Orientador: Mario Jose Abdalla Saad / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-11T14:59:49Z (GMT). No. of bitstreams: 1 Dertkigil_SergioSanJuan_M.pdf: 2116703 bytes, checksum: 70e0c18a251483a0c4be5861dc3adee8 (MD5) Previous issue date: 2006 / Resumo: Introdução A obesidade tem sido considerada uma das mais importantes doenças da atualidade, tanto pela sua crescente prevalência quanto pela sua alta relevância de morbi-mortalidade. A segmentação da gordura em seus diferentes compartimentos vem ganhando importância na tentativa de explicar e influir no prognóstico das alterações metabólicas envolvidas na obesidade. Objetivos Estudar os diferentes tipos de compartimentalização de gordura e correlacionar com suas alterações metabólicas mais freqüentes e relevantes. Material e Métodos Foram avaliados 64 pacientes obesos do ambulatório de obesidade do HC-UNICAMP, através de tomografia computadorizada, para medição das gorduras subcutânea, visceral, infiltração hepática, pancreática e muscular, e correlacionar esses achados da distribuição regional de gordura com os fatores metabólicos clássicos, entre os quais, glicemia de jejum, insulinemia de jejum, HOMA-IR, frações de colesterol, marcadores hepáticos (_GT) e medidas antropométricas. Resultados Foram analisados 64 pacientes, 30 homens e 34 mulheres, que demonstraram diferença estatística entre a área de gordura visceral, densidade hepática e muscular, e apresentaram alta correlação com fatores metabólicos clássicos (HOMA-IR, TG e TG/HDL). A área de gordura subcutânea e a densidade pancreática não apresentaram diferenças estatísticas entre os grupos ou com os fatores metabólicos. Os pacientes com baixa quantidade de gordura visceral e alta quantidade de gordura subcutânea, apresentaram fatores metabólicos de menor risco cardiovascular. Nesses pacientes com padrão subcutâneo a densidade muscular e não gordura visceral ou gordura hepática se correlacionou mais fortemente com esses fatores de risco metabólico. Dos fatores utilizados aquele com melhor correlação com a gordura visceral, gordura hepática e muscular foi o índice TG/HDL. Conclusão A deposição da gordura nos compartimentos visceral e hepático apresentam papel importante na gênese da síndrome metabólica em pacientes obesos viscerais, enquanto em pacientes com deposição subcutânea o depósito muscular apresenta a maior correlação com os fatores metabólicos / Abstract: Introdution During past decades obesity is being considered one of the most important disease, both for raising prevalence and high morbi-mortality. The regional distribution of adiposity into different compartments araises as an important marker for the earlier diagnostic of metabolic syndrome. It is well established a strong association between visceral adiposity and several metabolic abnormalities, including type 2 diabetes mellitus, lipid metabolism impairment, hypertension and impaired inflammatory factors that may contribute to increase the risk of cardiovascular disease. Objective. Study the different types of regional adipose depots and to correlate these depots and the metabolic risk factors. Material e Methods Subjects included sixty four obese volunteers who received medical examination (30 men and 34 women) between 2002 and 2005. Inclusion criteria required the subjects to be nonsmokers, BMI > 30 Kg/m2, age between 18 and 60 years. The subjects were evaluated with computed tomography for measurement of visceral adiposity area, subcutaneous area, hepatic density, pancreatic and muscle density, and correlate them with the metabolic risk factors ( fasting plasma glucose, fasting serum insulin, HOMA-IR, cholesterol fractions, hepatic marker (_GT) and anthropometric measurements. Results Visceral adiposity, hepatic density and muscle density were different in gender and showed high correlation with metabolic factors (HOMA-IR, TG e TG/HDL). Subcutaneous area and pancreatic density did not showed correlation with the metabolic factors. The patients with high subcutaneous depot showed lower metabolic risk factors. In those patients, the muscle depot and not the visceral or liver adiposity had strong correlation with metabolic factors. TG/HDL had the strongest relationship with visceral, liver and muscle depots. Conclusion In obese patients, the regional adiposity, in special visceral and liver depots play important roles in the genesis of metabolic syndrome. In subcutaneous obese patients, the muscle depot has the strongest correlation coefficient with metabolic syndrome / Mestrado / Medicina Experimental / Mestre em Fisiopatologia Médica

