Introdução: a adiponectina está envolvida na homeostase energética, através da regulação do metabolismo glicídico e lipídico. Adicionalmente, apresenta propriedades anti-inflamatórias e antiateroscleróticas. Polimorfismos no gene da adiponectina (ADIPOQ) podem modular as concentrações de adiponectina. A influência desses polimorfismos no desenvolvimento da hipertensão gestacional (HAG) e da pré-eclâmpsia (PE) é desconhecida. Objetivo: o objetivo deste trabalho foi analisar a influência dos polimorfismos no gene ADIPOQ sobre o desenvolvimento da hipertensão gestacional e da pré-eclâmpsia. Pacientes e métodos: Foram estudadas 401 gestantes sendo 161 grávidas saudáveis (GS), 113 com HAG e 127 com PE. Os polimorfismos do gene ADIPOQ -11391G>A (rs17300539), -11377C>G (rs266729), 45T>G (rs2241766) e 276G>T (rs1501299) foram genotipados através de discriminação alélica por reação de PCR em tempo real. Os haplótipos foram inferidos através do programa PHASE 2.1. Resultados: não foram observadas diferenças estatisticamente significativas nas freqüências genotípicas e alélicas dos polimorfismos estudados. Na analise dos haplótipos, observamos pequenas diferenças nas freqüências haplotípicas entre os grupos estudados, no entanto, nenhuma destas diferenças foi estatisticamente significativa (P>0,05). Conclusão: Não encontramos nenhuma associação entre as variantes genotípicas e alélicas dos polimorfismos no gene ADIPOQ com o desenvolvimento de hipertensão arterial gestacional e pré-eclâmpsia. / Introduction: adiponectin is involved in energy homeostasis by regulating glucose and lipid metabolism. Additionally, it presents anti-inflammatory and anti-atherosclerotic functions. Polymorphisms in adiponectin gene (ADIPOQ) can modulate the concentrations of adiponectin. The influence of these polymorphisms on the development of gestational hypertension (GH) and preeclampsia (PE) is unknown. Aim: The aim of this work was to examine the influence of polymorphisms in the gene ADIPOQ on the development of gestational hypertension and preeclampsia. Patients and Methods: we studied 401 pregnant women: 161 healthy pregnant (HP), 113 pregnants with gestational hypertension (GH) and 127 pregnants with preeclampsia (PE). Polymorphisms ADIPOQ -11391G>A (rs17300539), - 11377C>G (rs266729), 45T>G (rs2241766) and 276G>T (rs1501299) were genotyped by allelic discrimination by PCR in real time. Haplotypes were inferred using the PHASE 2.1 program. Results: there were no statistically significant differences in allele and genotype frequencies of the polymorphisms studied. In the analysis of haplotypes, we observed small differences in haplotype frequencies between groups, however, none of these differences was statistically significant (P> 0.05). Conclusion: we found no association between the genotypic and allelic variants of the ADIPOQ gene polymorphisms with the development of gestational hypertension and preeclampsia.

A obesidade assim como a gestação está relacionada com distúrbios dos metabolismos da glicose, lipídios, hormônios e produção de moléculas inflamatórias. Portanto, supõe-se que a obesidade na gestação pode influenciar o desenvolvimento do feto, interferindo na sua composição corporal e predispondo a doenças cardiovasculares na idade adulta. Este estudo avaliou a relação entre a composição corporal e leptina e adiponectina séricas materna e a composição corporal de neonatos. A composição corporal de 215 mães e seus respectivos neonatos foi determinada por bioimpedância segmentada e pletismografia por deslocamento de ar, respectivamente. Os níveis séricos de leptina e adiponectina maternos foram avaliados pelo método de Enzyme Linked Immuno Sorbent Assay ELISA. Utilizou-se análise de regressão univariada e análise de regressão linear múltipla para determinar a associação entre fatores maternos e composição corporal do neonato, considerando-se como variáveis resposta a massa de gordura e a massa livre de gordura do neonato. As mães apresentaram idade média de 25,9 (5,2) anos, 43,4 por cento eram pardas e 55,3 por cento pertenciam à classe econômica B. Cerca de 50 por cento das mães apresentaram Índice de Massa Corporal (IMC) pré-gestacional adequado, 27,7 por cento tinham sobrepeso e 10,8 por cento eram obesas.47,1 por cento dos partos foram normal e 29,1 por cento foram cesárea. Nasceram mais crianças do sexo feminino (55,4 por cento) que do masculino e a média de peso ao nascimento foi de aproximadamente 3373 (423) g. O IMC pré-gestacional materno, a massa livre de gordura materna, a massa muscular esquelética materna e a concentração plasmática de adiponectina apresentaram associação positiva com a massa de gordura do neonato. A massa livre de gordura materna, massa muscular esquelética materna e massa muscular do braço direito apresentaram associação positiva com a massa livre de gordura do neonato. A composição corporal materna e a adiponectina, proteína secretada pelo tecido adiposo, exercem influência sobre a composição corporal do neonato. Espera-se que mais estudos sejam conduzidos para investigar os mecanismos envolvidos nos achados desta pesquisa / Obesity as well as gestation is related to disturbances of glucose metabolism, lipids, hormones and production of inflammatory molecules. Therefore, it is assumed that obesity during pregnancy can influence the development of the fetus, interfering with its body composition and predisposing to cardiovascular diseases in adulthood. This study evaluated the relationship between body composition and maternal serum leptin and adiponectin and the body composition of neonates. The body