Hintergrund: Leptin ist ein unabhängiger kardiovaskulärer Risikofaktor und scheint prothrombotische Effekte zu besitzten. Adiponectin hingegen scheint vor Thrombosen zu schützen. Wir untersuchten deswegen die Bedeutung dieser beiden Adipozytokine bei Patienten mit einer akuten Lungenembolie. Durchführung: Im Rahmen einer prospektiven Fall-Kontroll-Studie schlossen wir zwischen 2003 und 2006 97 Patienten mit gesichterter Lungenembolie und 40 Patienten mit dem Ausschluß einer Lungenembolie ein. Die Lungenembolie-Patienten wurden bezüglich eines komplizierten Verlaufs innerhalb der ersten 30 Tage nach dem Ereignis (Tod, Katecholaminebedarf, Reanimation, Intubation, Hypotonie) sowie bezüglich des Langzeit-Überlebens beobachtet. Ergebnisse: Bei Patienten mit Lungenembolie ist ein höherer Leptinspiegel ein prognostischer Parameter für eine niedrigere 30-Tages-Komplikationsrate und ein besseres Langzeit-Überleben. Patienten mit einer Lungenembolie weisen signifikant höhere Adiponectinwerte als Patienten ohne Lungenembolie auf. Eine prognostische Bedeutung hat Adiponectin bei Patienten mit einer Lungenembolie nicht. Schlußfolgerung: Niedrige Leptinspiegel sind bei Patienten mit einer akuten Lungenembolie ein unabhängiger prognostischer Parameter für einen komplizierten 30-Tages-Verlauf und eine erhöhte Mortalität im Langzeit-Verlauf. Lungenembolie-Patienten weisen eine Hyperoadiponectinämie auf, dies könnten Ausdruck einer kardialen Sekretion und Wirkung des Asiponectins infolge der Lungenembolie sein.

Orientadores: Maria Salete Costa Gurgel, Sílvia de Barros-Mazon / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-22T03:12:53Z (GMT). No. of bitstreams: 1 Gimenez_RodrigoPinto_D.pdf: 2727620 bytes, checksum: 505f7780aca2f535e4882eb250f83b9d (MD5) Previous issue date: 2013 / Resumo: Introdução: A obesidade tem se mostrado responsável pelo aumento de 30% a 50% dos casos novos de câncer de mama, em particular na pós-menopausa. A mais recente hipótese para explicar tal fato situa os adipócitos e suas funções autócrina, parácrina e endócrina no centro do cenário, através da relação das adipocinas, por ele secretadas, com a obesidade e o câncer de mama. Objetivo: Artigo 1- Comparar o padrão de expressão imunoistoquímica da adiponectina (APN) e dos seus receptores tipos 1 e 2 (adipoR1/R2) no carcinoma invasor (CDI), carcinoma ductal in situ (CDIS) e lesões benignas da mama (BE) e correlacioná-los com parâmetros clínicos e histológicos. Artigo 2- Avaliar a expressão protéica da FABP4 nos tecidos epiteliais e adiposos mamário de portadoras de CDI, CDIS e lesões benignas da mama. Material e Métodos: Foram incluídos os blocos de parafina de 223 mulheres sendo 69 com CDI, 73 com CDIS e 81 com biópsias negativas para câncer de mama, tratadas no CAISM/UNICAMP de janeiro de 2008 a dezembro de 2011, e preparadas lâminas de Tissue Microarray (TMA). A expressão de APN e Adipo R1/R2 foi avaliada no tecido tumoral nos casos CDI e CDIS e no tecido epitelial e nos casos benignos. A expressão de FABP4 foi avaliada no tecido tumoral, na gordura peritumoral (GP) e na gordura mamária distante (GD) nos casos de CDI e CDIS, e no tecido epitelial e gorduras mamários nos casos benignos. Para avaliar uma possível relação entre a expressão dos marcadores entre si e com parâmetros antropométricos, clínicos e histopatológicos, foram utilizados os testes qui-quadrado ou exato de Fisher, Mann-Whitney, Kruskal-Wallis e correlação de Spearman. As determinações foram calculadas considerando o valor de ?