Introdução: Fatores genéticos estão entre os determinantes de obesidade, podendo influenciar a resposta a intervenções em estilo de vida. O impacto de polimorfismos de nucleotídeo único (SNPs) na resposta de biomarcadores a intervenções não é claro. Objetivo: Este estudo examinou as associações de seis SNPs FTO T/A, PPAR Pro12Ala, Apo A1 -75G/A, TNF- -308G/A, IL-6 - 174G/C e AdipoQ 45T/G com mudanças induzidas por uma intervenção em amostra de brasileiros de risco cardiometabólico. Métodos: Em um programa de nove meses de orientações em hábitos alimentares e atividade física, 180 indivíduos com prediabetes ou síndrome metabólica foram genotipados e agrupados segundo a presença do alelo variante de cada SNP e comparados quanto a variáveis antropométricas, metabólicas e inflamatórias. Resultados: A intervenção resultou em redução do consumo calórico, aumento da atividade física, melhora na antropometria e outros biomarcadores. Estratificando pelos SNPs, os principais achados estão contidos em dois artigos. Artigo 1: Houve melhor resposta do perfil glicêmico após a intervenção nos portadores do alelo variante do SNP TNF -308 G/A. Observou-se melhora das variáveis lipídicas nos portadores do alelo variante do SNP IL-6 -174 G/C, enquanto que aqueles com o genótipo referência obtiveram melhora no metabolismo da glicose. Carreadores do SNP AdipoQ 45T/G não obtiveram melhora no perfil lipídico nem no glicêmico.Artigo 2: O alelo variante do FTO T/A associou-se a melhores perfis 9 inflamatório e glicêmico em resposta à intervenção. Portadores do alelo variante do SNP PPAR Pro12Ala obtiveram melhora na pressão arterial, enquanto que indivíduos com o genótipo referência melhoraram o metabolismo lipídico. Carreadores do alelo variante do SNP Apo A1 -75G/A apresentaram melhora no perfil lipídico que, após ajuste para medicação, não se manteve significante. Conclusões: SNPs relacionados à obesidade e comorbidades podem influenciar a resposta de marcadores metabólicos e inflamatórios a intervenções em hábitos de vida em brasileiros. O SNP TNF -308G/A parece favorecer um melhor perfil glicêmico. O SNP IL-6 -174G/C pode conferir efeito benéfico no perfil lipídico, mas não na glicemia. O SNP AdipoQ 45T/G compromete a resposta à intervenção em indivíduos de risco cardiometabólico no nosso meio. O SNP FTO T/A pode favorecer a resposta do metabolismo da glicose e a atenuação da inflamação. O SNP PPAR Pro12Ala pode ter impacto benéfico na pressão arterial, mas não no metabolismo lipídico. Em contraste com a literatura, o SNP Apo A1 -75G/A não parece influenciar resposta dos lípides à intervenção. Mais estudos envolvendo estes SNPs são necessários para possível direcionamento de intervenções a subgrupos específicos de indivíduos de risco. / Introduction: Genetic factors are one of the determinants of obesity and may influence the response to interventions. The impact of single nucleotide polymorphisms (SNPs) in weight loss and inflammatory response to interventions is not clear. Objective: This study examined associations of six polymorphisms FTO T/A, PPAR Pro12Ala, Apo A1 -75G/A, TNF- -308G/A, IL-6 -174G/C and AdipoQ 45T/G with changes induced by lifestyle intervention in Brazilians at cardiometabolic risk. Methods: In a 9-month intervention on diet and physical activity, 180 individuals with prediabetes or metabolic syndrome were genotyped and compared according the presence of variant allele of the SNPs and antrophometric, metabolic and inflammatory variables. Results: The intervention resulted in lower energy intake and greater total physical activity as well as improvement in anthropometry and several biomarkers. Stratified by SNPs, the main findings are covered in two articles. Article 1: Variant allele carriers of TNF -308 G/A SNP decreased plasma glucose after intervention. Lipid profile improved after intervention in variant allele carriers of IL-6 -174 G/C, while individuals with reference genotype had better plasma glucose response. Variant allele carriers of AdipoQ 45T/G did not improve lipid and glycemic profile. Article 2: Only variant allele carriers of FTO T/A decreased fasting plasma glucose and C-reactive protein concentration after intervention. Blood pressure reduced after intervention in variant allele carriers of the PPAR Pro12Ala, while the reference genotype increased Apo A1. Apparent favorable response of lipid profile to intervention in variant allele carriers of Apo A1 -75G/A was not maintained after adjustments for lipid-lowering medication. Conclusions: SNPs associated with obesity and comorbidities may influence the response of metabolic and inflammatory markers after lifestyle intervention. The TNF -308G/A may predispose a better response of glucose metabolism. The IL-6 -174 G/C SNP may confer a beneficial effect on lipid profile but not in glucose metabolism. Our findings reinforce unfavorable effects of the AdipoQ 45T/G SNP in lipid and glucose metabolism after lifestyle intervention in Brazilians at cardiometabolic risk. FTO T/A SNP induces a favorable impact on inflammatory status and glucose metabolism. The reference genotype of PPAR Pro12Ala seems to favor a better lipid profile, while the variant allele to decrease blood pressure. In contrast to literature, our data did not support benefits on lipid profile of the variant allele of Apo A1 -75G/A SNP. Further studies of these SNPs are needed to direct interventions to specific subgroups of at-risk individuals.

