade visceral e resistência insulínica, sugerindo um melhor perfil metabólico, enquanto que os níveis de 2-AG se associaram positivamente com a PCRUS, apontando para piora nesse perfil. Os polimorfismos estudados não se associaram com o fenótipo obeso ou insulinorresistente. A presença do alelo 3813G no gene CNR1 mostrou associação independente com níveis reduzidos de adiponectina em obesos, sugerindo pior perfil metabólico nesse grupo. A presença do alelo 484G no gene PPARA, associando-se com níveis mais elevados de IMC e LDL-colesterol nos eutróficos pode indicar maior predisposição desses indivíduos para o desenvolvimento de obesidade e dislipidemia aterosclerótica. O genótipo homozigoto AA na posição 385 do gene FAAH e os níveis de PCRUS foram as principais associações, diretas e independentes, com os níveis de AEA, indicando claramente disfunção da enzima de degradação da AEA e, possivelmente, contribuindo para um perfil cardiometabólico mais vulnerável em portadores dessa variante genética. / To analyze the reciprocal association of cardiometabolic risk factors, levels of adipocytokines (leptin and high molecular weight adiponectin), endocannabinoids (anandamide [AEA] and 2-arachidonoylglycerol [2-AG]), cannabimimetic compounds (N-oleoylethanolamine [OEA] and N-palmitoylethanolamine [PEA]) and polymorphisms in genes encoding components of the endocannabinoid system (endocannabinoid degradation enzyme FAAH [FAAH gene] and endocannabinoid receptor CB1 [CNR1 gene]) and the PPAR-&#945; receptor (PPARA gene) in subjects with varying degrees of adiposity. Two hundred individuals between 18 and 60 years with varying degrees of body mass index (BMI) comprised the sample, divided in two groups: one hundred eutrophic (BMI < 25 kg/m2) and 100 obese (BMI &#8805; 30 kg/m2), 50 men and 50 women per group. The obese were distributed as follows: grade 1, with BMI < 35 kg/m2 (n = 54), 27 men and 27 women; grade 2, with BMI between &#8805; 35 and < 40 kg/m2 (n = 32), 16 men and 16 women and grade 3, with BMI &#8805; 40 kg/m2 (n = 14), 7 men and 7 women. All subjects were recruited from staff, students and residents of Pedro Ernesto University Hospital, as well as volunteers from Military Police of Rio de Janeiro State and selected based on a convenience sample. All were evaluated by anthropometric parameters, blood pressure determination, laboratory analysis and genotyping, to determine their metabolic profile, endocannabinoid and adipocytokine levels and investigate the polymorphisms FAAH 385C>A, CNR1 3813G>A and PPARA 484C>G. Those with a history of chronic comorbidities, acute inflammatory diseases, drug addiction of any kind and on medication in the ten days prior to study entry were withdrawn from the study. The inflammatory activity as assessed by high sensitive C reactive protein (hsCRP), accompanied the degree of insulin resistance. The levels of PEA negatively associated with visceral adiposity and insulin resistance, suggesting a better metabolic profile, whereas 2-AG levels were positively associated with hsCRP, pointing to a worse metabolic profile. The polymorphisms studied were not associated with the obese or insulin resistant phenotype. The presence of the allele 3813G in the CNR1 gene was independently associated with reduced levels of adiponectin in obese patients, suggesting a worse metabolic profile in this group. The presence of the allele 484G in the PPARA gene associating with higher levels of BMI and LDL-cholesterol in eutrophics may indicate a predisposition for the development of obesity and atherosclerotic dyslipidemia in these individuals. The homozygous genotype AA in position 385 of the FAAH gene, along with levels of hsCRP, were the main direct and independent associations with AEA levels, clearly indicating dysfunction of the degradation enzyme of AEA and possibly contributing to a more vulnerable cardiometabolic profile in individuals with this variant genotype.