=0,05 (p<0,05). Resultados: Artigo 1 - A APN mostrou-se expressa em 65% dos CDI, 48% dos CDIS e 12% das BE e AdipoR1 em 98%, 94% e 71%, respectivamente. Todos os casos de CDI e CDIS expressaram AdipoR2 contra 81% de BE. Nos CDI e CDIS observou-se associação entre maior expressão de APN e tumores RE negativo. No CDIS esta associação foi também observada com RP negativo. Artigo 2 - Observou-se expressão protéica da FABP4 no tecido epitelial em 90% dos CDI, 40% dos CDIS e 28% em BE. Considerando-se a GP e GD esta expressão foi maior nas BE que nos CDI, diferenças consideradas significativas. Nas pacientes com CDI a expressão da FABP4 foi maior quando o diagnóstico ocorreu até 50 anos de idade. A totalidade dos casos expressou moderada a intensamente este marcador no tecido gorduroso periepitelial e distante. Conclusões: As diferenças de expressões protéicas da adiponectina e dos seus receptores AdipoR1/R2 observadas em diferentes diagnósticos mamários sugerem sua participação no complexo mecanismo etiológico destas diferentes condições. Os resultados deste estudo indicam, ainda, que existe uma correlação direta entre expressão protéica da FABP4, câncer de mama e obesidade / Abstract: Introduction: Obesity has been shown to be responsible for a 30 to 50% increase in new breast cancer cases, in particular in the postmenopausal period. The most recent hypothesis that explains this fact places adipocytes and its autocrine, paracrine and endocrine functions at center stage, linking adipokines secreted by adipocytes to obesity and breast cancer. Objective: Article 1- to compare immunohistochemistry expression pattern of adiponectin (APN) and its receptors types 1 and 2 (adipoR1/R2) in invasive carcinoma (IDC), ductal carcinoma in situ (CDIS) and benign breast lesions (BE), correlated with clinical and histological parameters. Article 2- To assess FABP4 protein expression in epithelial and adipose breast tissue in women diagnosed with IDC, DCIS and benign breast lesions. Material and Methods: Paraffin-embedded blocks from 223 women were included. Of the total number of women, 69 had IDC CDI, 73 had CDIS and 81 had biopsies negative for breast cancer. The patients have been treated at CAISM/Unicamp from January 2008 to December 2011 and Tissue Microarray (TMA) slides were constructed. Expression of APN and Adipo R1/R2 was assessed in tumor tissue in cases of IDC and DCIS and in epithelial tissue in benign cases. FABP4 expression was evaluated in tumor tissue, peritumoral fat tissue (PF) and distant fat breast tissue (DF) in cases of IDC and DCIS and in the epithelial tissue and breast fat tissue in benign cases. To assess a possible relationship between marker expression and anthropometric, clinical and histopathological parameters, the chi-square test or Fisher's exact test, Mann-Whitney test, Kruskal-Wallis test and Spearman's correlation were used. Determinations were calculated, considering a value ?=0.05 (p<0.05) as significant. Results: Article 1 - APN was shown to be expressed in 65% of IDC, 48% of DCIS and 12% of BE and AdipoR1 in 98%, 94% and 71%, respectively. All IDC and DCIS cases expressed AdipoR2 versus 81% of BE. In IDC and DCIS, an association between a higher level of APN expression and ER-negative tumors was observed. In DCIS, this association was also observed with PR-negative tumors. Article 2 - FABP4 protein expression was observed in epithelial tissue in 90% of CDI, 40% of DCIS and 28% of BE. Considering PF and DF, FABP4 expression had a higher level in BE than in IDC, a difference that was considered significant. In patients with IDC, FABP4 expression was higher when diagnosis was made in patients aged up to 50 years. In all cases, this marker was moderately to intensely expressed in the peri-epithelial and distant fat tissue. Conclusions: Discrepancies in protein expression of adiponectin and its receptors AdipoR1/R2 observed in different breast diagnoses suggest its participation in the complex etiologic mechanism of these different conditions. Our results indicate that there is a direct correlation between FABP4 protein expression, breast cancer and obesity / Doutorado / Oncologia Ginecológica e Mamária / Doutor em Ciências da Saúde

No description available.

