O presente trabalho teve como objetivo estudar a psicodinâmica das Representações Sociais (RS) de endocrinologistas de hospital público sobre obesidade, identificando-as e buscando detectar seu inconsciente relativo, ou seja, a lógica emocional segundo a qual se estruturam. Foram realizadas 10 (dez) entrevistas com médicos endocrinologistas de rede pública, (05 do sexo feminino e 05 do sexo masculino) com idade variável de 28 a 44 anos de idade. O tempo de especialização variou de dois a dezoito anos. As entrevistas foram semi-estruturadas, no sentido de haver uma pré-estrutura mínima, permitindo ao entrevistado espontaneidade e fluência de expressão. Usou-se técnicas encobertas, com perguntas gerais e abrangentes. Desejou-se que o tema - obesidade - surgisse espontaneamente. O tratamento dos dados foi de acordo com o referencial psicodinâmico, numa abordagem qualitativa. Conclui-se que o médico é o intérprete das ideologias socialmente circulantes a respeito da obesidade. Suas condutas são pautadas pelas características de personalidade, pelas informações científicas, e pela influência midiática / Not informed by the author

O GLUT4 (gene Slc2<font face=\"symbol\">a4) é responsável pela captação de glicose sob estímulo insulínico, e alterações na sua expressão se relacionam à resistência à insulina (RI). Variações na concentração de estradiol (E2) estão relacionadas a RI e menor expressão deste transportador, mecanismo que pode ser mediado pelo fator transcricional NF<font face=\"symbol\">k-B, um repressor de Slc2<font face=\"symbol\">a4. Avaliou-se em células 3T3-L1 a regulação da expressão de Slc2<font face=\"symbol\">a4/GLUT4, a atividade de ligação de NF<font face=\"symbol\">k-B e a captação de glicose pelo E2 e o papel de ESR1 (isoforma 1 do receptor de E2) nesta regulação. Tratou-se as células por 1 dia com E2 e PPT (agonista de ESR1). O PPT aumentou a expressão de Slc2<font face=\"symbol\">a4/GLUT4 na ausência ou presença de E2 bem como a captação de glicose e diminuiu a atividade de ligação de NF<font face=\"symbol\">k-B. Os resultados apresentados demonstram que o E2, atuando via ESR1 aumenta a expressão de Slc2<font face=\"symbol\">a4/GLUT4, efeitos estes parcialmente mediados por NF<font face=\"symbol\">k-B, resultando em alteração na captação de glicose. / GLUT4 (gene Slc2<font face=\"symbol\">a4) is responsible by insulin-induced glucose uptake and alterations in its expression are related to insulin resistance (IR). Variability in estradiol levels (E2) is related with IR and lower glucose transporter expression and this mechanism can be mediated by transcriptional factor NF<font face=\"symbol\">k-B, which is an Slc2<font face=\"symbol\">a4 repressor. Our aim was to evaluate in 3T3-L1 adipocytes the role of E2 in Slc2<font face=\"symbol\">a4/GLUT4 expression, NF<font face=\"symbol\">k-B binding activity and glucose uptake as well as the ESR1 (estrogen receptor 1) role in this regulation. For this, 3T3-L1 cells were treated for 1 day with E2 and PPT (ESR1-agonist). PPT enhanced Slc2<font face=\"symbol\">a4/GLUT4 expression in the absence or presence of E2 as well as the glucose uptake and decreased NF<font face=\"symbol\">k-B binding activity. Our results show that E2 increases Slc2<font face=\"symbol\">a4/GLUT4 expression via ESR1 and this effect is partially mediated by NF<font face=\"symbol\">k-B, and allow parallel changes in glucose uptake.

<p> Diabetes has become a longstanding public health challenge around the world. Over the last 3 decades, the number of people with Type II diabetes (T2DM) has grown to an epidemic level in Canada. Prior research indicated African immigrants residing in Ontario, Canada experienced a 2&ndash;4 times higher prevalence of T2DM than Canadian-born individuals. The social determinants of health theoretical framework guided this study assessing the relationship of the risk factors with T2DM. A quantitative, cross-sectional design was employed using the 2007&ndash;2014 Canadian Community Health Survey data. The random sample included 1,526 African immigrants residing in Ontario, Canada. Descriptive, bivariate, and multivariate analyses were conducted. Study results indicated a lower income level, high acculturation index, and a country of origin significantly associated with T2DM in adjusted and unadjusted binary logistic regression models. Using the results of the study to create a valid and reliable acculturation measurement scale and a cultural-based design of public health programs, increase awareness, and change policies that consider the needs of the sample populations could lead to positive social change by curbing the prevalence of T2DM observed in African immigrants residing in Ontario and Canada at large.</p><p>