composition of 215 mothers and their respective neonates was determined by segmented bioimpedance and air displacement plethysmography, respectively. Serum levels of maternal leptin and adiponectin were assessed by Enzyme Linked Immuno Sorbent Assay ELISA. We used univariate regression analysis and multiple linear regression analysis to determine the association between maternal factors and body composition of the newborn, considering as variables the fat mass and the fat free mass of the newborn. The mothers had a mean age of 25.9 (5.2) years, 43.4 per cent were brown and 55.3 per cent belonged to economic class B. Approximately 50 per cent of the mothers presented Body Mass Index (BMI) adequate pre-gestational age, 27.7 per cent were overweight and 10.8 per cent were obese.47,1 per cent of births were normal and 29.1 per cent were cesarean. More female children (55.4 per cent) were born than male children and the mean birth weight was approximately 3373 (423) g. Maternal pre-gestational BMI, maternal fat-free mass, maternal skeletal muscle mass, and adiponectin plasma concentration were positively associated with neonatal fat mass. The maternal fat free mass, maternal skeletal muscle mass and right arm muscle mass were positively associated with the fat free mass of the newborn. Maternal body composition and adiponectin, a protein secreted by adipose tissue, influence the body composition of the neonate. It is expected that further studies will be conducted to investigate the mechanisms involved in the findings of this research

A obesidade, caracterizada pelo excesso de tecido adiposo (TA), é uma doença epidêmica com crescente prevalência desde a infância. Os primeiros meses de vida são considerados críticos para o desenvolvimento humano devido a relação com repercussões duradouras na fisiologia do organismo. O TA tem sua formação desde a fase fetal e secreta inúmeras citocinas relacionadas com a obesidade. Destacam-se neste âmbito: a adiponectina, associada à sensibilidade a insulina; a leptina, pela sua interação com o dispêndio energético e a zinco-α-glicoproteína (ZAG) devido à ação moduladora na expansão do TA. Conhecendo-se a importância da ação destas citocinas e a relevância dos primeiros meses de vida sobre a saúde do indivíduo, o objetivo deste estudo do tipo coorte foi analisar as concentrações de adiponectina, leptina e ZAG do cordão umbilical e relacionar com a composição corporal de lactentes do nascimento ao 4º mês de vida. As citocinas foram determinadas no sangue do cordão umbilical por ELISA. A composição corporal foi avaliada mensalmente pelo PEA POD® (Infant Body Composition, Cosmed, USA). Realizou-se análise de variância (ANOVA) para comparações de médias das variáveis qualitativas. A análise de regressão linear múltipla foi utilizada para determinar a relação entre as citocinas e a composição corporal. A adiponectina se associou inversamente com o percentual de gordura no 1º mês de vida em lactentes não alimentadas por leite materno. A leptina mostrou associação positiva com o percentual de massa gorda ao nascimento para o sexo feminino (R²=0,29; P=0.001), porém essa associação não se manteve significante após o primeiro mês de vida. No modelo final estratificado por sexo, a ZAG foi a única variável analisada que explicou o percentual de gordura no 3º mês (R²=0,21; P=0,003) e no 4º mês de vida (R²=0,14; P=0,03) para o sexo feminino. Os resultados desta investigação reforçam a possível influência positiva do papel da leptina no sangue do cordão umbilical no percentual de gordura ao nascimento e do papel da ZAG com influência negativa no percentual de gordura no 3º e 4º meses de vida. / Obesity, characterized by excess adipose tissue (AT), is an epidemic disease with increasing prevalence since childhood. The the first months of life are considered critical to human development because of the relationship with long-lasting effects on the physiology of the organism. The TA formation starts in fetal stage and secretes numerous cytokines related to obesity. Stand out in this context: adiponectin is associated with insulin sensitivity; leptin by its interaction with the energy expenditure and zinc-α-glycoprotein due to their modulating effects of the expansion of the TA. Knowing the importance of the action of these cytokines and the relevance of the first months of life on the health of an individual, the aim of this cohort study was to analyze the concentrations of adiponectin, leptin and ZAG cord and relate to body composition of children from birth to 4 months of life. Cytokines were assayed in the cord blood by ELISA. Body composition was assessed by the PEA POD ® (Infant Body Composition, Cosmed, USA) monthly. An analysis of variance (ANOVA) for mean comparisons of qualitative variables. A multiple linear regression analysis was used to determine the relationship between the cytokines and body composition. Adiponectin was inversely associated with the percentage of fat in the 1st month of life in infants not being breast fed. Leptin was positively associated with the percentage of fat mass at birth for females (R ² = 0.29), but this association did not remain after the first month of life. In the final model stratified by sex, ZAG was the only variable that explained analyzed the percentage of fat in 3 (R ² = 0.21) and 4 months (R ² = 0.14) for females. The results of this study reinforce the positive influence of the role of leptin in umbilical cord blood for the percentage of fat at birth and the role of ZAG with negative influence on the percentage of fat in the third and fourth months of life.