Obesity affects about 520 million people world-wide and more recently studies have shown that fat cells produce proteins called adipokines which have various influences on the human metabolism and has helped to change the perspectives of researchers on the concept of the adipose tissue being just a store of energy. As a result of this, adipokines have been reported to represent a connection between obesity and cardiovascular diseases (CVD) and diabetes mellitus. The concentrations and the bases of the effects of the adipokines in beta cell failure of diabetes mellitus and endothelial cell dysfunction of cardiovascular diseases are still not fully understood. The effect of leptin and adiponectin, which are two adipokines with opposing effects, has been explored in this study. In the present study, therefore, the concentrations of leptin and adiponectin with significant effect on beta cell and endothelial cell function and the basis of these functions were explored. Also, attempts were made in the present study to correlate the concentrations of leptin and adiponectin with possible clinical pointers to complications. In order to achieve this, beta cells (BTC) were grown, made into pseudo-islets (which are said to produce more insulin) and treated with various concentrations of leptin and adiponectin and cells assayed for insulin and amylin (to investigate the role of amylin in insulin secretion). Also the cells were collected and mRNA extracted from these cells, reverse transcription PCR carried out to find out the role of protein phosphatase 1 (PP-1) in the effect of leptin on insulin secretion. PP-1 is a substrate that increases insulin secretion by allowing calcium influx into the cell and is said to be blocked by leptin). Leptin at 500ng/ml was found to significantly (p<0.05) inhibit the secretion of insulin and the expression of PP1 gene, thus supporting this as a basis for the effect of leptin on insulin secretion. Adiponectin however increased insulin secretion significantly but was not as consistent in its effect as leptin was in inhibiting insulin secretion. In order to explore the role of adipokines in cardiovascular diseases, EAHY human endothelial cells were cultured and treated with various concentrations of adiponectin and leptin both individually and in combinations and cells collected and mRNA extracted in order to carry out a reverse transcription PCR for the expression of angiogenic (TIMP2, TIMP3 and MMP2) genes and atherosclerotic (LPA and LPL) genes. Leptin (1nM) was shown to increase the expression of atherosclerotic and angiogenic genes while adiponectin (100nM) inhibited the expression of the atherosclerotic and angiogenic genes. A combination of leptin and adiponectin caused a reduction in the stimulatory effect of leptin on the expression of atherosclerotic and angiogenic genes. This shows that leptin may predispose to CVD while adiponectin reduces the risk of CVD. The clinical part of this study involved recruiting 150 patients with diabetes after the ethical approval for the clinical study was granted. The data collected from the patients included their age, sex, race, and physical parameters like the body mass index (BMI). Also blood samples were collected to measure the clinical indicators for CVD and renal function such as cholesterol, HDL levels, eGFR, albumin levels and their retinopathy status checked as these are the common complications seen in diabetic patients. The blood samples were also assayed in the laboratory for leptin and adiponectin levels and the leptin, adiponectin and the leptin/adiponectin ratio (LAR) were then correlated with the laboratory determinants of CVD, renal and retinopathy risks. It was found that the LAR and the leptin levels correlates significantly with the BMI, while the leptin levels were significantly correlated with the risk of nephropathy in diabetic patients while adiponectin levels correlated significantly with a reduced risk for developing CVD. The role of the enzymes in the leptin and adiponectin signaling pathway was also explored and it was discovered that ERK, P38 and AMPK all had roles in the effect of leptin and adiponectin on the expression of atherosclerotic and angiogenic genes. These data indicate that leptin and adiponectin play significant roles in the beta cell and endothelial cell function and are links between obesity and CVD and diabetes mellitus.

Background: Cardiovascular disease (CVD) is the leading cause of death worldwide. Well-established risk factors for CVD include increasing age, male sex, sedentary lifestyle, obesity, smoking, diabetes, hypertension, dyslipidaemia and low socio-economic status. Traditional risk factors do, however, not fully explain cardiovascular risk in general. In this thesis we focused on two conventional risk factors (smoking, blood pressure), and two unconventional risk markers (adiponectin, an adipocyte derived protein; and sialic acid (SA), a marker of systemic inflammation) for prediction of CVD events. Aims: In Paper I we examined to what degree smoking habits modify the risk of CVD in relation to systolic blood pressure levels in middle-aged men. In Paper II we investigated the predictive role of adiponectin for risk of CVD as well as the cross-sectional associations between adiponectin and markers of glucose metabolism, also in men. In Paper III we examined if increasing pulse pressure (PP) and increasing levels of SA both increase the risk of CVD and whether their effects act in synergism. In Paper IV the association of SA with risk of incident diabetes mellitus and related complications, resulting in hospitalization, was studied. Subjects and Methods: Two large-scale, population-based, screening studies with long follow-up periods have been used. The Malmö Preventive Project (MPP) was used with 22,444 individuals in Paper I and a sub cohort of 3,885 individuals in Paper II. The Värmland Health Survey (VHS) was used in Papers III and IV with 37,843 and 87,035 individuals, respectively. Results: CVD risk increases with increasing systolic blood pressure levels and this risk is almost doubled in smokers. Total adiponectin level is not associated with increased risk of future CVD but it is inversely associated with markers of glucose metabolism. PP and SA both contribute to risk of future CVD. Adjustment for mean arterial pressure reduces the risk induced by PP. Elevated SA contributes to increased risk of incident diabetes and related complications leading to hospitalization.