Maintaining redox homeostasis is crucial for normal cellular functions. Electron leak by the cytochrome P450 enzymes renders steroidogenic tissues acutely vulnerable to redox imbalance and oxidative stress is implicated in several potentially lethal adrenal disorders. This thesis aims to further delineate the role of oxidative stress in triple A syndrome and familial glucocorticoid deficiency (FGD). Triple A syndrome incorporates adrenal failure and progressive neurodegenerative disease. The AAAS gene product is the nuclear pore complex protein ALADIN, of unknown function. Patient dermal fibroblasts are sensitive to oxidative stress, with failure of nuclear import of DNA repair proteins and ferritin heavy chain protein. To provide an adrenal and neuronal-specific disease model, I established AAAS-knockdown in H295R human adrenocortical tumour cells and SH-SY5Y human neuroblastoma cells. This had effects on cell viability, exacerbated by hydrogen peroxide treatment. Redox homeostasis was impaired in AAAS-knockdown H295R cells, with depletion of key components of the steroidogenic pathway and a significant reduction in cortisol production, with partial reversal following treatment with N-acetylcysteine. Mutations in the mitochondrial antioxidant, nicotinamide nucleotide transhydrogenase (NNT), causing FGD, have recently highlighted the importance of redox regulation in steroidogenesis. I investigated seven individuals from a consanguineous Kashmiri kindred, mutation negative for known causes of FGD. A stop gain mutation, p.Y447* in TXNRD2, encoding the mitochondrial selenoprotein thioredoxin reductase 2 segregated with the disease trait; with complete absence of the 56 kDa TXNRD2 protein in patients homozygous for the mutation. TXNRD2-knockdown led to impaired redox homeostasis in H295R cells. This is the first report of a homozygous mutation in any component of the thioredoxin antioxidant system leading to inherited disease in humans.

Enteroendocrine cells (EEs) are critical components in our bodies' ability to maintain homeostasis after eating a meal. Hormones released by EEs mediate processes ranging from triglyceride processing to glucose balance to hydration maintenance. Despite their importance, they remain relatively poorly understood in terms of development as well as function. Drosophila melanogaster is a promising model in which to study EEs. I performed a gene expression assay in Drosophila, and found 19 transcription factors likely to be specific to EEs. I am in the process of analyzing their mutant phenotypes in the fly midgut. Additionally, by a limited screen of the homologs to the fly EE-specific transcription factors, I was able to identify two candidates for novel transcriptional regulators involved in EE specification or functionality. I will be analyzing the mutant phenotypes for these two genes, Lmx1a and Lmx1b, in addition to a third mutant Prox1, chosen because of the strong phenotype of its homologous gene's knockdown in the fly. I am hoping I will be able to add to the ever-growing body of knowledge in reference to enteroendocrine development. Additionally, several assays were performed on flies lacking EEs. I found that flies without EEs lay significantly fewer eggs, and have apparent defects in oviposition and defecation. I will outline several experiments to continue the phenotype analysis of flies lacking EEs.

Pancreatic beta cell specification is a complex process, requiring proper function of numerous transcription factors. Nkx2.2 is a transcription factor that is crucial for beta cell formation, and is expressed early and throughout pancreatic development. Nkx2.2-/- mice display complete loss of the beta cell lineage and defects in the specification of other endocrine cell types, demonstrating the importance of Nkx2.2 in establishing proper endocrine cell ratios. Recent studies have also demonstrated a role for Nkx2.2 within the mature beta cell to maintain identity and function. This thesis work investigated the timing of pancreatic beta cell specification and the mechanism of this process. In these studies, Nkx2.2 was ablated specifically within the Ngn3-expressing endocrine progenitor population in vivo. These mice displayed defects similar to Nkx2.2-/- mice. Surprisingly, the disruption of endocrine cell specification did not require loss of expression of multiple essential transcription factors known to function downstream of Nkx2.2, including Ngn3, Rfx6, and NeuroD1. While these factors are all necessary for beta cell specification, their preserved expression did not rescue beta cell formation. ChIP-Seq analyses also revealed co-occupancy of Nkx2.2, Rfx6, and NeuroD1 near endocrine-related genes, suggesting Nkx2.2 may cooperate with its downstream targets to regulate beta cell fate. These results have revealed a unique requirement for Nkx2.2 during a critical window of beta cell development. In addition, the role of a conserved domain of Nkx2.2, the specific domain (SD), was assessed using Nkx2.2SDmutant mice. Transcriptional profiling of Nkx2.2SDmutant endocrine progenitors revealed a critical role for the SD domain in regulating the transcription of endocrine fate genes early in the process of endocrine differentiation. In addition, beta cell-specific deletion of the Nkx2.2 SD domain resulted in hyperglycemia, glucose intolerance and dysregulation of beta cell functional genes. This suggests the SD domain is important for mediating Nkx2.2 function within the beta cell to maintain glucose homeostasis. Together, these results have elucidated a critical developmental window for beta cell specification and demonstrated an essential role for Nkx2.2 and specifically its SD domain in this process. Furthermore, these studies suggest that beta cell transcription factors may also regulate endocrine fate in a combinatorial manner, and exert changes within the endocrine progenitor lineage. These findings have provided us with a better understanding of in vivo pancreatic development, and will improve current research efforts to differentiate beta cells in vitro from hPSCs.