Orientador: Miriane de Oliveira / Resumo: Introdução: O hormônio triiodotironina (T3) influencia o metabolismo e desenvolvimento do tecido adiposo (TA), modulando a proliferação e diferenciação de adipócitos, podendo agir sobre os reguladores do processo de adipogênese, como o receptor ativado por proliferador de peroxissomo (PPARy). O TA está envolvido na regulação da energia corporal, sintetizando e secretando substâncias denominadas adipocinas, dentre elas a adiponectina e leptina. A adiponectina está relacionada ao aumento da sensibilidade à insulina, enquanto a leptina está envolvida com o gasto energético. O T3 pode desencadear ações por ativação de vias extranucleares, dentre elas a via MAPK/ERK e integrina αVβ3. Objetivo: Verificar a ação do T3, com participação das vias extranucleares MAPK/ERK e integrina αVβ3, na modulação de adiponectina e leptina, além de avaliar os parâmetros relacionados ao perfil adipogênico e dano de DNA. Métodos: Adipócitos, 3T3-L1, foram tratados com T3 (10nM) por uma hora, na ausência ou presença dos inibidores de MAPK/ERK – PD98059 (PD, 50uM) e da integrina αvβ3 – ácido tetraiodotiroácetico (Tetrac, 10-4M). A ausência de qualquer tratamento foi considerada grupo controle (C). Após o período de tratamento foi realizado PCRq-RT para analisar a expressão de mRNA de adiponectina e leptina, e Western Blot para expressão proteica de adiponectina, leptina, PPARy, pAKT e pERK; a viabilidade celular foi realizada pelo ensaio de MTT; a quantificação do acúmulo lipídico pelos ens... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Introduction: The hormone triiodothyronine (T3) influences the metabolism and development of adipose tissue (TA), modulating the proliferation and differentiation of adipocytes, and can act on regulators of the adipogenic differentiation process, such as the peroxisome proliferator activated receptor). TA is involved in the regulation of body energy, synthesizing and secreting substances called adipokines, among them adiponectin and leptin. Adiponectin is related to increased insulin synaptic, since leptin is involved in energy expenditure. T3 can trigger actions by activation of extranuclear pathways, including MAPK / ERK and integrin α Vβ3. Objective: Given the role of T3 in TA and the importance of adipokines, the objective of this study is to verify the action of T3 with the participation of extranuclear pathways in the modulation of adiponectin and leptin and the parameters related to the adipogenic profile. Methods: Adipocytes, 3T3-L1, were treated with a physiological dose of T3 (10nM) for one hour, in the absence or presence of MAPK / ERK-PD98059 (PD) and integrin αvβ3 - tetraiodothyrocetic (Tetrac) integrin inhibitors. The absence of any treatment was considered as a control group (C). After the treatment period PCRqRT was performed to analyze the expression of leptin and adiponectin mRNA, and Western Blot for protein expression of adiponectin, leptin, PPARγ, pAKT and pERK; cell viability was performed by the MTT assay; the quantification of lipid accumulation by the... (Complete abstract click electronic access below) / Mestre

Atherosclerotic cardiovascular disease is a leading cause of death worldwide. Dysregulation of vascular redox state plays a crucial role in the atherosclerotic process. Increased production of vascular superoxide (O2·-) and other reactive oxygen species (ROS) leads to endothelial dysfunction, a key early step in atherogenesis. Adipose tissue is a source of vasoactive, hormone-like molecules which are termed adipokines. One of the most important adipokines is adiponectin. Adiponectin has been shown to have antioxidant, anti-atherosclerotic effects in cell culture studies and animal models. However, its role in human cardiovascular disease has not been extensively investigated. More specifically, its effects on the human vascular wall and the mechanisms regulating its synthesis in adipose tissue have not been studied before in humans. The aim of my thesis is to explore the role of adiponectin in human atherosclerosis. This was achieved through use of the Oxford CABG Bioresource: a well-phenotyped cohort and tissue bank of patients undergoing cardiac surgery. By employing a range of in vivo and ex vivo techniques, I demonstrate for the first time in humans that adiponectin has direct antioxidant effects in the vascular wall, by directly suppressing pro-oxidant vascular enzymes and restoring redox balance. These effects persist in type 2 diabetes, presence of which is linked to reduced circulating adiponectin levels. Indeed, a variety of stimuli affect adiponectin synthesis in human adipose tissue, with brain natriuretic peptide being a major driver of adiponectin synthesis. However, different adipose tissue depots demonstrate diverse responses to stimuli affecting adiponectin synthesis, owing to their functional and morphological differences. Of particular interest is the fact that synthesis of adiponectin in perivascular adipose tissue is driven by the oxidative stress status of the underlying vessel. This observation led me to document for the first time in humans the existence of a reciprocal, two-way interaction between perivascular adipose tissue and the vascular wall: high vascular oxidative stress leads to release of factors with the ability to up-regulate adiponectin expression in perivascular adipose tissue, acting as a local paracrine defence mechanism attempting to restore vascular redox state. My thesis provides proof-of-concept for this novel cross-talk between adipose tissue and the vascular wall. This can have significant impact in designing new therapeutic strategies against atherosclerosis.