A promoção a amamentação representa uma importante estratégia de saúde pública no manejo do sobrepeso e obesidade mundial. É possível que os hormônios reguladores do metabolismo energético, como a adiponectina, leptina e melatonina do colostro humano, possa beneficiar o sistema imunológico do lactente e minimizar os impactos ocasionados pelo excesso de peso materno pré-gestacional. Dado que, esses hormônios também possuem ação imunomoduladora. Assim, mudanças nas concentrações desses hormônios, podem comprometer a atividade funcional das células mononucleares (MN) do colostro humano e contribuir para o aumento de infecções neonatais. Por isto, o objetivo desta pesquisa foi analisar a atividade funcional dos fagócitos MN do colostro de mulheres com excesso de peso pré-gestacional, na ausência e presença de adiponectina, leptina e melatonina. As amostras de colostro foram coletadas de 109 doadoras saudáveis e foram divididas em dois grupos: grupo controle e grupo com excesso de peso. O colostro foi centrifugado para obtenção do botão celular e sobrenadante. O sobrenadante foi utilizado para dosagem de melatonina, quantificada por ELISA. As células MN foram utilizadas no ensaio de fagocitose, por citometria de fluxo, e a produção de espécies reativas de oxigênio (EROS), cálcio intracelular e apoptose foram realizadas por fluorimetria. Foram consideradas diferenças significativas quando p<0,05. O colostro de mulheres com excesso de peso pré-gestacional apresentou uma maior concentração de melatonina (p<0,05). Os fagócitos MN do grupo excesso de peso teve um menor índice de fagocitose (p<0,05). No entanto, os estímulos foram capazes de restaurar a atividade fagocítica para este grupo (p<0,05). A adiponectina+leptina foi o estímulo que desenvolveu uma resposta mais efetiva, com restauração dos níveis de EROS, manutenção do cálcio intracelular e elevação do índice de apoptose para o grupo com excesso de peso (p<0,05). Os dados em conjunto reforçam a hipótese de que amamentação é benéfica para a saúde da criança. A manutenção dos níveis endógenos de adiponectina, leptina e melatonina pode aumentar a proteção e diminuir os índices de infecção neonatais, em filhos de mulheres com excesso de peso. Assim, políticas públicas que apoiam o controle de peso pré-gestacional devem ser encorajadas / Breastfeeding promotion represents an important public health iniciative in worldwide overweight and obesity management strategies. It is possible that the hormones regulating energy metabolism, such as adiponectin, leptin and melatonin of human colostrum can benefit the infant\'s immune system and minimize the impacts caused by pre-gestational maternal overweight. As these hormones also have immunomodulatory action, changes in their concentrations can affect the functional activity of mononuclear cells of human colostrum and contribute to the increase of neonatal infections. Therefore, the aim of this study is to analyze the functional activity of colostrum mononuclear phagocytes in women with pregestational overweight, with absence or presence of adiponectin, leptin and melatonin. Colostrum samples collected from 109 healthy donors were divided into two groups: the control group and the high body mass index (BMI) group. Colostrum samples were centrifuged to obtain the cell button and supernatant. The supernatant was used for melatonin dosing performed by ELISA, mononuclear cells used to phagocytosis assay, by flow cytometry and production of reactive species of oxygen, intracellular calcium and apoptosis assays were performed by fluorimetry using plate reader. Statistically significant differences were considered when p <0.05. Colostrum of pre-gestational high BMI group had higher concentration of melatonin (p <0.05). Mononuclear phagocytes of high BMI group had a lower index of phagocytosis (p <0.05). However, the stimuli restored the phagocytic activity for high BMI group (p <0.05). Adiponectin+leptin was the stimulus that developed a more effective response, with restoration of reactive oxygen species levels, maintenance of intracellular calcium and elevation of apoptosis index (p < 0.05) in the high BMI group. These data reinforce that breastfeeding is beneficial to child\'s health and maintaining endogenous levels of adiponectin, leptin and melatonin may increase protection and decrease neonatal infection rates in children of women with high BMI. Thus, public policies that support pre-gestational weight control should be encouraged.