INTRODUÇÃO: A exposição materna à frutose durante a gestação e lactação pode contribuir para o desenvolvimento de doenças crônicas na vida adulta da prole. OBJETIVO: Estudar os efeitos da ingestão de frutose durante a gestação e lactação sobre a vida pós-natal no que diz respeito às alterações metabólicas, de expressão gênica e ao comportamento alimentar em ratos machos. METODOLOGIA: Foram utilizados ratos Sprague-Dawley, provenientes de mães alimentadas com ração controle e de mães alimentadas com ração rica em frutose (60%), durante a gestação; a lactação e gestação/lactação. Após o desmame, a prole foi alimentada com ração controle até os 91 dias de vida. Foram analisados os parâmetros: biométricos, dietéticos, metabólicos quanto a glicemia, sensibilidade periférica à insulina, leptina e insulina (séricas e vias de sinalização), neuropeptídios envolvidos no controle do comportamento alimentar, e deposição hepática de gordura. RESULTADOS: Houve redução do índice de Lee no nascimento e hipoleptinemia aos 90 dias de vida, intolerância à glicose na vida pós-natal desde o desmame, concomitante com alterações na sensibilidade à ação da insulina na vida adulta, hiperinsulinemia, dislipidemia, deposição hepática de TAG, estímulo hedônico do comportamento alimentar alterado aos 14 dias de vida pós-natal via núcleo accumbens shell com maior expressão de CART. CONCLUSÃO: As proles possuem possível marca epigenética que pode contribuir para o prejuízo na produção e ação da insulina, ocasionando alterações na homeostase do metabolismo glicídico e lipídico hepáticos, levando a deposição hepática de gordura e alterações no perfil lipídico, com redução da leptinemia na vida adulta, e no controle hedônico central do comportamento alimentar apenas aos 14 dias de vida pós-natal. / INTRODUCTION: Maternal exposure to fructose during gestation and lactation can contribute to the development of chronic diseases in the adult life of offspring. OBJECTIVE: To study the effects of ingestion of fructose during gestation and lactation on postnatal life with respect to metabolic changes, gene expression and feeding behavior in male rats. METHODS: Male Sprague-Dawley rats from mothers fed with control rat chow (AIN-93) and from mothers fed a high fructose diet (60%). Both isocaloric, during gestation; lactation and gestation/lactation. After weaning, the offspring were fed with control rat chow until the 91st days of life. The following parameters were analyzed: biometric, dietary, metabolic for glycaemia, peripheral insulin sensitivity, leptin and insulin (serum and signaling pathways), neuropeptides involved in food behavior control, and hepatic deposition of fat. RESULTS: Reduction in the Lee index at birth and hypoleptinemia at 90 days of age (only in the offspring that the mothers consumed fructose during pregnancy), glucose intolerance in postnatal life since with changes in insulin sensitivity in adult life, hyperinsulinemia, dyslipidemia, hepatic deposition of GAD, hemodialysis of altered eating behavior at 14 days of age). CONCLUSION: The offspring from mothers who consumed fructose rat chow during gestation and lactation have a possible epigenetic mark that may contribute to the impairment in the production and action of insulin, leading to changes in hepatic glucose and lipid metabolism homeostasis, leading to hepatic fat deposition and alterations in the lipid profile, with reduction of leptinemia in adult life, and in the central hedonic control of dietary behavior only at the 14 days postnatal life.