INTRODUÇÃO: A doença de Gaucher (DG) é um erro inato do metabolismo causado pela atividade deficiente da enzima glicocerebrosidase e subdivide-se em três tipos: tipo I (DG tipo I), que é o mais frequente e não apresenta comprometimento do sistema nervoso central; o II (DG tipo II), agudo e neuronopático; e o III (DG tipo III), subagudo e neuropático. Todos os tipos caracterizam-se pela heterogeneidade clínica, com manifestações de intensidade distintas, tais como: hepatoesplenomegalia, alterações hematológicas e dores ósseas. Alterações no metabolismo energético também são descritas. A terapia de escolha para a DG é a reposição enzimática (TRE). OBJETIVO PRINCIPAL: Avaliar o estado nutricional e a homeostase de energia em pacientes com DG em TRE. MÉTODOS: A presente tese contemplou 4 etapas: Etapa 1) Elaboração de revisão sistemática da literatura sobre aspectos nutricionais da DG tipo I. Etapa 2) Avaliação da coorte de pacientes acompanhados no Centro de Referência para DG do Rio Grande do Sul (CRDG/RS; n= 38; DG tipo I=35; DG tipo III= 3) quanto a dados relativos ao estado nutricional. Etapa 3) Avaliação do gasto energético basal por calorimetria indireta dos pacientes com DG tipo III do CRDG/RS. Etapa 4) Avaliação, por meio de estudo transversal controlado, dos níveis de grelina, leptina e adiponectina de pacientes com DG tipo I do CRDG/RS, com idade superior a 18 anos e em TRE há mais de 6 meses (n=15); os pacientes foram pareado por sexo, idade e IMC com controles hígidos. RESULTADOS: Etapa 1) Foram localizados 175 estudos, dos quais 28 preencheram os critérios de inclusão. Etapa 2) Avaliação da coorte de pacientes acompanhados no Centro de Referência para DG do Rio Grande do Sul (CRDG/RS; n= 38; DG tipo I=35; DG tipo III= 3) quanto a dados relativos ao estado nutricional. Etapa 2) Os dados antropométricos dos pacientes adultos com DG tipo I (n=31) revelaram que quatorze apresentavam sobrepeso ou obesidade grau I e todos os pacientes com idade inferior a 18 anos estavam com peso e estatura adequados. A idade dos pacientes apresentou alta correlação com o IMC e com o nível de ferritina. O IMC apresentou correlação com a ferritina e esta com o colesterol total e com o LDL-colesterol. O colesterol total apresentou correlação com o HDL, com o LDL e uma correlação negativa com a quitotriosidase. O subgrupo que iniciou o tratamento com idade superior a 18 anos (n=16) teve um aumento significativo de IMC após a TRE (p=0,001) e o que iniciou o tratamento antes de 16 anos (n=10) teve um aumento significativo no escore-z para estatura e IMC (p=0,004 e p= 0,032, respectivamente). Etapa 3) Os pacientes com DG tipo III apresentaram hipermetabolismo e dois deles estavam desnutridos. Etapa 4) A mediana dos níveis de grelina, leptina e adiponectina dos pacientes não diferiu da dos controles. Os níveis de grelina e adiponectina apresentaram correlação positiva entre si e com o HDL-colesterol; e inversa com o IMC, circunferência de cintura e triglicerídeos. Os níveis de leptina apresentaram correlação inversa com o LDL-colesterol e direta com o IMC, circunferência da cintura, dose de enzima, triglicerídeos, insulina e HOMA-IR. Oito pacientes preenchiam os critérios para síndrome metabólica, quatro dos quais estavam com resistência à insulina pelo índice HOMA-IR. CONCLUSÕES: Os dados da revisão sistemática indicaram que o tratamento com imiglucerase melhora os índices de crescimento de crianças e adolescentes com DG tipo I o que está em consonância com os dados encontrados nesta coorte. Em relação aos pacientes avaliados, o estado nutricional classificado pelo IMC mostrou que quase metade dos pacientes com DG tipo I estava com excesso de peso e que a TRE parece contribuir para esse achado. O hipermetabolismo em pacientes com DG tipo III parece constituir-se num biomarcador da gravidade da doença. A leptina apresentou alta associação com a insulina e com o índice HOMA-IR, podendo tornar-se um biomarcador para avaliar indícios precoces de resistência à insulina em pacientes com DG. Aumento de peso, síndrome metabólica e resistência à insulina parecem ser frequentes em pacientes com DG tipo I. Estudos adicionais são necessários para investigar as associações encontradas. / INTRODUCTION: Gaucher disease (GD) is an inborn error of metabolism, caused by the deficient activity of the glucocerebrosidase enzyme and is divided into three types: type I, which is the most frequent and does not present neurological compromise; type II, which is acute and neuronopathic; and type III, which is subacute and neuronopathic. All types are characterized by clinical heterogeneity and symptomatic manifestations of varied intensity, such as hepatosplenomegaly, hematologic dysfunction, bone pain; energy homeostasis dysfunction is also present. The choice therapy for GD is enzyme replacement therapy (ERT). OBJECTIVE.To assess the nutritional status and the energy homeostasis in patients affected by Gaucher Disease under enzyme replacement therapy. METHODS.This present study is composed of 4 stages. Stage 1) Systematic literature review on GD type I nutritional aspects. Stage 2) Assessment of data revolving around nutritional status of the patients cohort followed at the GD Reference Center in Rio Grande do