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-&#945;-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-&#945;-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.

Introdução: A neoplasia maligna da mama é a mais frequentes entre as mulheres, respondendo, no Brasil, por 26,3 por cento de todos os cânceres no sexo feminino e por 14 por cento dos óbitos. Sabe-se que a obesidade é também uma doença crônica, que apresenta um panorama epidemiológico crescente, capaz de modificar as concentrações de hormônios esteroides, hormônios do crescimento, que envolve processos inflamatórios crônicos e de baixa intensidade os quais favorecem a proliferação celular e redução da apoptose. Portanto, é plausível que mulheres com câncer de mama que tenham excesso de peso e adiposidade apresentem maior risco para um prognóstico clínico menos favorável. Objetivo: Avaliar o papel da adiposidade sobre a oxidação e as adipocitocinas na neoplasia mamária. Material e Métodos: Estudo observacional do tipo caso-controle, com 101 mulheres com tumor de mama (Caso) e 100 mulheres sem câncer (Controle), selecionadas no Hospital Geral de Fortaleza (Fortaleza-CE), nos anos de 2011 e 2012. Realizou-se avaliações socioeconômicas, clínica (estado de menopausa, uso de terapia de reposição hormonal-TRH, história reprodutiva, amamentação, tabagismo, sedentarismo e história familiar de câncer; estadiamento clínico (EC), tamanho do tumor e presença de linfonodos comprometidos), antropométrica (peso, índice de massa corporal -IMC, circunferência da cintura - CC) e de composição corporal ( por cento Massa Gorda - por cento MG; por cento Massa Magra - por cento MM; Ângulo de fase - AF) por impedância bioelétrica. Após jejum de 12h obteve-se alíquotas de sangue e a partir do plasma analisou-se marcadores de estresse oxidativo [TBARS; LDL(-); anti-LDL(-); 8-OHdG; vitaminas antioxidantes] e adipocitocinas (leptina e adiponectina). Comparação entre os grupos Caso e Controle total e segundo excesso de peso e obesidade foram realizadas por meio dos testes t-Student e Man-Whitney. Modelos de regressão linear simples e múltipla, assim como analises logísticas foram testadas entre variáveis brutas e ajustadas visando identificar associações entre adiposidade e marcadores bioquímicos de estresse oxidativo e adipocitocinas. Todos os testes estatísticos foram realizados no programa estatístico SPSS versão 20.0, onde considerou-se p < 0,05, como nível de significância. Resultados: Os grupos Caso e Controle se mostraram semelhantes em relação aos aspectos socioeconômicos e clínicos. Entre as variáveis antropométricas e de composição corporal apenas a CC (p=0,002) foi maior nas mulheres com tumor de mama. Com relação aos marcadores oxidativos e adipocitocinas, independente da adiposidade e do excesso de peso, o grupo Caso apresentou perfil menos favorável com maiores concentrações plasmáticas de TBARS (p<0,001), LDL(-) (p=0,026), auto-anticorpo anti-LDL(-) (p<0,001) e 8OHdG (p=0,021) e adiponectina (p<0,001) em menores concentrações. Entre as pacientes com tumor de mama, as com excesso de peso mostraram menores concentrações de adiponectina (p=0,018) e maiores de 8OHdG (p=0,02) e leptina (p=0,01), sendo essa adipocitocina 9 associada de modo positivo com CC (p=0,012) e por cento MG (p=0,001). Os nutrientes antioxidantes não se alteraram em função da presença do tumor e tão pouco pelo peso e adiposidade. Entretanto no câncer de mama, retinol e ß-caroteno, estiveram inversamente associados com linfonodos comprometidos (p=0,034) e EC III e IV (p=0,014), respectivamente. O risco de câncer de mama foi maior nos maiores tercis de CC, (OR=2,69; IC=1,33-5,47) TBARS (OR=6,99; IC=2,99-16,32) e Anti-LDL(-) (OR=10,28; IC=4,11-25,75) e nos menores tercis de adiponectina (OR=0,44; IC=0,22-0,91). Conclusão: A adiposidade intensificou as alterações oxidativas e de adipocitocinas promovidas pela neoplasia da mama. A obesidade abdominal aumentou