O presente trabalho teve por objetivo avaliar a microbiota subgingival pela técnica de Checkerboard e o perfil de citocinas por imunoensaio com princípio sanduíche baseado na tecnologia fluxometria do fluido gengival e soro em indivíduos não obesos; e em indivíduos com obesidade, antes e após cirurgia bariátrica. Diferenças na microbiota bucal foram observadas entre não obesos e obesos para 19 espécies bacterianas, particularmente E. corrodens que apresentou diferenças significativas em obesos, com consequente redução após a perda de peso. As citocinas IL-1b, IL-6, IL-10, IL-13, IL-17, TNF-a, leptina e adiponectina apresentaram diferenças estatisticamente significantes (p<0,05) quando esses indivíduos foram comparados. Todas as citocinas analisadas no soro diminuíram após a redução de peso, apenas a adiponectina apresentou concentrações significativamente mais elevadas (p<0,05). Assim, a obesidade promove alterações na microbiota subgengival e na resposta imunológica local e sua prevenção ou controle pode favorecer a saúde bucal. / In this study, the aimed to evaluate the subgingival microbiota using Checkerboard technique and the cytokines profile by using immunoassay based on the flowmetry gingival fluid and serum in non-obese and obese individuals, before and after bariatric surgery. Differences were observed in the oral microbiota between nonobese and obese for 19 bacterial species, particularly E. corrodens that showed significant differences in obese, with a consequent reduction after weight loss. The cytokines IL-1b, IL-6, IL-10, IL-13, IL-17, TNF-a, leptin and adiponectin were statistically different (p <0.05) when these individuals were compared. All analyzed cytokines in serum decreased after weight reduction only adiponectin concentrations showed significantly higher (p <0.05). Thus, obesity causes changes in the subgingival microbiota and the local immune response, and prevention and control can promote oral health.

Diabetes mellitus (DM) is a group of non-infectious diseases that cause hyperglycemia. DM symptoms were first clinically described by ancient Greek physicians whose prescriptions included plant-based remedies. Today, DM affects >400 million people globally and prevalence rates are rapidly increasing in developing countries where basic healthcare relies on local knowledge of botanical remedies. Many developing countries are home to diverse peoples and plants—providing fodder for varied plant-selection strategies and unique botanical pharmacopoeias. I addressed the plant-selection strategies used in a multi-ethnic, developing country, Trinidad and Tobago (T&T), to ascertain their role in shaping the local antidiabetic pharmacopoeia and to assess their benefits and risks in identifying safe and useful remedies. Using literature reviews, field surveys, and laboratory bioassays, I completed three categories of analysis. Ethnobotanical analyses showed that T&T’s antidiabetic pharmacopoeia is primarily of recent origin as >50% of the 48 historical DM remedies were Neotropical natives, including congenerics of well-known medicinal Paleotropical genera. Nevertheless, conservative knowledge transmission was also evident as several Paleotropical species of T&T’s pharmacopoeia, including Momordica charantia and Catharanthus roseus were also used in Africa, India and across the Caribbean. Paleotropical natives with a long history of use are likely to be safer remedies. Ethno-medicinal analyses of the pre- and post-2000 DM remedies of T&T, totaling 99 species, suggest that the centuries-old hot/cold folk disease-model was the model predominantly used in plant-selection. Parallels found between T&T folk concepts and biomedical mechanisms of DM provide probable bases for efficacy but the chronic use of purgatives and bitter-tasting plants is likely to be risky. Phytochemical analyses revealed that 69% of the tested plant extracts contained phenolic compounds, with more than half producing >80% alpha-glucosidase inhibition. Phenolic content and alpha-glucosidase inhibition were strongly correlated among food plants used as medicines, suggesting higher probability of selection as a result of non-target effects. The medicinal use of food plants may provide the best margins of safety and efficacy in identifying antidiabetic remedies. Together, these analyses showed how culture-specific plant-selection strategies can identify safe, useful remedies for developing countries to address their increasing DM prevalence in a cost-effective and sustainable manner.

Examining factors that affect vitamin D status in the fast-growing elderly population of Miami-Dade, Florida, is needed. Vitamin D deficiency in older adults has been linked to correlates of disability, including falls and fractures, and cardiovascular disease. The purpose of this study was to determine the proportion of vitamin D insufficient individuals and their relationship with vitamin D insufficiency in older adults (n=97) living in Miami-Dade. We evaluated the association between vitamin D status and 1) dual task physical performance to understand the link between vitamin D and cognition in the context of mobility; and 2) cardiometabolic risk, measured by galvanic skin response, pulse oximetry, and blood pressure to create a composite score based on autonomic nervous system and endothelial function. Participants completed baseline assessments that included serum levels of vitamin D, anthropometrics, body composition, dual task physical performance and cardiometabolic risk. Surveys to evaluate vitamin D intake, sun exposure, physical activity, and depressive symptoms were completed. Spearman’s correlations, independent t-tests, paired t-tests, repeated measures ANOVAs, and multiple logistic and linear regressions were used to examine the relationship of vitamin D insufficiency (25(OH)D /ml) and sufficiency (25(OH)D ≥30 ng/ml) with determinants of vitamin D status, dual task physical performance variables and cardiometabolic risk scores. Although the proportion of vitamin D insufficient individuals was lower when compared to the prevalance of the general United States elderly population, it was still common in healthy community-dwelling older adults living in Miami-Dade County, especially among Hispanics. Factors that affected skin synthesis (ethnicity, and sun exposure), and bioavailability/metabolism (obesity) were significant predictors of vitamin D status. Vitamin D insufficiency was not significantly correlated with worse dual task physical performance; however, cognitive performance was worse in the vitamin D insufficient group. Our results suggest a relationship of vitamin D insufficiency with executive dysfunction, and support an association with cardiometabolic risk using an innovative electro-sensor complex, possibly by modulating autonomic nervous system activity and vascular function, thus affecting cardiac performance.