Introdução: Doenças cardiometabólicas são problemas de saúde pública mundial com repercussões sociais e econômicas. Dieta inadequada é apontada como um dos principais fatores de risco modificáveis, de importância central na prevenção destas doenças. Apesar da constatação de que certos nutrientes se associam a doenças, ainda existem dúvidas quanto às relações causais. Objetivos: 1) Revisar a participação dos alimentos e nutrientes na gênese e controle de doenças crônicas não-transmissíveis integrantes da síndrome metabólica (manuscrito 1); 2) Descrever de forma detalhada a estrutura do programa de intervenção interdisciplinar em hábitos de vida, desenvolvido para usuários da rede pública de saúde do município de São Paulo (manuscrito 2); 3) Investigar o efeito de mudanças em fatores dietéticos sobre o metabolismo glicídico, decorrentes de intervenção em hábitos de vida em indivíduos de risco cardiometabólico da rede pública de saúde (manuscrito 3). Métodos: Foram incluídos adultos com diagnóstico de pré-diabetes ou síndrome metabólica sem diabetes em ensaio clínico aleatorizado envolvendo dois tipos de intervenções de 18 meses: tradicional e intensiva. A intervenção tradicional consistiu de consultas trimestrais com endocrinologista; na intensiva, além dos atendimentos médicos, os indivíduos participaram de sessões psicoeducativas em grupo com equipe multiprofissional. As orientações dietéticas visaram à adequação do consumo de gorduras totais (redução de saturadas e trans e elevação de insaturadas) e aumento na ingestão de fibras. As variáveis coletadas nos momentos pré- e pós-intervenção incluíram dados sócio-demográficos, antropométricos, dietéticos e bioquímicos (glicemia de jejum e póssobrecarga, perfil lipídico, insulina, adiponectina, proteína C reativa, IL-6, TNF-, apolipoproteína A1 e B). A dieta foi avaliada por recordatórios de 24 horas, processados pelo Nutrition Data System software. Foram empregados os testes: t de Student, coeficientes de correlações, ANOVA com p de tendência e análises de regressão múltipla para identificar fatores dietéticos associados à melhora do metabolismo glicídico. Resultados: O manuscrito 1 consiste de um capítulo de livro (Nutrição em Saúde Coletiva) abordando aspectos epidemiológicos de doenças do espectro da síndrome metabólica com ênfase em fatores alimentares e estado nutricional. O manuscrito 2 detalha a estrutura, a equipe integrante, as orientações preconizadas e as principais estratégias psicoeducativas utilizadas no programa de intervenção em hábitos de vida desenvolvido (artigo metodológico submetido e website). Análises do manuscrito 3 mostraram que, ao final da intervenção, o aumento na ingestão de ácidos graxos monoinsaturados e fibras solúveis associaramse de forma independente à redução da glicemia de jejum e os primeiros também à melhora da glicemia pós-sobrecarga. Ajustes por medidas antropométricas não alteraram os resultados, o que ocorreu, porém, após inclusão da variável mudança na insulina nos modelos (artigo original). Conclusão: Justifica-se divulgar programas de intervenção como o aqui desenvolvido considerando-se o atual cenário das doenças cardiometabólicas na atualidade. No presente estudo, o aumento na ingestão de ácidos graxos monoinsaturados e de fibras solúveis promoveu benefícios no metabolismo glicídico, independente da adiposidade, ao final da intervenção no estilo de vida. Possíveis mecanismos mediadores destes processos podem incluir principalmente a melhora da sensibilidade à insulina. Dessa forma, nossos achados sugerem fortemente que um aumento factível no consumo destes nutrientes deva ser estimulado como estratégia para a proteção do metabolismo glicídico em indivíduos de risco cardiometabólico / Introduction: Cardiometabolic diseases are global public health problems with social and economic repercussions. Unhealthy diet is seen as one of the main modifiable risk factors, being of central importance for the prevention of these diseases. Despite the evidence that certain nutrients are associated with diseases, causal relationships are still under discussion. Objectives: 1) To review the involvement of foods and nutrients in the genesis and control of non-communicable chronic diseases, that comprise the metabolic syndrome (manuscript 1); 2) To describe in detail the structure of the interdisciplinary intervention program on lifestyle, developed for costumers of public health system of Sao Paulo city (manuscript 2); 3) To investigate the impact of changes in dietary factors on glucose metabolism, induced by a lifestyle intervention in individuals at cardiometabolic risk attended by the public health system (manuscript 3). Methods: Adults with prediabetes or metabolic syndrome without diabetes were included in a randomized clinical trial involving two types of 18-month interventions: a traditional or an intensive one. The traditional intervention consisted of quarterly consultations with an