Sul(CRDG/RS; n= 38; GD type I=35; GD type III= 3. Stage 3) Assessment of basal energetic expenditure by indirect calorimetry in GD type III patients at CRDG/RS. Stage 4) Assessment, by means of controlled transversal study, of ghrelin, leptin and adiponectin levels in GD- I patients, age over 18 yo and under ERT for at least 6 months (n=15); the patients were pair matched with healthy controls for sex, age and BMI. RESULTS: Stage 1) 175 studies were found, of which 28 met the inclusion criteria. These studies have shown ERT is associated to: growth normalization in children and teenagers with delayed development; partial correction of hypermetabolism and glycemic profile dysfunctions; and increase in weight as well as insulin resistance and development of Diabetes mellitus type 2 in adults. Stage 2) The anthropometric data of adult patients with GD type I (n=31) pointed out fourteen showed overweight or obesity level 1, and all patients aged under 18yo showed adequate weight and height. The patient’s age showed high correlation with BMI and ferritin levels. BMI presented correlation with ferritin and the latter with total cholesterol and LDL- cholesterol. Total cholesterol showed correlation with HDL, with LDL and negative correlation with chitotriosidase. The subgroup comprising those who were over 18 years of age (n=16) at the beginning of treatment had a significant increase in BMI after ERT (p=0,001) and those beginning treatment under the age of 16 showed (n=10) significant increase in the z-score for height and BMI (p=0,004 and p= 0,032, respectively). Stage 3) GD type III patients showed hypermetabolism and two of them (2/3) were malnourished. Stage 4) The median of ghrelin, leptin and adiponectin levels of patients did not differ from that of the controls. The ghrelin and adiponectin levels presented positive correlation between themselves, with HDL-cholesterol, and inverse correlation with BMI, waist circumference, and triglycerides. The leptin levels presented inverse correlation with LDL-cholesterol and direct correlation with BMI, waist circumference, enzyme dose, triglycerides, insulin, and HOMA-IR. Eight patients (n=15) met the criteria for metabolic syndrome, four of which had insulin resistance, as measured by the HOMA-IR index. DISCUSSION AND CONCLUSIONS: Data from the systematic review showed the treatment with imiglucerase improves growth in children and adolescents with GD type I, this meets the findings in this cohort. In relation to the patients assessed, the nutritional status measured by BMI showed that almost half of the GD type I patients were overweight and that ERT seems to contribute to this finding. Hypermetabolism in GD type III patients seems to be a biomarker of the severity of this disease. Leptin presented high association with insulin and with the HOMA-IR index, and may eventually become a biomarker to evaluate early evidence of insulin resistance in GD patients. Weight increase, metabolic syndrome and insulin resistance seem to be frequent in GD type I patients. Further research is necessary to investigate the findings herein researched.

A obesidade é definida como acúmulo excessivo de gordura corpórea, derivada de um desequilíbrio crônico entre energia ingerida e gasta. Neste desequilíbrio estão relacionados fatores como estilo de vida (dieta e atividade física), alterações neuro-endócrinas e fatores hereditários (MARQUES-LOPES et al., 2004). A obesidade não acomete apenas seres humanos, tornando-se um elemento importante de estudos e pesquisas, inclusive em animais de companhia como cães e gatos. O diagnóstico da obesidade geralmente é feito por inspeção direta. Cães e gatos devem ter costelas facilmente palpáveis com configuração de ampulheta, quando vistos de cima. Incapacidade de palpar as costelas e presença de depósitos de gordura facilmente palpáveis na base da cauda, sobre os quadris ou na área inguinal sugerem obesidade. Condições ideais de gordura corporal giram em torno de 15% a 20% para cães (LEWIS et al., 1987). O tecido adiposo é conhecido como um local de armazenamento de energia e síntese de vários hormônios, dentre eles, destaca-se a adiponectina, proteína responsável pela correlação entre obesidade associada à ateroesclerose (ISHIOKA et al., 2006). Expressa exclusivamente em adipócitos, sua concentração plasmática diminui com o aumento da gordura corporal (ISHIOKA et al., 2006). Vários estudos têm sugerido também que a adiponectina tenha seus efeitos como uma molécula anti-aterogênica e anti-inflamatória, demonstrando ser um fator de proteção para doenças cardiovasculares (OUCHI et al., 1999; OUCHI et al., 2000), porém valores circulantes de adiponectina devem ser interpretados com cautela. Sabe-se que a obesidade em seres humanos está relacionada ao aumento da morbidade e da letalidade por doenças cardiovasculares (ATKINS, 1991; GRUNDY; ABATE, 2004; WOFFORD; HALL, 2004), portanto a mensuração deste polipeptídeo pode auxiliar a demonstrar se pacientes obesos e/ou cardiopatas estão expostos a um maior ou menor risco do desenvolvimento de eventos cardiovasculares. Assim, considerando que os diversos estudos com adiponectina em humanos obesos associado à doenças cardiovasculares são controversos, e os poucos relatos, relativos