Pancreatic beta-cells regulate blood glucose by secreting insulin in response to nutrients. The development of Type 2 Diabetes (T2D) is characterized by elevated insulin secretion in the fasted state and a failure to adequately respond to nutrient influx, particularly glucose. Current dogma states that insulin resistance is the initiating event in the development of T2D, with compensation by beta-cells necessary to maintain glucose homeostasis. An alternative model, which will be a central theme throughout this thesis, is that hypersecretion of insulin is the initiating and sustaining event in the development of T2D. The underlying cause of insulin hypersecretion is unclear. Determining this is important in order to test this alternative model as a viable target for prevention and treatment of T2D. Because of the association between obesity and hyperinsulinemia, we hypothesized that exposure of the β-cell to high levels of nutrients stimulates insulin hypersecretion. We found that chronic incubation of β-cells in high glucose and/or oleate, which mimics nutrient conditions in obesity, lowered the half-maximal response for glucose to stimulate insulin secretion. The degree of the left-shift correlated with lipid stores. We determined that heightened sensitivity of granule exocytosis to Ca2+ was driving this left-shift. Thus glucose, while not necessarily abnormal in obesity, may cause hypersecretion of insulin due to altered sensitivity of the β-cell to this secretagogue. Iron stores are increased in obesity and are predictive of T2D development. We found that iron acutely stimulated both basal and glucose-stimulated insulin secretion (GSIS) in a reactive oxygen species dependent manner. Interestingly, iron did not increase insulin secretion via Ca2+ influx. Thus, both iron and glucose/oleate induce insulin hypersecretion via an aspect of the triggering pathway that is not Ca2+, the putative triggering signal. Previous work in our laboratory documented that exogenous mono-oleoyl-glycerol, an endogenous lipid signaling molecule and food additive, increases basal insulin secretion. We found that inhibition of monoacylglycerol lipase, which increases cellular monacylglycerol species, reduced GSIS, possibly via a reduction in long-chain CoA. Collectively, our works supports the hypothesis that chronic exposure to high nutrient levels drives insulin hypersecretion in obesity. / 2018-06-15T00:00:00Z