o risco de câncer de mama, bem como as maiores concentrações plasmáticas de marcadores oxidativos, sugerindo prognóstico menos favorável. / Introduction: Breast malignant neoplasm is more frequent among women. In Brazil, it corresponds to 26, 3 per cent of all cancers in the female gender and to 14 per cent of the causes of death. It is well known that obesity is also a chronic disease, which presents an increasing epidemiological panorama, capable of modifying the concentrations of steroids hormones, the growth hormones, which involves chronic and low-intensity inflammatory processes, enabling cellular proliferation and the reduction of apoptosis. Therefore, it is plausible that women with breast cancer who are overweight and have adiposity present a higher risk of a less favorable clinical prognosis. Objective: To evaluate the role of adiposity over oxidation and the adipokines on breast neoplasia. Material and Methods: It was an observational study of the case-control type, with 101 women with a breast tumor (Case) and 100 women without cancer (Control), selected at Hospital Geral de Fortaleza (Fortaleza-CE), in the years of 2011 and 2012. Socio-economic evaluations were accomplished, clinic (menopause, use of Hormone Replacement Therapy (HRT), reproductive history, breastfeeding, smoking, sedentarism and family-history of cancer; clinic staging (CS), size of the tumor and presence of affected lymph nodes), anthropometrics (weight, body mass index BMI, waist circumference - WC) and of body composition ( per cent Fat Mass - per cent FM; per cent Lean Mass - per cent LM; Phase Angle - PA) by bioelectrical impedance. After a 12-hour-fasting, blood aliquots were obtained and markers of oxidative stress were analyzed from the plasma [TBARS; LDL(-); ANTI-LDL (-); 8-OHdG, antioxidant vitamins] and adipokines (leptin and adiponectin). The comparison between the groups Case and total Control and according to overweight and obesity were accomplished through the tests t-Student and Man-Whitney. Models of simple and multiple linear regression, as well as logistical analyses were tested among gross and adjusted variables aiming at identifying association between adiposity and biochemical markers of oxidative stress and adipokines. All the statistic tests were accomplished on the statistic program SPSS version 20.0, in which p<0,05 was considered as a level of significance. Results: The groups Case and Control were similar with relation to the socioeconomic and clinic aspects. Among the anthropometric and body composition variables, only CC (p=0,002) was higher in women with breast tumor. With relation to oxidative markers and adipokines, independently from adiposity and overweight, the Case group presented a less favorable profile, with higher plasmatic concentrations of TBARS (p<0,001), LDL (-) (p=0,026), auto-antibody, anti-LDL(-) (p<0,001) and 8OHdG (p=0,021) and adiponectin (p<0,001) in lower concentrations. Among the patients with breast tumor, the overweight ones showed lower concentrations of adiponectin (p=0,018) and higher of 8OHdG (p=0,02) and leptin (p=0,01). This adipokine was associated in a positive way to CC (p=0,012) and FM (p=0,001). The antioxidant nutrients did not alter due to the presence of the tumor or due to weight and 11 adiposity. However, in breast cancer, retinol and beta carotene were inversely associated to affected lymph nodes (p=0,034) and CS III and IV (p=0,014), respectively. The risk of breast cancer was higher in the bigger WC tertiles, (OR=2,69; IC=1,33-5,47) TBARS (OR=6,99; IC=2,99-16,32) and Anti-LDL(-) (OR=10,28; IC=4,11-25,75) and in the smaller adiponectin tertiles (OR=0,44; IC=0,22-0,91). Conclusion: Adiposity intensified oxidative and adipokines alterations promoted by breast neoplasia. Abdominal obesity increased the risk of breast cancer, as well as higher plasmatic concentrations of oxidative markers, suggesting a less favorable prognosis.