ao tema, publicados na medicina veterinária, objetivou-se avaliar a concentração sérica de adiponectina em cães: normais, obesos, com doença valvar crônica da mitral e em obesos com insuficiência valvar mitral concomitante, por meio de técnicas laboratoriais de radioimunoensaio (RIE) e enzyme linked immuno sorbent assay (ELISA), verificando se existe correlação entre níveis séricos diminuídos da adiponectina na obesidade e no paciente com insuficiência valvar crônica de mitral. Para isto, selecionaram-se 53 cães de raças, sexo e idades variadas, divididos nos quatro grupos de estudo. Realizou-se avaliação clínica e complementares, além da mensuração das concentrações séricas da adiponectina. O grupo de cães obesos associados à insuficiência valvar crônica mitral apresentou tendência a diminuição nas médias das concentrações circulantes da adiponectina pela técnica de radioimunoensaio, quando comparado aos outros grupos de estudo. / Obesity is defined as excessive accumulation of body fat, derived from a chronic imbalance between food intake and energy expended. This imbalance is related factors such as lifestyle (diet and physical activity), neuroendocrine disorders, and hereditary factors (MARQUES-LOPES et al., 2004). Obesity is not only affecting humans, making it an important element of studies and research, including pets such as dogs and cats. The obesity is usually done by direct inspection. Dogs and cats must be easily palpable ribs with hourglass configuration when viewed from above. Inability to palpate the ribs and the presence of fat deposits easily palpable at the base of the tail, on the hips or in the inguinal area suggest obesity. Ideally body fat are around 15% to 20% clothing (LEWIS et al., 1987). Adipose tissue is known as a local energy storage and synthesis of several hormones, among them, there is adiponectin, a protein responsible for the correlation between obesity associated with atherosclerosis (ISHIOKA et al., 2006). Exclusively expressed in adipocytes, its plasmatic concentration decreased with increase in body fat (ISHIOKA et al., 2006). Several studies have also suggested that adiponectin has its effect as a molecule anti-atherogenic and anti-inflammatory, proving to be a protective factor for cardiovascular disease (OUCHI et al., 1999, OUCHI et al., 2000), although values of circulating adiponectin should be interpreted with caution. It is known that obesity in humans is associated with increased morbidity and mortality from cardiovascular disease (ATKINS, 1991; GRUNDY, SLAUGHTER, 2004; WOFFORD; HALL, 2004), so measurement of the polypeptide can help show whether patients obese and / or heart are exposed to a greater or lesser risk of developing cardiovascular events. Thus, considering that several studies of adiponectin in obese humans associated with cardiovascular disease are controversial, and few published reports in veterinary medicine, aimed to evaluate the serum adiponectin in dogs: normal, overweight, with chronic mitral valve disease and In obese patients with concomitant mitral valve insufficiency using laboratory techniques for radioimmunoassay (RIA) and enzyme linked immuno sorbent assay (ELISA), checking whether a correlation exists between low serum adiponectin in obesity and in patients with chronic mitral valve insufficiency. For this, we selected 53 breeds, sex and ages were divided into four study groups. We carried out clinical evaluation and complementary addition to the measurement of serum adiponectin. The group of obese dogs associated with chronic mitral valve regurgitation tended to decrease in mean circulating concentrations of adiponectin by radioimmunoassay, when compared to other study groups.

L'obésité est actuellement considérée, d'une part, comme un facteur de risque de développement du cancer du sein en post-ménopause et, d'autre part, comme un facteur de risque de mortalité faisant suite à cette pathologie. Parmi les différentes hypothèses permettant d'expliquer le lien entre obésité et cancer du sein, il est suggéré que les sécrétions adipocytaires (i.e. les adipokines), dont les taux plasmatiques sont connus pour être modulés en situation d'obésité, jouent un rôle important. L'objectif de ce travail de thèse a donc consisté à évaluer l'impact des sécrétions adipocytaires globales et d'adipokines d'intérêt afin de mieux comprendre l'implication potentielle du microenvironnement tumoral adipocytaire sur les phénomènes de cancérogenèse mammaire. Dans une première partie, afin de resituer l'expression protéique de plusieurs adipokines d'intérêt dans l'ensemble complexe des perturbations engageant la cellule tumorale, nous avons mis en relation l'expression de ces adipokines entre elles et avec celle de biomarqueurs connus du cancer du sein (récepteurs aux œstrogènes et à la progestérone, Bax, Bcl2,Ki67...). Pour cela, nous avons comparé, sur des prélèvements mammaires tumoraux et normaux, l'expression de la leptine, de l'adiponectine et de la zinc-α2-glycoprotéine (ZAG). Les tissus cancéreux ou avoisinant la tumeur expriment la leptine et la ZAG et, plus faiblement l'adiponectine, alors que l'expression de ces adipokines n'est pas retrouvée au niveau du tissu sain de femmes non malades. De plus, l'expression