INTRODUÇÃO: Síndrome antifosfolípide está associada com aterosclerose acelerada. Embora adipocitocinas exerçam um papel fundamental na interface entre obesidade, inflamação, resistência insulínica e aterosclerose, a exata natureza e relativa contribuição das adipocitocinas, como potenciais marcadores, requer investigação na síndrome antifosfolípide primária (SAFP). OBJETIVO: Este estudo foi desenvolvido para avaliar a possível associação das adipocitocinas com síndrome metabólica (SM), inflamação e outros fatores de risco cardiovascular na SAFP. MÉTODOS: 56 pacientes com SAFP e 72 controles saudáveis pareados por sexo e idade foram incluídos. Adiponectina, leptina, visfatina, resistina, inibidor do ativador de plasminogênio-1 (PAI-1), lipoproteina (a), glicemia, insulina, VHS, PCR, ácido úrico e perfil lipídico foram dosados. SM foi definida de acordo com os critérios da Federação Internacional de Diabetes (IDF) e resistência insulínica foi estabelecida pelo índice de homeostasis model assessment (HOMA). RESULTADOS: Leptina [21,5 (12,9- 45,7) vs 12,1 (6,9-26,8) ng/mL, P=0.001] foi maior em SAFP do que em controles. Adiponectina (P=0,10), resistina (P=0,23), visfatina (P=0,68) and PAI-1 (P=0,77) não diferiu entre os grupos. Em SAFP, leptina e PAI-1 foram positivamente correlacionada com IMC (r=0,61 and 0,29), HOMA-IR (r=O,71 and 0,28) and CRP (r=0,32 and 0,36). Adiponectina foi negativamente correlacionada com IMC (r=-0,28), triglicérides (r=-0,43), HOMA-IR (r=-0,36) e positivamente correlacionada com HDL (r=0,37), aCL IgG (r=0,41), anti- 2GPI IgG (r=0,31) e anti- 2GPI IgM (r=0,38). A análise de pacientes com e sem SM revelou uma associação positiva com leptina (P=0,002) e PAI-1 (P=0,03) e uma associação negativa com adiponectina (P=0,042). No modelo de regressão linear múltipla, observamos que as variáveis que independentemente influenciam a adiponectina foram triglicérides (P<0,001), VLDL-c (P=0,002) e anti-2GPI IgG (P=0,042), leptina foram IMC (P<0,001), glicemia (P=0,046), HOMA-IR (P<0,001) e VHS (P=0,006) e PAI-1 foram PCR (P=0,013) e SM (P=0,048). CONCLUSÕES: O presente estudo demonstra que as adipocitocinas podem estar envolvidas com inflamação, resistência insulínica e SM em pacientes com SAFP / INTRODUCTION: Antiphospholipid syndrome is associated with accelerated atherosclerosis. Although adipocytokines play a key role in the interface between obesity, inflammation, insulin resistance and atherosclerosis, the exact nature and relative contribution of adipocytokines as potential markers warrant further investigation in primary antiphospholipid syndrome (PAPS). OBJECTIVE: This study was undertaken to evaluate a possible association of adipocytokines with metabolic syndrome (MetS), inflammation and other cardiovascular risk factors in PAPS. METHODS: Fifty-six PAPS patients and 72 age- and gender-matched healthy controls were included. Sera samples were tested for adiponectin, leptin, visfatin, resistin, plasminogen activator inhibitor-1 (PAI-1), lipoprotein (a), glucose, insulin, ESR, CRP, uric acid and lipid profiles. MetS was defined according to the guidelines of the International Diabetes Federation (IDF) and insulin resistance was established using the homeostasis model assessment (HOMA) index. RESULTS: Concentrations of leptin [21.5 (12.1-45.7) vs 12.1 (6.9-26.8) ng/mL, P=0.001] were higher in PAPS than in controls. Concentrations of adiponectin (P=0.10), resistin (P=0.23), visfatin (P=0.68) and PAI-1 (P=0.77) did not differ between patients and controls. In PAPS, leptin and PAI-1 levels were positively correlated with BMI (r=0.61 and 0.29), HOMA-IR (r=0.71 and 0.28) and CRP (r=0.32 and 0.36). Adiponectin was negatively correlated with BMI (r=-0.28), triglycerides (r=-0.43) and HOMA-IR index (r=-0.36) and positively correlated with HDL (r=0.37), aCL IgG (r=0.41), anti- 2GPI IgG (r=0.31) and anti- 2GPI IgM (r=0.38). Further analysis of patients with and without MetS revealed a positive association of the syndrome with leptin (P=0.002) and PAI-1 (P=0.03) and a negative association with adiponectin (P=0.042). In the multiple linear regression model, we observed that the variables that independently influence the adiponectin were triglycerides (P<0.001), VLDL-C (P=0.002) and anti-2GPI IgG (P=0.042), leptin were BMI (P<0.001), glucose (P=0.046), HOMA-IR (P <0.001) and ESR (P=0.006) and PAI-1 were CRP (P=0.013) and MetS (P=0.048). CONCLUSION: The findings of the present study provide evidence that adipocytokines may be involved in inflammation, insulin resistance and metabolic syndrome of PAPS patients