endocrinologist, while in the intensive participants also attended psychoeducational group sessions with a multidisciplinary team, in addition to the medical visits. The dietary recommendations aimed at the adequate intake of fat (reduction of saturated and trans and increase of unsaturated fatty acids) and increase in fiber intake. Socio-demographic, anthropometric, dietary and biochemical (fasting and post-load plasma glucose, lipid profile, insulin, adiponectin, C-reactive protein, IL-6, TNF-, apolipoprotein A1 and B) data were collected at baseline and after 18-month of follow-up. Diet was assessed by 24-h dietary recalls, processed by Nutrition Data System software. Student t test, correlation coefficients, ANOVA with p for trend and multiple linear regressions analyses were employed to identify dietary factors associated with glucose metabolism improvement. Results: Manuscript 1 consists of a book chapter (Nutrition in Public Health) about epidemiological aspects of diseases of the spectrum of metabolic syndrome with emphasis on dietary factors and nutritional status. Manuscript 2 details the structure, professional team, recommendations and the main psychoeducative strategies used in the lifestyle intervention program developed (methodological article submitted and website). Analyses of manuscript 3 showed that the intervention-induced increase in monounsaturated fatty acids and soluble fiber intake were independently associated with reduction on fasting plasma glucose and the former also with 2h-plasma glucose improvement. Adjustment for anthropometric measurements did not change these results but did after including change in insulin in the models (original article). Conclusion: Intervention programs such as the developed herein should be reported taking into consideration the current scenario of cardiometabolic diseases. In the present study, increases in monounsaturated fatty acids and soluble fiber intake promoted benefits in glucose metabolism, independent of adiposity, at the end of the lifestyle intervention. Possible mechanisms mediating these processes may mainly include improvement in insulin sensitivity. Therefore, our findings strongly suggest that a feasible increase in consumption of these nutrients should be encouraged as a strategy for the protection of glucose metabolism in individuals at cardiometabolic risk

Background: The burden of cardiometabolic disease (CMD) is rising in sub-Saharan Africa (SSA). However, there are limited population-based prevalence estimates of CMD risk factors to inform public health initiatives for the prevention and management of CMDs in these populations. This thesis aims to contribute to this evidence gap by assessing the prevalence and distribution of established and emerging CMD risk factors, associations between risk factors, and tools for their identification, in a South African population. Methods: The Durban Diabetes Study (DDS), a population-based cross-sectional survey of CMD risk factors, was designed and data were collected on 1204 participants from the eThekwini Municipality, South Africa. Key findings: In this urban South African population, the prevalence of most CMD risk factors was high, and varied across demographic and socioeconomic groups. The prevalence of smoking and alcohol consumption was higher in men, whilst the prevalence of obesity, hypertension, dyslipidaemia, and hyperglycaemia was higher in women. Wealth was associated with obesity and hypercholesterolemia, whilst education level and employment status were associated with smoking, physical activity and diabetes. Despite several potential advantages, the use of glycated haemoglobin (HbA1c) for diagnosis of diabetes is not established in SSA. Using plasma glucose measures as the reference, HbA1c ≥6.5% detected diabetes with high sensitivity and specificity. Furthermore, the association of anaemia, HIV, and antiretroviral therapy (ART) with HbA1c was modest and no statistically significant differences in the prevalence of diabetes were found in those with anaemia or HIV based on plasma glucose and HbA1c measurements. This is the first evidence for the utility of HbA1c for the diagnosis of diabetes in a black SSA population. There is emerging evidence for the association of HIV and ART with CMD risk factors. In the DDS, the prevalence of HIV was high (43.5%) and untreated HIV was associated with low high-density lipoprotein cholesterol, whilst ART-treated HIV was associated with high triglycerides. Finally, 30.8% of participants were at high risk of CMD based on metabolic syndrome, but only 7.9% had high 10-year cardiovascular disease risk based on the Framingham risk score. Conclusion: This thesis has added to the evidence base on CMD risk factors in South Africa. These findings highlight the need for longitudinal studies to investigate the aetiology of CMDs and robustly assess the utility of tools to identify risk of CMD in SSA populations.