de la ZAG et de la leptine est corrélée positivement à celle des récepteurs aux œstrogènes, suggérant qu'il existe un lien étroit entre les voies adipokinique et œstrogénique. Dans une seconde partie, nous avons évalué in vitro, d'une part, le rôle des sécrétions adipocytaires globales, grâce à la mise en place d'un modèle original de «derme adipeux tridimensionnel» épithélialisé en présence des cellules mammaires, fibrokystiques ou tumorales, et, d'autre part, l'impact d'adipokines d'intérêt (leptine et ZAG) sur différentes lignées de cellules mammaires cancéreuses. Nous avons montré qu'il existe un dialogue réciproque entre le microenvironnement adipeux et les cellules mammaires cancéreuses, favorisant la croissance tumorale. Nous avons également établi que la leptine et la ZAG exercent des effets prolifératifs et anti-apoptotiques. Dans une troisième partie, nous avons cherché à mieux comprendre le fait que l'obésité augmente le risque de mortalité due au cancer du sein, en émettant deux hypothèses complémentaires : i) il pourrait y avoir une moindre efficacité des traitements d'hormonothérapie et/ou de chimiothérapie en cas d'obésité liée à une interférence avec certaines adipokines,et ii) il pourrait exister un risque accru d'apparition de métastases provenant notamment d'une influence des adipokines sur les processus angiogéniques. Ainsi, in vitro, nous avons montré que la leptine diminue l'efficacité de plusieurs traitements anti-cancéreux et augmente les processus angiogéniques et d'invasion tumorale, notamment quand elle est utilisée à des concentrations reflétant une imprégnation plasmatique en situation d'obésité, alors que l'adiponectine inhibe l'angiogenèse pour des concentrations reflétant l'imprégnation plasmatique en situation physiologique. Nos résultats suggèrent que les sécrétions adipocytaires sont impliquées dans la régulation du développement du tissu cancéreux au niveau mammaire et laissent entrevoir des pistes prometteuses concernant le ciblage des adipokines dans la prévention et/ou le traitement de la pathologie cancéreuse mammaire, plus particulièrement en cas de surcharge pondérale. / Obesity is now considered, firstly, as a risk factor for developing breast cancer in postmenopausal women and, secondly, as a risk factor for mortality in response to this pathology. Among the various hypotheses to explain the link between obesity and breast cancer, it is suggested that the adipocyte secretions (ie adipokines), whose plasma levels are known to be modulated in obesity are important. The objective of this work was therefore to assess the overall impact of adipocyte secretions and adipokines of interest to better understand the potential involvement of adipocyte tumor microenvironment in mammary carcinogenesis. In the first part, in order to situate the protein expression of several adipokines of interest in the complex disturbances involving the tumor cell, we have related the expression of these adipokines together and with that of more classical biomarkers of breast cancer (estrogen and progesterone receptor, Bax, Bcl2, Ki67...). For this, we compared, on mammary tumor and normal samples, the expression of leptin, adiponectin and zinc-α2-glycoprotein (ZAG). Cancerous tissue or normal tissue surrounding the tumor express leptin and ZAG and, more weakly, adiponectin, whereas expression of leptin and ZAG is not found in healthy tissue from women without disease. Furthermore, the expression of ZAG and leptin is positively correlated with that of the estrogen receptor, suggesting that there is a close connection between the adipokine and estrogen pathways. In the second part, we evaluated in vitro, on the one hand, the role of overall adipocyte secretions, through the establishment of an original model of "three-dimensional dermis fat" epithelialized in the presence of mammary cells, tumor or fibrocystic, and,on the other hand, the impact of interest adipokines (leptin and ZAG), on different lines of breast cancer cells. We have shown that there is a reciprocal dialogue between the adipose microenvironment and breast cancer cells, promoting tumor growth. Wealso found that leptin and ZAG exert proliferative and anti-apoptotic effects. In the third part, we try to understand the fact that obesity increases the risk of mortality from breast cancer, by issuing two additional assumptions :i) there may be a less effective treatment in situation of obesity related to an interference with some adipokines, and ii) there may be an increased risk of metastasis due to an influence of adipokines on the angiogenic process. Thus, in vitro, we showed that leptin decreases the efficacy of several cancer treatments and increases the angiogenic process and tumor invasion, especially when leptin is used at concentrations reflecting plasma impregnation in a situation of obesity, while adiponectin inhibits angiogenesis, particularly for concentrations reflecting impregnation in plasma in physiological situation. Our results suggest that adipocyte secretions are involved in regulating of breast cancer development and suggest promising ways for targeting adipokines in the prevention and / or treatment of breast cancer pathology, especially in case of overload weight.

