It is well established that exposure to adverse environments in early life including both maternal under and over-nutrition predisposes individuals to similar adverse traditionally adult onset diseases such as the metabolic syndrome. Epidemiological observations and animal models have highlighted that early life exposure to maternal under-nutrition has a detrimental effect on offspring kidney health. The prevalence of chronic kidney disease has increased rapidly in recent years, concurrently with the growing obesity epidemic. Obesity is now prevalent in all age groups within the population including women of child-bearing age. Despite this, the effect of early life exposure to maternal obesity on long-term kidney health has not been investigated in humans. Studies in animals have demonstrated that exposure to early life under-nutrition programs the offspring kidney. Offspring exposed to maternal calorie restriction or a low protein diet typically display a reduced number of nephrons and increased glomerular areas. No studies to date have investigated the effect of maternal obesity on early life kidney and glomerular morphology. To address this, as part of this thesis, kidney morphology was assessed at weaning in male mice exposed to maternal diet-induced obesity throughout gestation and lactation. There was no effect of maternal diet on the number of nephrons counted within a distinct region in the offspring kidneys. However, glomerular density was decreased and glomerular area was increased in offspring exposed to maternal obesity. Alterations in renal morphology in early life have been linked to hypertension and renal disease in adulthood in both epidemiological and animal studies. Therefore, a second aim of this thesis was to assess blood pressure, renal function and markers of renal damage in offspring exposed to maternal obesity throughout the life-course. Post-pubescent male offspring (8 weeks of age) exposed to maternal obesity displayed increased blood pressure but no signs of renal dysfunction or damage. However, by six months of age offspring exposed to maternal obesity had increased glomerulosclerosis and tubulointerstitial fibrosis. The obesity epidemic is attributed to a shift in behaviours towards consumption of energy dense foods and inactivity. In addition, evidence from human and animal studies has highlighted that exposure to maternal obesity primes offspring to prefer sugary and fatty foods and to consume more calories. As such, offspring exposed to maternal obesity are likely to encounter an obesogenic environment in later life. A third aim of this thesis was therefore to determine the effect of maternal obesity in combination with a post-weaning obesogenic diet on offspring kidney health. To address this aim, offspring either exposed to an obesogenic diet or control diet throughout pregnancy and lactation were weaned onto either an obesogenic or control diet themselves. Six month old offspring exposed to a post-weaning obesity alone displayed indices of renal dysfunction and damage including glomerulosclerosis and tubulointerstitial fibrosis. Importantly, exposure to maternal obesity exacerbated the renal fibrosis in offspring exposed to a post-weaning obesogenic diet. With the growing prevalence of maternal obesity globally, there is great interest in determining an effective intervention to prevent adverse health outcomes in exposed individuals. The Ozanne laboratory has shown that maternal exercise in obese dams during pregnancy reduces maternal serum insulin and offspring insulin to control levels, highlighting that maternal exercise may be a promising intervention to limit adult-onset diseases in offspring exposed to early life obesity. The final aim of this thesis was to therefore assess the effect of exercise during an obese pregnancy on markers of offspring renal development during late gestation. Gene markers of ureteric bud branching, an important precursor of nephrogenesis, were increased in fetuses exposed to maternal obesity with exercise as opposed to obesity alone. Additionally one of these gene markers correlated negatively with maternal insulin levels. Protein markers indicative of an active ureteric bud branching pathway were also increased in offspring exposed to maternal obesity with exercise. In conclusion, studies conducted in this thesis demonstrate that offspring exposed to maternal obesity show alterations in renal morphology in early life and are predisposed for renal disease in later life, especially when they are challenged with a post-weaning obesogenic diet. Maternal exercise might be an effective intervention to rescue offspring renal morphology and later life health associated with maternal obesity, however this requires further investigation. These results have important implications for future generations within the setting of an ever increasing obesity epidemic and a growing prevalence of chronic kidney diseases.

Corneal Confocal Microscopy (CCM) is a non-invasive imaging technique to quantify small nerve fibre structure in patients with diabetic somatic and autonomic neuropathy and increasingly other metabolic, hereditary, toxic and inflammatory peripheral neuropathies. This thesis establishes that CCM is indeed a powerful imaging technique which can identify early small fibre degeneration and regeneration in relation to the clinical phenotype of subjects with obesity, impaired glucose tolerance and Type1/2 diabetes. We demonstrate a precise relationship between small fibre neuropathy and erectile dysfunction in subjects with Type 1 diabetes. We also demonstrate the utility of CCM in demonstrating relative protection from small fibre damage in Type 1 patients with extreme duration diabetes (medallists) at baseline and over 3 years and repair in patients undergoing simultaneous pancreas and kidney transplantation. This thesis provides further evidence for the utility of CCM as a marker of early small fibre neuropathy by demonstrating nerve damage in subjects with morbid obesity with and without diabetes and explore the mechanisms underlying nerve damage at baseline and repair following bariatric surgery. We also show that CCM can track dynamic changes in small fibre degeneration and regeneration in subjects with impaired glucose tolerance in relation to change in glucose tolerance status and following continuous subcutaneous insulin infusion in subjects with Type 1 diabetes.