Introdução: Altas prevalências de diabetes mellitus tipo 2 e outros fatores de risco cardiovascular previamente detectadas na população nipo-brasileira motivaram a implementação de um programa de intervenção em mudança de estilo de vida. Objetivos: Avaliar os efeitos de 2 anos de intervenção comportamental sobre o perfil cardiometabólico desses indivíduos, independente da condição de tolerância à glicose no início do estudo. Métodos: A existência de dados relativos a 2000-2005 permitiu conhecer o comportamento de variáveis no período pré-intervenção. Em 2005, 728 indivíduos iniciaram o seguimento, sendo, 650 reavaliados em 2006 e 500 em 2007. Nestas ocasiões, os indivíduos foram submetidos a exames médico e laboratorial e consulta com nutricionista e educador físico. O programa constou de atendimentos individualizados e em grupo, enfocando as metas do programa: redução 5% de peso corporal; prática de 150minutos/semana de exercício; ingestão de <10% de ácidos graxos saturados do valor calórico total; ingestão de 400g/dia de frutas, verduras ou legumes. Resultados: Comparado ao período pré-intervenção, o comportamento de variáveis antropométricas e metabólicas durante o programa foi significantemente mais favorável. O impacto do programa dependeu do alcance de metas em indivíduos sem diabetes. As frequências de intolerância à glicose e diabetes reduziram após um ano de intervenção (de 58,4% para 35,4%; p<0,001 e de 30,1% para 21,7%; p<0,001, respectivamente). Após excluir os indivíduos com diabetes no início do estudo, 71,7% dos participantes mantiveram ou regrediram seu estado de tolerância à glicose (\"non-progressors\") no final de 2 anos de seguimento. A presença de intolerância à glicose e níveis mais baixos de PCR no início do estudo associaram-se independentemente com a não deterioração da tolerância à glicose, ajustado para idade e variáveis antropométricas. As mudanças em peso e estilo de vida não se associaram com a nãodeterioração da tolerância à glicose após intervenção. Conclusões: A intervenção trouxe benefícios no perfil cardiometabólico de nipo-brasileiros de alto risco cardiovascular após o primeiro e o segundo anos do programa, independente do grau de tolerância à glicose no início do estudo. As mudanças em fatores de risco cardiovascular foram proporcionais ao sucesso no alcance das metas do porgrama. A maioria dos indivíduos sem diabetes manteve ou melhorou a tolerância à glicose após 2 anos de intervenção. Os achados sugerem que níveis mais baixos de PCR e a presença inicial de intolerância à glicose podem ser características preditivas dos indivíduos que se beneficiam desta estratégia de intervenção em termos de não-deterioração do metabolismo da glicose, independente da adiposidade corporal. Esse estudo deve encorajar profissionais da saúde a instituir estratégias simples de intervenção comportamental em grupos populacionais com alto risco cardiometabólico, independente do estado de tolerância à glicose. / Introduction: High prevalence rates of diabetes mellitus type 2 and other cardiovascular risk factors, previously reported in the Japanese-Brazilian population, motivated an intervention program for change in lifestyle. Aims: To evaluate the effect of 2-year behavioral intervention on cardiometabolic profile of these individuals, independent of the glucose tolerance status at the beginning of the study. Methods: The availability of data regarding the period 2000-2005 provided information about the behavior of variables during the pre-intervention period. In 2005, 728 individuals started in the program; 650 were re-examined in 2006 and 500 in 2007. In each occasion, participants were scheduled for laboratory procedures, medical exams and visits with nutritionist and physical educator. Participants were scheduled for individualized dietary counseling and group sessions, focusing the achievement of the goals: 5% weight loss from baseline for individuals with excessive adiposity; 150 minutes/week of physical activities; intake £ 10% of saturated fat of total energy consumed per day; intake of 400g/day of fruits and vegetables. Results: Compared to the pre-intervention period, the changes in metabolic variables induced by the program were significantly more favorable. The impact of the program was dependent on the number of goals achieved in individuals without diabetes at baseline. Prevalence rates of glucose tolerance disturbances decreased after the first year of intervention (from 58.4% to 35.4%, p<0.001; and from 30.1% to 21.7%, p<0.001, respectively). After excluding individuals with diabetes at baseline, 71.7% of participants improved or maintained their glucose tolerance status (non-progressors) after 2-year intervention. Lower levels of CRP and the diagnosis of glucose intolerance at baseline were associated with improvement or maintenance of glucose tolerance status, adjusted age and anthropometric variables. Changes in lifestyle and anthropometric variables after intervention were not associated with non-deterioration of glucose tolerance status. Conclusion: The intervention induced benefits on cardiometabolic profile of the japanese-Brazilians with high cardiovascular risk after the first and second years of the program, independent of the glucose tolerance status at baseline. Most of the participants maintained or improved the glucose tolerance status following the intervention. Our findings suggest that lower levels of CRP and the presence of glucose intolerance at baseline may be predictive characteristics of those who benefit from this intervention strategy regarding non-deterioration of glucose metabolism, independent of body adiposity. This study should encourage health care providers to make efforts to achieve and maintain a healthy diet and physically active lifestyle in subsets of the population at high cardiometabolic risk.