Adiponectina é um hormônio produzido e secretado em abundância pelo tecido adiposo, que regula o metabolismo melhorando a sensibilidade à insulina pela sua ação hepática e muscular. Diferentemente dos outros hormônios do tecido adiposo, seus níveis séricos diminuem à medida que aumenta a adiposidade e são inversamente correlacionados com a obesidade, resistência à insulina e síndrome metabólica. Variações no gene da adiponectina foram associadas a níveis de adiponectina, resistência à insulina e risco de diabetes. O objetivo deste estudo foi avaliar os níveis de adiponectina e as variantes no gene da adiponectina em crianças e adolescentes obesos e sem obesidade e correlacionar os achados às características antropométricas e metabólicas. Níveis de adiponectina sérica foram mais baixos em obesos e em indivíduos púberes. Em não obesos, os níveis de adiponectina a correlacionaram-se negativamente com a adiposidade, entretanto nos obesos, a resistência à insulina e o desenvolvimento puberal foram os fatores de diminuição dos níveis de adiponectina. Independentemente da adiposidade, da resistência à insulina e da puberdade, menores níveis de adiponectina (abaixo de 10g/mL) correlacionaram-se com maior risco de hipertrigliceridemia, baixo HDLC e síndrome metabólica. Na análise do gene da adiponectina foram identificados os SNPs -11391G>A (rs17300539), -11377C>G (rs822387) na região promotora, +45T>G (rs22411766) no exon 2, +349A>G (rs6773957) no intron 2, Y111H (rs17366743) e a mutação G90S no exon 3. O SNP-11391G>A estava em desequilíbrio de ligação de Hardy-Weinberg. As variantes Y111H e G90S estavam em forte desequilíbrio de ligação com SNP-11377C>G e G90S com SNP+45T>G. Foi observada associação do alelo G do SNP-11377 a maior adiposidade central e menores níveis séricos de glicose. Após construção dos haplótipos com os SNPs -11377C>G, +45T>G e +349A>G observou-se que a presença do alelo G do SNP-11377T>G associou-se a maior obesidade (GTA vs CTA) , enquanto que a presença dos alelos recessivos dos outros SNPs diminuiu essa associação (GTA vs GGG). Na presença do alelo G do SNP+349A>G (CTG vs CTA), foi observada maior freqüência de indivíduos hipertensos, entretanto a associação dos alelos recessivos dos SNPs -11377C>G e +45T>G (CTG vs GGG) diminuiu a freqüência de hipertensão. Os resultados do presente estudo demonstram que níveis de adiponectina diferem em crianças e adolescentes dependendo do grau de adiposidade e puberdade e que níveis mais baixos estão associados às alterações metabólicas de maior risco cardiovascular na obesidade. Variantes no gene da adiponectina podem estar em desequilíbrio de ligação com um SNP funcional ou um pool gênico responsável por maior risco de obesidade e desenvolvimento de alterações metabólicas relacionadas ao aumento da adiposidade / Adiponectin, present in high concentrations in blood circulation is produced in adipocytes. Adiponectin regulates insulin sensibility acting in liver and muscle. Plasma adiponectin decreases as adiposity increases and are inversely related to insulin resistance and metabolic syndrome. Variants in the adiponectin encoding gene have been associated with adiponectin levels, insulin resistance and type 2 diabetes. The aim of this study was to evaluate adiponectin levels, identify variants in the adiponectin gene and determine the relationship between adiponectin levels, genetic variances and anthropometric and metabolic features in obese and non-obese children and adolescents. We found lower adiponectin levels in obese and pubertal individuals. Adiponectin was inversely correlated to adiposity in non-obese. Instead, in obese youngsters, adiponectin levels were negatively associated to insulin resistance and pubertal state. Independent of adiposity, insulin resistance and pubertal stage, lower adiponectin levels (under 10g/mL) were related to lower HDLC, higher triglycerides and higher risk of having metabolic syndrome. We have identified 6 variants in adiponectin gene: SNPs -11391G>A (rs17300539), -11377C>G (rs822387) in promoter region, SNP+45T>G (rs22411766) in exon 2, SNP+349A>G (rs6773957) in intron 2 and SNP Y111H (rs17366743) and G90S mutation in exon 3. We found strong linkage disequilibrium between variant Y111H and -11377C>G