ABSTRACT It has been widely recognized that microRNAs are involved in nearly all cellular processes that have been investigated and contribute to a variety of diseases including cancer. Our prior studies demonstrated the depletion of one-carbon metabolism related B-vitamins, including folate, vitamin B2, B6 and B12, induced a genomic DNA hypomethylation and an elevation of the tumorigenic Wnt signaling in mouse colonic epithelium. The present study aimed to define whether microRNAs serve as mediators between these B-vitamins and the Wnt signaling, and thereby influence intestinal tumorigenesis. MicroRNA expression profiles were measured using miRNA microarray and real-time PCR on colonic epithelial cells from Apc1638N mice fed with diets deplete or sufficient in those B-vitamins. In silico bioinformatic analysis were performed to predict microRNA gene targets within the Wnt signaling cascade. Out of 609 microRNA examined, 18 microRNAs were found to be either significantly (p < 0.05) or mildly (p < 0.10) differentially expressed in the colonic epithelium of mice fed the depleted diet when compared to the counterpart. Bioinformatic prediction of microRNA gene targets identified 40 genes within the Wnt pathway to have homology with microRNA seed sequences within their 3’-UTR or protein coding sequence. Of the 6 genes tested for experimentally target validation, the expression of Sfrp1 was shown to be significantly inhibited (p < 0.05) whereas β-catenin was shown to be significantly elevated (p < 0.05) with alterations of others in a fashion indicating the activation of Wnt signaling. These findings indicate that microRNAs may constitute a mechanism by which one-carbon B-vitamin depletions regulate the Wnt signaling pathway and thereby inform intestinal tumorigenesis.

Adipose tissue inflammation has an impact on liver health and it has been demonstrated that chronic alcohol consumption leads to the expression of pro-inflammatory markers in the adipose tissue. A thorough characterization of alcohol-induced adipose inflammation is lacking, and is important to understand in order to identify immune-related mechanisms that drive this phenomenon. Current therapeutic regimens for alcoholic liver disease are ineffective. It is critical to understand how other organs influence liver injury in this disease when developing novel and effective therapies in the future. Alcoholic liver disease exhibits a sexual dimorphism; women are more susceptible to liver injury than men and the same paradigm exists in rodent models. Here, I demonstrate that female mice have greater alcohol-induced adipose tissue inflammation than male mice, evidenced by greater expression of pro-inflammatory cytokines and cell markers. Further, female mice also exhibit higher expression of toll-like receptor genes in the adipose tissue, suggesting a potential role for the innate immune system in alcohol-induced adipose inflammation. Toll-like receptor 4 (TLR4) has been demonstrated to drive inflammation in both the liver and adipose tissue. I used both germline and conditional knockouts of Tlr4 to characterize alcohol-induced changes in the immune cell composition of adipose tissue. Alcohol increased the number of pro-inflammatory adipose tissue macrophages. This macrophage phenotype switching is partially dependent on TLR4; germline, but not myeloid-specific, Tlr4-deletion prevents macrophage phenotype switching. Overall, my work demonstrates that alcohol-induced adipose tissue inflammation is related to liver injury and that TLR4 contributes to adipose macrophage phenotype switching.

Metabolic disorders are commonly associated with obesity, a condition where excess caloric intake leads to massive adipose tissue (AT) expansion and eventual dysfunction. When adipose tissue loses its ability to store excess energy properly, lipids accumulate in non-adipose tissues such as liver, and muscle. This ectopic lipid deposition is a significant risk factor in the development of a collection of disorders described as metabolic syndrome. While metabolic syndrome is typically linked with obesity, patients who have an inability to develop adipose tissue depots (lipodystrophy) develop similar clinical outcomes. There is evidence that aberrant mTORC1 signaling may occur in both settings, and may be a factor that contributes to adipose dysfunction. I find that adipocyte specific loss of Raptor, a key mTORC1 subunit, leads to progressive lipoatrophy, and associated metabolic dysfunction including AT inflammation, hepatosteatosis, and insulin resistance. Interestingly, inhibition of autophagy, a pathway upregulated during Raptordeletion, prevents lipoatrophy but does not protect from ectopic lipid deposition and AT inflammation. These results suggest that outputs of mTORC1 in adipocytes individually regulate adipocyte storage capacity, and AT health. Furthermore, ablation of the amino acid sensing RagGTPases, thought to be necessary for mTORC1 activity, does not phenocopy Raptor KO, suggesting RagGTPase independent functions of mTORC1 in adipocytes. RagA/B deletion, however, did consistently increase Ucp1 expression in WAT, indicating a possible noncanonical role of the Rags in regulating Ucp1. Overall, these studies advance our understanding of regulation of adipose tissue metabolism, and shed light on previously unstudied nutrient specific signaling pathways in adipocytes.