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: Fatores genéticos estão entre os determinantes de obesidade, podendo influenciar a resposta a intervenções em estilo de vida. O impacto de polimorfismos de nucleotídeo único (SNPs) na resposta de biomarcadores a intervenções não é claro. Objetivo: Este estudo examinou as associações de seis SNPs FTO T/A, PPAR Pro12Ala, Apo A1 -75G/A, TNF- -308G/A, IL-6 - 174G/C e AdipoQ 45T/G com mudanças induzidas por uma intervenção em amostra de brasileiros de risco cardiometabólico. Métodos: Em um programa de nove meses de orientações em hábitos alimentares e atividade física, 180 indivíduos com prediabetes ou síndrome metabólica foram genotipados e agrupados segundo a presença do alelo variante de cada SNP e comparados quanto a variáveis antropométricas, metabólicas e inflamatórias. Resultados: A intervenção resultou em redução do consumo calórico, aumento da atividade física, melhora na antropometria e outros biomarcadores. Estratificando pelos SNPs, os principais achados estão contidos em dois artigos. Artigo 1: Houve melhor resposta do perfil glicêmico após a intervenção nos portadores do alelo variante do SNP TNF -308 G/A. Observou-se melhora das variáveis lipídicas nos portadores do alelo variante do SNP IL-6 -174 G/C, enquanto que aqueles com o genótipo referência obtiveram melhora no metabolismo da glicose. Carreadores do SNP AdipoQ 45T/G não obtiveram melhora no perfil lipídico nem no glicêmico.Artigo 2: O alelo variante do FTO T/A associou-se a melhores perfis 9 inflamatório e glicêmico em resposta à intervenção. Portadores do alelo variante do SNP PPAR Pro12Ala obtiveram melhora na pressão arterial, enquanto que indivíduos com o genótipo referência melhoraram o metabolismo lipídico. Carreadores do alelo variante do SNP Apo A1 -75G/A apresentaram melhora no perfil lipídico que, após ajuste para medicação, não se manteve significante. Conclusões: SNPs relacionados à obesidade e comorbidades podem influenciar a resposta de marcadores metabólicos e inflamatórios a intervenções em hábitos de vida em brasileiros. O SNP TNF -308G/A parece favorecer um melhor perfil glicêmico. O SNP IL-6 -174G/C pode conferir efeito benéfico no perfil lipídico, mas não na glicemia. O SNP AdipoQ 45T/G compromete a resposta à intervenção em indivíduos de risco cardiometabólico no nosso meio. O SNP FTO T/A pode favorecer a resposta do metabolismo da glicose e a atenuação da inflamação. O SNP PPAR Pro12Ala pode ter impacto benéfico na pressão arterial, mas não no metabolismo lipídico. Em contraste com a literatura, o SNP Apo A1 -75G/A não parece influenciar resposta dos lípides à intervenção. Mais estudos envolvendo estes SNPs são necessários para possível direcionamento de intervenções a subgrupos específicos de indivíduos de risco. / Introduction: Genetic factors are one of the determinants of obesity and may influence the response to interventions. The impact of single nucleotide polymorphisms (SNPs) in weight loss and inflammatory response to interventions is not clear. Objective: This study examined associations of six polymorphisms FTO T/A, PPAR Pro12Ala, Apo A1 -75G/A, TNF- -308G/A, IL-6 -174G/C and AdipoQ 45T/G with changes induced by lifestyle intervention in Brazilians at cardiometabolic risk. Methods: In a 9-month intervention on diet and physical activity, 180 individuals with prediabetes or metabolic syndrome were genotyped and compared according the presence of variant allele of the SNPs and antrophometric, metabolic and inflammatory variables. Results: The intervention resulted in lower energy intake and greater total physical activity as well as improvement in anthropometry and several biomarkers. Stratified by SNPs, the main findings are covered in two articles. Article 1: Variant allele carriers of TNF -308 G/A SNP decreased plasma glucose after intervention. Lipid profile improved after intervention in variant allele carriers of IL-6 -174 G/C, while individuals with reference genotype had better plasma glucose response. Variant allele carriers of AdipoQ 45T/G did not improve lipid and glycemic profile. Article 2: Only variant allele carriers of FTO T/A decreased fasting plasma glucose and C-reactive protein concentration after intervention. Blood pressure reduced after intervention in variant allele carriers