SNP and between G90S mutation and -11377C>G and +45T>G SNPs. We detected an association between -11377C>G G allele and higher central adiposity and lower glucose levels. Haplotypes were constructed using the SNPs -11377C>G, +45T>G and +349A>G, and the results showed an association between -11377SNP G allele presence and higher adiposity (GTA vs CTA), whereas the presence of the recessive alleles of SNPs +45T>G and +349A>G was associated to a lower adiposity (GTA vs GGG). Hypertension was more frequent in the presence of +349A>G G allele (CTG vs CTA), whereas the presence of the recessive alleles of SNPs -11377 and +45T>G (CTG vs GGG) was not associated to hypertension. This study suggests that adiponectin levels, in Brazilian children and adolescents, depends on degree of adiposity and pubertal stage and that lower adiponectin concentrations are associated to altered metabolic features and higher cardiovascular risk. Variants in the adiponectin encoding gene can be in linkage disequilibrium with susceptibility regions responsible to higher risk of obesity and metabolic related features

Neste estudo, avaliamos o efeito da restrição calórica e do treinamento resistido na massa corporal e na sensibilidade à insulina de ratas ovariectomizadas. 80 ratas fêmeas da linhagem Holtzman foram distribuídas em 8 grupos (n=10 cada): ovariectomizado (OVX), ovariectomizado com restrição calórica (OVX RC), ovariectomizado com treinamento resistido (OVX TR), ovariectomizado com restrição calórica e treinamento resistido (OVX TR+RC), Sham operado (SHAM), Sham com restrição calórica (SHAM RC), sham com treinamento resistido (SHAM TR), sham com restrição calórica e treinamento resistido (SHAM TR+RC). Após 13 semanas de intervenção, foram analisados: massa corporal, gordura corporal; concentrações sanguíneas de glicose, insulina e adiponectina; conteúdo de AKT total e fosforilada, pi3k e Glut 4 (nos tecidos adiposos subcutâneo e retroperitoneal). As ratas ovariectomizadas (OVX, OVX RC, OVX TR e OVX TR+RC) apresentaram maior massa corporal e gordura corporal quando comparadas ao grupo SHAM. As concentrações de glicose e insulina foram semelhantes em todos os grupos experimentais, porém a concentração de adiponectina foi menor nos grupos ovariectomizados (OVX, OVX RC, OVX TR e OVX TR+RC), quando comparados ao grupo SHAM. A RC e o TR aumentaram a concentração de adiponectina quando comparado ao grupo OVX. Não houve diferença entre os grupos em relação à via de sinalização da insulina nos tecidos adiposos subcutâneo e retroperitoneal. Concluímos que a ovariectomia causa aumento de massa e gordura corporal, levando à menor concentração de adiponectina, e que a RC e o TR alteram estas modificações. / In this study, we evaluated the effect of calorie restriction and strength training on the body weight and insulin sensitivity of ovariectomized rats. Eighty female Holtzman rats were divided into eight groups (n=10 per group): ovariectomized (OVX), ovariectomized plus calorie restriction (OVX-CR), ovariectomized plus strength training (OVX-ST), ovariectomized plus strength training and calorie restriction (OVX-ST+CR), sham operated (SHAM), sham plus calorie restriction (SHAM-CR), sham plus strength training (SHAM-ST), and sham plus strength training and calorie restriction (SHAM-ST+CR). The following variables were analyzed after 13 weeks of intervention: body weight; body fat; blood concentrations of glucose, insulin and adiponectin; total and phosphorylated AKT content; pi3k and Glut 4 (in subcutaneous and retroperitoneal adipose tissues). Ovariectomized rats (OVX, OVX-CR, OVX-ST, and OVX-ST+CR) had a higher body weight and body fat than SHAM animals. Glucose and insulin concentrations were similar in all experimental groups, but adiponectin concentration was lower in the ovariectomized groups (OVX, OVX-CR, OVX-ST, and OVX-ST+CR) when compared to the SHAM group. Calorie restriction and ST increased the concentration of adiponectin when compared to the OVX group. There was no difference between groups in terms of insulin signaling in subcutaneous or retroperitoneal adipose tissue. We conclude that ovariectomy increases body weight and body fat, reducing adiponectin concentration, and that CR and ST alter these modifications.