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Orientador: Flávia Heloísa dos Santos / Banca: Vânia Cristina Lamônica / Banca: Sandra Leal Calais / Resumo: A obesidade possui alta prevalência no Brasil. É fator de risco para demências, doenças cardiovasculares, cânceres e diabetes, e está associada a transtornos psiquiátricos. A cirurgia bariátrica é uma alternativa para os casos de obesidade mórbida, pois, inibe a progressão de comorbidades. Contudo a literatura é escassa quanto ao funcionamento cognitivo e emocional dos pacientes que vivenciam a rápida redução de peso por meio do processo cirúrgico em contraste com a perda de peso lenta decorrente de reeducação alimentar. O objetivo deste estudo prospectivo foi avaliar o funcionamento emocional e mnemônico de indivíduos obesos, antes e quatro meses depois do emagrecimento. Participaram do estudo 76 voluntários divididos em dois grupos, conforme a fase do tratamento: redução de peso por meio de cirurgia bariátrica (RPCB, N=40) ou redução de peso preparatória para bariátrica (RPPB, N= 36), avaliados por meio de testes cognitivos para memória episódica e operacional, bem como escalas comportamentais. Os instrumentos utilizados para a avalição eram os mesmos em ambas as avaliações. O teste t de Student indicou diferença estatística entre a 1ª avaliação e a 2ª avaliação. Houve mudanças mais robustas para o grupo RPCB, que vivenciou o emagrecimento rápido no âmbito comportamental para os âmbitos de depressão, ansiedade, compulsão e obsessão, resiliência e em especial para cinco categorias da escala que medem a qualidade de vida. O grupo RPCB ainda teve melhor desempenho no seguimen... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Obesity has a high prevalence in Brazil. It is a risk factor for dementia, cardiovascular diaseses, cancer and diabetes, and is associated with psychiatric disorders. Bariatric surgery is an alternative for cases for morbid obesity, since it inhibits the progression of comorbidities. However, the literature is scarce regarding the cognitive and emotional functioning of patients who experience rapid weight reduction through the surgical process in constrast to the slow weight loss due to dietary reeducation. The purpose of this prospective study was to evaluate the emotional and mneumonic functioning of obese individuals before and after weight loss. Participants were 76 volunteers divided into two groups, according to the treatment phase: weight reduction through bariatric surgery (RPCB, N = 40) or preparatory weight reduction for bariatric (RPPB, N = 36) evaluated by means of Cognitives tests for episodic and operational memory, as well as behavioral scales. The instruments used for the assessment were the same in both evaluations. Student's test indicated statistical difference between the 1 st evaluation and the 2nd evaluation. There were more robust changes for the RPCB group, which experienced rapid weight loss in the behavioral setting for the areas of depression, anxiety, compulsion and obsession, resilence and in particular for five categories of the scale that measures the quality of life. The RPCB group still had better performance in the follow-up regarding operational memory capacity, verbal memory and attention assessed by the Span Span test. The improvement of the RPPB group in the 2nd evaluation may be associated to the multidisciplinary follow-up as preparation for CB. The study shows, therefore, that CB produced men-mentics and emotional benefits to the patients / Mestre

Objective: To evaluate if fruits and vegetables consumption is associated with overweight and obesity in Peruvian adults and as to describe the sociodemographic profi le of the people with overweight and obesity. Subjects and methods: Populationbased study that used data from the National Demographic and Health Survey (DHSENDES) performed in the 25 regions of Perú. The outcomes were overweight and obesity assessed using the Body Mass Index, whereas the exposure variable was the fruit and vegetable consumption evaluated by self-report during the last seven days. Poisson regression models adjusted by potential confounders were used to evaluate associated factors with overweight and obesity, as well as the association of interest, reporting prevalence ratios (PR) and 95% confi dence intervals (95%CI). Results: Data from 4,641 participants, mean age 37.1 years (SD: 11.8) and 53.6% women, were analyzed. Only 220 (4.8%; 95%CI 4.1%-5.4%) individuals reported a fruit and vegetable consumption of ≥5 portions per day, whereas 1,818 (39.2%; 95% CI 37.8%-40.6%) had overweight and 865 (18.6%; IC95% 17.5%-19.8%) presented obesity. Factors associated with overweight and obesity included gender, age, education level, socioeconomic level, marital status, and hypertension diagnosis. No association was found between a greater fruit and vegetable consumption and overweight (p=0.98) or obesity (p=0.99). Conclusions: No evidence of association between overweight and obesity with fruit and vegetable consumption was found. Only 1 out of 20 individuals reported consuming the recommended amount of fruit and vegetables per day, whereas 60% had overweight and obesity. / Revisión por pares