of the PPAR Pro12Ala, while the reference genotype increased Apo A1. Apparent favorable response of lipid profile to intervention in variant allele carriers of Apo A1 -75G/A was not maintained after adjustments for lipid-lowering medication. Conclusions: SNPs associated with obesity and comorbidities may influence the response of metabolic and inflammatory markers after lifestyle intervention. The TNF -308G/A may predispose a better response of glucose metabolism. The IL-6 -174 G/C SNP may confer a beneficial effect on lipid profile but not in glucose metabolism. Our findings reinforce unfavorable effects of the AdipoQ 45T/G SNP in lipid and glucose metabolism after lifestyle intervention in Brazilians at cardiometabolic risk. FTO T/A SNP induces a favorable impact on inflammatory status and glucose metabolism. The reference genotype of PPAR Pro12Ala seems to favor a better lipid profile, while the variant allele to decrease blood pressure. In contrast to literature, our data did not support benefits on lipid profile of the variant allele of Apo A1 -75G/A SNP. Further studies of these SNPs are needed to direct interventions to specific subgroups of at-risk individuals.

En Guadeloupe, la prévalence du diabète est deux fois plus élevée qu'en France hexagonale, avec une prédominance féminine. En dehors des facteurs environnementaux, la vitamine D et certains polymorphismes de gènes impliqués dans son métabolisme seraient associés à un risque de pathologies métaboliques. Les androgènes sont également associés aux anomalies du métabolisme glucidique, soit directement, soit via leur transporteur SHBG (Sex Hormone Binding Protein). Nous avons émis les hypothèses de recherche suivantes: 11 le statut en vitamine D et les polymorphismes des gènes impliqués dans son métabolisme pourraient être associés aux paramètres métaboliques chez des sujets Afro-Caribéens (AC). Ils expliqueraient l'importance des pathologies cardiométaboliques en Guadeloupe. 2/ la SHBG pourrait être associée aux anomalies du métabolisme glucidique, indépendamment des stéroïdes sexuels. Nos travaux sont présentés dans 4 études. Nous avons mis en évidence une prévalence élevée du déficit en vitamine D chez les sujets AC diabétiques de type 2. Nous avons trouvé une association significative entre le statut vitaminique D et le risque cardiométabolique chez ces sujets, mais aussi dans une population de sujets en hémodialyse chronique. Les polymorphismes des gènes impliqués dans le métabolisme de la vitamine D sont aussi associés à ce risque. Chez les sujets dysmétaboliques, une relation entre la SHBG, la graisse intra-hépatique, les hépatokines et les paramètres métaboliques a été mise en évidence, indépendamment des stéroïdes sexuels. En conclusion, la vitamine D et la SHBG pourraient être des marqueurs d'intérêt pour le dépistage des sujets à haut risque cardiométabolique. / In Guadeloupe, the prevalence of diabetes is two times higher than in Metropolitan France, with a female predominance. Apart from environmental factors, vitamin D and polymorphisms of genes involved in vitamin D metabolism would be associated with increased risk of metabolic diseases. Androgens are also associated with abnormal glucose metabolism, directly or through the Sex Hormone Binding Protein (SHBG). Our main hypotheses were: 11 Vitamin D status and polymorphisms of genes involved in its metabolism may be associated with metabolic pammeters in Afro-Caribbean (AC). They could explain the importance of cardiometabolic diseases in Guadeloupe. 2/ SHBG may be associated with abnormal glucose metabolism, independently of sex steroids. Our research is presente<! in four studies. We have demonstrated a high prevalence of vitamin D deficiency in AC patients with type 2 diabetes. We found a significant association between vitamin D status and cardiometabolic risk in these subjects, but also in a population of patients undergoing in chronic hemodialysis. Polymorphisms in genes involved in vitam in D metabolism are also associated with this risk, In dysmetabolic patients, a relationship between SHBG, intmhepatic fat, hépatokines and metabolic parameters was demonstrated, independently of sex steroids hormones. In conclusion, vitamin D and SHBG may be markers of interest for screening patients at high cardiometabolic risk.