Obesity and diabetes are major public health problems facing the world today. Extending our understanding of adipose tissue biology, and how it changes in obesity, will hopefully better equip our society in dealing with the obesity epidemic. Macrophages and other immune cells accumulate in the adipose tissue in obesity and secrete cytokines that can promote insulin resistance. Adipose tissue macrophages (ATMs) are thought to originate from bone marrow-derived monocytes, which infiltrate the tissue from the circulation. Much work has been done to demonstrate that inhibition of monocyte recruitment to the adipose tissue can ameliorate insulin resistance. While monocytes can enter the adipose tissue, we have shown here that local macrophage proliferation may be the predominant mechanism by which macrophages self-renew in the adipose tissue. We demonstrated that two cell proliferation markers, Ki67 and EdU, can be readily detected in macrophages isolated from adipose tissue of both lean and obese mice. These analyses revealed that 2-4% of ATMs in lean and 10-20% of ATMs in obese mice express the proliferation marker Ki67. Importantly, Ki67+ macrophages were identified within the adipose tissue in crown-like structures. Similarly, a 3-hour in vivo pulse with the thymidine analog EdU showed that nearly 5% of macrophages in epididymal adipose tissue of ob/ob mice were in the S-phase of cell division. Interestingly, obesity increased the rate of macrophage proliferation in adipose tissue but did not affect macrophage proliferation in other tissues. We also used clodronate liposomes to deplete circulating monocytes in obese mice. Surprisingly, monocyte depletion for a total of at least 80 hours did not cause a decrease in ATM content in adipose tissue. Prolonged exposure of mice to EdU in drinking water revealed that approximately half of the ATMs in the epididymal fat pads of ob/ob mice had proliferated locally within 80 hours. Amazingly, these rates were the same with or without monocyte depletion, meaning that the proliferating cells were not freshly recruited monocytes. Overall, these results suggest that local proliferation unexpectedly makes a major contribution to maintaining the large population of macrophages present in the obese adipose tissue in the steady state. This suggests that increased rates of local macrophage proliferation may also be partly responsible for the massive increase in ATM content that occurs in obesity. This information could have implications for future therapeutic strategies in the management of diabetes.

No description available.

Adult women bear a disproportionate burden of overweight and obesity in Sub-Saharan Africa (SSA). Precise information to understand disease distribution and assess determinants is lacking. Therefore, this dissertation aimed to: (i) analyze the prevalence of adult female overweight and obesity combined in lower-level administrative units; (ii) analyze the effect modification of educational attainment and age on the association between household wealth and adult female overweight and obesity; (iii) synthesize qualitative research evidence to describe contextual factors contributing to female overweight and obesity at different life stages. Bayesian and logistic regression models were constructed with Demographic and Health Survey (DHS) data to respectively estimate the prevalence of overweight and obesity and assess the interaction of education on the association between household wealth and overweight. The synthesis of qualitative research studies was conducted in accordance with PRISMA guidelines and findings were grouped by themes. Prevalence estimates revealed heterogeneity at second-level administrative units in the seven SSA countries examined, which was not visible in first-level administrative units. The combined prevalence of overweight and obesity ranged from 7.5 – 42.0% in Benin, 1.4 – 35.9% in Ethiopia, 1.6 – 44.7% in Mozambique, 1.0 – 67.9% in Nigeria, 2.2 - 72.4% in Tanzania, 3.9 – 39.9% in Zambia, and 4.5 - 50.6% in Zimbabwe. Additionally, education did not have a statistically significant modifying effect on the positive association between household wealth and overweight in the 22 SSA countries eligible for the study. Body shape and size ideals, barriers to healthy food choices and physical activity were key themes in the research synthesis encompassing four SSA countries. Positive symbolism, including beauty, was linked to overweight and obesity in adult women. Among adolescents, although being overweight or obese was not accepted, girls were expected to be voluptuous. Body image dissatisfaction and victimization characterized the experiences of non-conforming women and girls. Barriers to healthy nutrition included migration and the food environment. Whereas, barriers to physical activity included ageism. While additional work is encouraged to validate the prevalence estimates, overweight and obesity interventions must consider whether the determinants identified in this study are relevant to their context to inform improved outcomes.