Chronic inflammation is associated with a dysregulation of the immune response. Inflammation is also associated with decreased reproductive capacity in women, however an exact mechanism has yet to be identified. Physiological states such as obesity and disease states such as endometriosis are both associated with chronic inflammation, an insufficient immune response, and infertility in women; therefore these two conditions serve as excellent models to study the effects of inflammation on reproductive function. Early indications of inflammation may aid in early detection of immune dysregulation associated with different physiological and pathological conditions. One way to measure immune balance between pro- and anti-inflammatory states in the female urogenital tract is by observing changes in the bacterial species that populate the mucosal surface. Commensal bacteria that make up the microbiome play a critical role in the development and maturation of the immune system in humans. Because these microbes and the host’s immune system are constantly influencing each other, several immunological conditions and disease states have been shown to have an altered microbial profile than that of healthy individuals. The goal for this study was to examine how triggers of inflammation alter the peripheral immune response, urogenital microbial communities, and reproductive function. Specifically, our aims were to 1) use an animal model of obesity to determine whether this physiological model of inflammation decreases immune protection of the urogenital microbiome and alters ovarian function; and 2) use endometriosis as a disease model of inflammation to assess whether the presence of endometriotic lesions alters urogenital microbial dynamics, and also whether surgical intervention restores commensal bacterial profiles to that of a non-disease state. The results of this study revealed that the urogenital microbial community dynamics were altered in both our obese and disease models of inflammation compared to their respective controls. In the obesity study, we also found that our obese model had decreased markers of inflammation, which may be due to dietary composition. In the endometriosis study, we observed that patients with disease had a unique urogenital microbiome profile and that surgery had an effect in shifting the urogenital microbial profiles of several patients. Overall, our long-term goal is to determine whether the urogenital microbiome is a good indicator of immune stress and if alternative therapies can alter microbial community dynamics, eliminate immune stress associated with disease. Ultimately we are looking at the microbiome as an indicator of overall immune health and implementing alternative diagnostic and treatment strategies to immune diseases that affect reproductive function in women.

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Made available in DSpace on 2014-06-11T19:32:12Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-02-08Bitstream added on 2014-06-13T20:23:13Z : No. of bitstreams: 1 seiva_fr_dr_botfm.pdf: 3896394 bytes, checksum: 25ac2f0fac725c9d2ad1833b75059c15 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / O envelhecimento populacional mundial é considerado um processo relativamente novo na história da humanidade e está associado a melhorias na área de prevenção e tratamento na saúde publica, bem como à diminuição da taxa de fertilidade, elevando rapidamente assim, o número de pessoas com mais de 60 anos em vários países ao redor do mundo (ACEVEDO, 1998). Embora esse aumento possa ser visto como um ponto positivo, ainda é preciso alcançar também melhorias na qualidade de vida entre as pessoas idosas. Comorbidades e complicações advindas de processos que acompanham o envelhecimento, tais quais, diabetes, sobrepeso e obesidade, hipertensão arterial, doenças neurodegenerativas e principalmente complicações cardiovasculares, ainda são problemas, que além de onerarem o sistema único de saúde, elevam a taxa de mortalidade na população senil. GH, ou hormônio de crescimento, produzido e secretado na hipófise anterior, atua direta ou indiretamente, via IGF-I (hormônio de crescimento insulina-símile) produzido principalmente no fígado, levando ao crescimento longitudinal ósseo, muscular e das cartilagens. O GH também é um importante mediador de algumas vias metabólicas, como a oxidação lipídica. Em relação ao metabolismo dos carboidratos, o GH apresenta efeitos antagônicos aos efeitos clássicos da insulina, sendo por muitos, considerado um hormônio diabetogênico (COPELAND et al, 1990; HAJIMA et al, 2005) / Life expectancy is increasing in world population and with it, the incidence of public health problems such as obesity and cardiac alterations. Because growth hormone (GH) concentration is referred to be decreased in aging conditions, a question must be addressed: what is the effect of GH on aging related adverse changes? To investigate the effects of GH on cardiac energy metabolism and its association with calorimetric parameters, lipid profile and oxidative stress in aged and obese rats, initially 32 male Wistar rats were divided into two groups (n=16):(C) given standard-chow and water;(H) given hypercaloric-chow and receiving 30% sucrose in its drinking water. After 45 days, both C and H groups were divided into two subgroups (n=8):(C+PL) standard-chow, water and receiving saline subcutaneously;(C+GH) standard-chow, water and receiving 2 mg/kg/day rhGH subcutaneously;(H+PL) hypercaloricchow, 30% sucrose, receiving saline subcutaneously;(H+GH) hypercaloric-chow, 30% sucrose, receiving rhGH subcutaneously. After 30 days, C+GH and H+PL rats had higher body mass index, Lee-index, body fat content, percent-adiposity, serum triacylglycerol, cardiac lipid-hydroperoxide and triacylglycerol than C+PL. Energy-expenditure (RMR)/body weight, oxygen consumption and fat-oxidation were higher in H+GH than in H+PL. LDLcholesterol was highest in H+GH rats, whereas cardiac pyruvate-dehydrogenase and phosphofrutokinase activities were higher in H+GH and H+PL rats than in C+PL. In conclusion, the present study brought new insights on aging and obesity, demonstrating for the first time that GH therapy was harmful in aged and obesity conditions, impairing calorimetric parameters, lipid profile and oxidative stress. GH was disadvantageous in old rats, having undesirable effects on cardiac energy metabolism