La déficience partielle en lipoprotéine lipase (LPLD) est associée à une augmentation du risque cardiométabolique chez les hommes et les femmes. L’adiponectine, le syndrome métabolique et la ménopause sont des modulateurs importants de ce risque. L’objectif de cette étude était d’évaluer la contribution de l’adiponectine au profil de risque cardiométabolique de femmes porteuses de variants dans le gène LPL connus pour être associés avec la LPLD. L'échantillon étudié comprenait 568 femmes d'origine canadienne-française, dont 127 avec une LPLD et 441 non LPLD (contrôles). L'influence de l'adiponectine sur le risque associé à la LPLD a été évaluée en utilisant des analyses de régression multiples prenant en compte l’influence du statut ménopausique, des variables anthropométriques, du bilan lipidique, de la glycémie à jeun et du tabagisme. Les résultats montrent que les niveaux d'adiponectine étaient significativement plus faibles dans les groupes LPLD. La contribution des valeurs faibles d’adiponectine au profil de risque cardiométabolique des sujets LPLD était indépendante du statut ménopausique et de toutes les autres covariables étudiées. Cela suggère que l'adiponectine contribue au profil de risque cardiométabolique chez les femmes porteuses d’une mutation connue pour être associée avec la LPLD. / The cardiovascular risk significantly increases after menopause. Lipoprotein lipase (LPL) is a key enzyme in the metabolism of triglyceride (TG)-rich lipoproteins which contributes to cardiometabolic homeostasis. Adiponectin is an adipocytokine which also influences the cardiometabolic status. The objective of this study was to evaluate the contribution of plasma adiponectin to the cardiometabolic status of women carrying loss-of-function LPL gene variants (LPLD). A total of 568 French Canadian women (127 LPLD and 441 controls) were included. The association of plasma adiponectin with LPLD was assessed using multiple regression models. Cardiometabolic covariates included anthropometrics, lipids (TG, HDL-C, LDL-C, apo B), fasting glucose and smoking. Mean plasma adiponectin concentration was significantly lower in women with LPLD. Women carrying loss-of function LPL gene mutations also presented a significantly higher risk of coronary artery disease. In conclusion, these results suggest that low plasma adiponectin significantly contributes to the cardiometabolic risk profile of postmenopausal women carrying loss-of-function LPL gene mutations, independently of anthropometrics, lipids and other covariates.

Objective: To compare psychological work and life stress indicators among female hospital employees in both shift work (SW) and non-shift work (NSW) positions, and determine associations with demographic and vocational factors, and indicators of cardiovascular risk (CVR). Methods: Female employees from one Southeastern Ontario acute care hospital (n=212) provided fasting blood samples, demographic and work related data, and completed a physical assessment and questionnaires. Work stress was measured with the Job Content Questionnaire and Effort-Reward Balance Index (ERI). Life stress was assessed with the Derogatis Stress Profile. Metabolic Syndrome (MS) was determined based on Interim Societies Joint Guidelines. Results: SW in comparison to NSW employees reported higher mean scores in: global ERI (.70 (SD .4) vs. .58 (SD.29) p<.05), psychological job demands (21.2 (SD 4.8) vs. 19.2 (5.7) p<.01), physical job demands (13.8 (SD 2.6) vs. 10.2 (SD 3.8), skill discretion (36.5 (SD 4.4) vs. 34.7 (SD 5.4) p<.01), lower decision authority (31.6 (SD 5.8) vs. 33.5 (SD 6.5) p<.05), and lower total life stress scores (39.2 (SD 7.3) vs. 42.1 (SD 9.4) p<.05). There were no significant differences between SW and NSW group for MS or CVR factors. MS was present among 17% of all employees, 18.5% of SW, and 15.5% of NSW. In logistic regression analysis MS occurrence was associated with chronic SW exposure of 6 or more years (AOR 5.41 (95% CI, 1.84 – 15.87), decisional authority (AOR 1.09 (95% CI, 1.00 – 1.18), skill discretion (AOR 1.13 (95% CI, 1.01 – 1.26), and depression (AOR 1.26 (95% CI 1.08 – 1.46). Conclusions: Women working in SW positions experience more psychological and physical work stress, and effort-reward imbalance. The interplay between effort and reward aspects of the work environment may significantly contribute to psychological work stress and persist with increasing age among female hospital employees regardless of SW status. Among female hospital employees SW status and psychological stress measures do not appear to have an immediate effect upon CVR, as measured by the MS, but may contribute to its development with prolonged exposure. / Thesis (Master, Nursing) -- Queen's University, 2014-04-27 21:22:11.951