Leung Ling Yan. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 218-259). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Two distinct nonapeptide systems, consisting of the vasotocin- and oxytocin-related peptides have evolved in vertebrates, and their role in male reproduction is well-described in mammals. In contrast, their comparative role in reproduction in basal vertebrate species, and teleost fishes in particular, has not been investigated in great detail. Using two cyprinid species, the zebrafish (D. rerio) and the goldfish (C. auratus), I address the hypothesis that the teleost nonapeptides vasotocin and isotocin stimulate male cyprinid reproductive physiology by affecting central neuronal and/or peripheral endocrine pathways. To test this hypothesis in zebrafish, an indeterminate breeder, I conducted pharmacological inhibition experiments employing vasotocin and isotocin-specific antagonists in males, a treatment predicted to inhibit reproductive success in mating trials. Because nonapeptides can act both as central peptide neuromodulators and as secreted hormone, I further quantified indices of male courtship behavior (nudging, circling and chasing) and major androgens (testosterone and 11-keto-testosterone) as key endocrine indices of the male reproductive axis. Together, these experiments revealed a dose-dependent, differential inhibition of spawning success, with significant reductions (-65%) in egg fertilization rate observed in pairs in which males had been i.p. injected with 5 ng/g vasotocin and significant reductions (-79%) observed at 500 ng/g i.p injected isotocin. In either case, these partial inhibitions of reproductive success were correlated with significant decreases in specific indices of male courtship behavior, but not endocrine indices, suggesting that individual nonapeptides mediate their effects via central modulation of behavioural neurocircuits. Interestingly, a co-administration of vasotocin and isotocin antagonists completely abolished reproductive success, however this effect was neither correlated with decreases in male courtship behavior, nor endocrine indices, suggesting a separate mode of action, possibly at the level of male pheromone release. To further probe the role of nonapeptides in male zebrafish reproduction, I subsequently tested the hypothesis that nonapeptide systems are acutely activated by key reproductive cues, specifically the releaser pheromone PGF2α, which serves as a chemoattractant and acutely stimulates male reproductive behavior in male cyprinids. Using a chemoattractant choice assay in conjunction with immunohistochemistry and gene expression approaches, I determined whether male zebrafish are attracted to pheromonal cues and acutely activate isotocinergic neurons in the short term and/or regulate nonapeptide gene expression in the longer term. My results show that individual male zebrafish are attracted to PGF2α in an acute choice test. Furthermore, an increase in p-ERK immunoreactivity, a marker of neuronal activation, was observed in the olfactory bulb 10 min following exposure, suggesting a specific response to the pheromone compared to EtOH vehicle. However, no co-localization of p-ERK and IT-positive perikarya was observed in the preoptic area (POA), refuting the hypothesis that PGF2α exposure acutely activates isotocinergic neurons in zebrafish. Analysis of whole brain relative mRNA transcript abundance revealed that PGF2α exposure time-dependently regulates whole brain isotocin, but not vasotocin transcript abundance, suggesting secondary longer-term effects of PGF2α exposure on the isotocinergic system. Using an analogous experimental approach, I further tested the hypothesis that nonapeptides stimulate male reproductive physiology in goldfish, a determinate breeder. Sexually mature male goldfish pretreated with saline or vasotocin or isotocin antagonists were exposed to saline or PGF2α-injected stimulus females and male courtship behavior (chasing, circling), endocrine indices (circulating testosterone) and milt release were quantified. Both nonapeptide antagonists reduced strippable male milt quantity in response to PGF2α-injected females, suggesting a neuronal or hormonal action of both nonapeptides on goldfish milt release. Together, I show that nonapeptides contribute to male reproductive physiology in two species of cyprinids with different reproductive tactics. However, the mode of action may differ from one species to another, with evidence suggesting that nonapeptides play a role in the regulation of reproductive behavior and, possibly, male pheromone, release in zebrafish, while effects on male goldfish seem to be exclusively related to the release of milt. Future studies should compare other teleost species with specific reproductive biology and focus on the gonadal roles of nonapeptides in sperm maturation and/or release.

A endocrinologia reprodutiva do muriqui do sul B. arachnoides foi avaliada em quatro fêmeas adultas pela dosagem de metabólitos fecais de estrógenos e em quatro machos adultos e um macho subadulto pela dosagem de metabólitos de testosterona e glicocorticóides durante um período de onze meses em duas diferentes condições restritivas, ilha de 600m2, Curitiba (PPC) e viveiro (15,40x5,85x4,70m) Rio de Janeiro (CPRJ). As fêmeas apresentaram grande variação individual nas concentrações de estrógenos e progestinas fecais ao longo do período de estudo, três não apresentaram atividade ovariana no período de outubro-dezembro e apenas uma apresentou atividade durante todos os períodos amostrados. Mesmo com níveis baixos de esteróides as fêmeas apresentaram comportamento perceptivo e cópulas. Os machos do PPC apresentaram níveis significativamente mais altos de glicocorticóides e níveis significativamente mais baixos de testosterona do que os machos do CPRJ (p<0,05) apresentaram. O macho subadulto apresentou níveis significativamente mais baixos para metabólitos de testosterona. Nos machos as cópulas ocorreram próximo às elevações das concentrações de testosterona. Em três situações grandes elevações dos níveis de glicocorticóides fecais puderam ser relacionadas a situações estressantes. Nosso estudo comprovou a eficácia do método empregado para monitoramento reprodutivo bem como para avaliar situações estressantes. / The reproductive endocrinology of the southern muriqui (Brachyteles. Arachnoids) was evaluated through the dosage of fecal metabolites steroids for 04 adult females and fecal metabolites of testosterone and glucocorticoids for 04 adult males and 01 subadult male. The study was conducted over an eleven month period at two environmental conditions: a) an island of 600 m2, with natural vegetation, at Curitiba Zoo (PPC) and b) a large cage of 15,40X5,85X4,70m at Rio de Janeiro Primatological Centre (CPRJ). It was observed that females had large strogen interindividual variation and fecal progestins: three females did not show ovarian activity over a partial period of the study, while ovarian activity was observed for all sample periods for one female. Despite the detection of low levels of steroids, proceptive behaviour and copulations were observed. The PPC males showed significant levels of glicorticoids and testosteorne when compared to the CPRJ males (p<0.05). The subadult male exhibited the lowest level of testosterone metabolites and those differences were significant when compared to the adult males (p<0.05). For all males, copulations occurred when testosterone levels were highest and peaks of glucorticoids were linked to stressfull situations. This study have shown that the method used was effective for reproductive monitoring as well as for evaluating stressfull situations.