Schizophrenia is a severe and debilitating disorder, primarily treated with antipsychotic medications. Weight gain is a serious side-effect associated with most second generation antipsychotic drugs such as clozapine. The mechanism behind clozapine-induced weight gain remains poorly understood, but changes in eating behaviour and energy homeostasis may be involved. Recently, genome-wide association studies have identified a number of genetic variants associated with obesity risk; however the effects of these risk variants on clozapine-induced weight gain have not been investigated. This doctoral thesis focused on the following research questions: (1) Does schizophrenia share a genetic link with obesity? (2) Can various antipsychotics alter the expression of obesity-related genes? (3) What is the initial signalling event by which clozapine could induce a change in mRNA expression of the obesity-related genes? The major findings from this work included that there was no demonstrable association between obesity-related variants and schizophrenia, and that low and intermediate doses of clozapine (0.125 μg/ml and 0.25 μg/ml) induced changes in mRNA expression of a panel of obesity-related genes in U937 cells. This effect was not observed in cells treated with haloperidol. However, the mRNA expression of most obesity-related genes tested was also altered by treatment with olanzapine in most obesity-related genes tested but only in one gene when treated with risperidone. Treatment with 5-HT promoted an increase in mRNA expression of some obesity-related genes, which was similar to the treatment with 0.25 μg/ml clozapine although this effect was not apparent with a combination of clozapine and 5-HT. Changes in mRNA expression in clozapine-treated cells were likely mediated by the IP3 signalling pathway. In conclusion, the mechanism behind weight gain in patients treated with either clozapine or olanzapine is multi-factorial: this study suggests that there may be an additional risk factor that could facilitate antipsychotic-induced weight gain: the altered the mRNA expression of obesity-related genes.

The attentional system has evolved to be proficient at responding to the presence of food cues, particularly to those which are energy dense (Berthoud, 2007). Individuals who pay heightened attention to food stimuli within their feeding environment are likely to be motivated to overeat as a consequence. This current thesis presents 6 experiments which explore the extent to which paying enhanced attention to food cues in the environment influences eating behaviour. Experiment 1 established that individuals who are responsive to the pull of food cues, sensitive to reward and have high disinhibition are at risk of developing obesity. Experiment 2 demonstrated that individuals with high disinhibition were quicker to respond to high calorie food stimuli shown on a visual dot probe task. Whereas experiment 3 indicated that attentional retraining (learning to attend or avoid food stimuli on a visual dot probe task) could successfully manipulate food processing bias and calorie intake. Experiments 4 and 5 investigated the extent to which reward can determine the incentive salience of cues. Novel cues which had been paired with chocolate reward during a training task were found to elicite greater attention both at a behavioural and neurophysiological level. Finally Experiment 6 demonstrated that these trained cues could successfully manipulate craving. These results are discussed in terms of theoretical perspectives of attentional bias and the wider implications for understanding overeating.