No músculo reside um conjunto de células miogênicas indiferenciadas denominadas células satélites (CS), que são essenciais na homeostasia e na regeneração muscular. No entanto, as fases de ativação, proliferação e diferenciação das CS podem ser influenciadas por vários fatores extracelulares, como, a adiponectina. Essa adipocina tem sido amplamente estudada em relação a seus efeitos anti-inflamatórios e antidiabéticos, e foi proposta como reguladora da miogênese in vitro, porém sua atuação na regeneração in vivo, ainda não é bem elucidada. O objetivo deste trabalho foi avaliar a regeneração muscular em camundongos deficientes de adiponectina. A lesão foi induzida pela injeção de 50 ul de cloreto de bário no músculo tibial anterior esquerdo de animais machos selvagens (WT) e deficientes em adiponectina (AdKO). Após 3, 7 e 14 dias os animais foram eutanasiados e as amostras coletadas para análises morfológicas, gênica e proteica. O grupo AdKO apresentou maior quantidade de núcleos centralizados comparado com o grupo WT após 7 dias da lesão. Foram encontrados redução da expressão gênica de Pax7, MyoD e Miogenina nos AdKO após 3 dias. Houve aumento dos níveis das citocinas anti-inflamatórias IL-10 e IL-4 após 3 e 7 dias, respectivamente, e aumento das citocinas pró-inflamatórias IL-1 &#946, IL-17, TNF- &#945 e IFN após 7 dias nos animais AdKO. Apesar de não haver diferença entre os genótipos na expressão gênica de F4/80, os animais AdKO apresentaram aumento de CD206. Os animais WT tiveram aumento de mRNA de adiponectina com 7 dias da lesão. Não foram encontradas diferenças significativas entre os genótipos quanto ao infiltrado inflamatório, a deposição de colágeno total, a área de secção transversal e a recuperação da massa muscular. Concluímos que a adiponectina é importante no processo de remodelamento tecidual durante a regeneração e que sua deficiência não compromete a maturação das fibras musculares, devido aumento da resposta anti-inflamatória, apesar de haver um possível comprometimento na resposta pró-inflamatória. / In the muscle resides a set of undifferentiated myogenic cells, called satellite cells (SC), which are essential in the maintenance of homeostasis and muscle regeneration. However, the control and activation of SC can be influenced by several extracellular myogenic factors, such as adiponectin. Adiponectin, an adipokine, mainly produced by subcutaneous adipose tissue, has been widely studied in relation to its anti-inflammatory and anti-diabetic effects, but its role as regulator of in vivo regeneration is not yet well elucidated. Here we evaluate muscle regeneration in adiponectin deficient mice. Barium chloride was administered to the left anterior tibial muscle of wild type (WT) and adiponectin deficient (AdKO) animals. The right anterior tibial muscle was not injured and was used as control. The animals were euthanized after 3, 7 and 14 days after injury. We measured the area of the fibers by laminin, in addition to qualitatively evaluating the response to injury by HE and picrosirius. The inflammatory response was verified by the concentration of several cytokines in the muscle, by ELISA, and by the gene expression of some inflammation pathways (RT-qPCR). The regeneration response was obtained by the analysis of regulatory genes of this process by RT-pPCR. The data were compared statistically and the significant differences considered presented p <0.05. The lesion was effective in causing tissue damage, and the activation of regulatory genes of the regeneration process besides inducing inflammation in WT. However, we observed that the animals with deletion for the adiponectin gene presented a myogenic response potentially similar to the control animals, however, the cellular response presents differences. We conclude that adiponectin deficiency does not compromise muscle regeneration, although there is a possible compromise of the pro-inflammatory response.

Obesity is increasing globally and related to major changes in lifestyle. This increase is associated with an increased risk of cardiovascular disease (CVD). Knowledge about adipose tissue as a metabolic-endocrine organ has increased during the last few decades. Adipose tissue produces a number of proteins with increased body weight, many of which are important for food intake and satiety, insulin sensitivity, and vessel integrity, and aberrations have been related to atherosclerosis. Notably, the risk for developing CVD over the course of a lifetime differs between men and women. In Northern Sweden, men have a higher risk for myocardial infarction (MI). However, the incidence is declining in men but not in women. These sex differences could be due to functional and anatomical differences in the fat mass and its functions. The primary aim of this thesis was to evaluate associations between the adipocyte-derived hormones leptin and adiponectin, and fibrinolysis and other variables associated with the metabolic syndrome, and particularly whether these associations differ between men and women. Another aim was to evaluate these associations during physical exercise and pharmacological intervention (i.e. enalapril). Finally, whether leptin and adiponectin predict a first MI or sudden cardiac death with putative sex differences was also investigated. The first study used a cross-sectional design and included 72 men and women  recruited from the WHO MONICA project. We found pronounced sex differences in the associations with fibrinolytic variables. Leptin was associated with fibrinolytic factors in men, whereas insulin resistance was strongly associated with all fibrinolytic factors in women. The second study was an experimental observational study with 20 men exposed to strenuous physical exercise. During exercise, leptin levels decreased and adiponectin levels increased, and both were strongly associated with an improved fibrinolytic capacity measured as decreased PAI-1 activity. Changes in insulin sensitivity were not associated with changing adiponectin levels. The third study was a randomised, double-blind, single centre clinical trial including 46 men and 37 women who had an earlier MI. The study duration was one year, and participating subjects were randomised to either placebo or ACE inhibitor (i.e. enalapril). Circulating leptin levels were not associated with enalapril treatment. During the one-year study, changes in leptin levels were associated with changes in circulating levels of tPA mass, PAI-1 mass, and tPA-PAI complex in men, but not vWF. These associations were found in all men and men on placebo treatment. In women on enalapril treatment there was an association between changes in leptin and changes in vWF. In the fourth study, the impact of leptin, adiponectin, and their ratio on future MI risk or sudden cardiac death was tested in a prospective nested casecontrol study within the framework of the WHO MONICA, Västerbotten Intervention Project (VIP), and Västerbotten  Mammary Screening Program (MSP). A total 564 cases (first-ever MI or sudden cardiac death) and 1082 matched controls were selected. High leptin, low adiponectin, and a high leptin/adiponectin ratio independently predicted a first-ever MI, possibly with higher risk in men in regards to leptin. The association was found for non-fatal cases with ST-elevation MI. Subjects with low adiponectin levels had their MI earlier than those with high levels. In conclusion, the adipocyte-derived hormones leptin and adiponectin are related to the development of CVD with a sex difference, and fibrinolytic mechanisms could be possible contributors to CVD risk.