Obesity is often associated with multiple other clinical conditions, including hypertension and cardiovascular disease. Currently, more than one-third of the world’s population is classified as obese. Leptin is a neuropeptide that is released from adipose cells and is responsible for reducing appetite and increasing metabolism. Leptin also has a role in the activation of cardiovascular and metabolic pre-sympathetic neurons and has been reported to increase blood pressure and heart rate. Thus, understanding the activation of the autonomic nervous system by leptin has implications in the development and safety of drugs to avoid activation of cardiovascular pre-sympathetic neurons. This is important because a drug that causes an increase in blood pressure or heart rate would not be effective in diminishing cardiovascular-related comorbidities. This study tests the hypothesis that intracerebroventricular leptin activates sympathetic metabolically-related neurons in the hypothalamus. To identify leptin receptor-expressing neurons, we created a colony of transgenic reporter mice expressing tdTomato in the presence of the leptin receptor (ObRb) gene. To determine if treatment with leptin activated sympathetic metabolically-related neurons, we performed neuroanatomical tracer studies in the mice. The metabolically-related neurons were identified by microinjection of green FluoSpheres (505/515) into medullary raphe nucleus which is considered the sympathetic metabolic regulatory output center. After microinjection, hypothalamic neurons that express green Fluosphere project to the raphe and therefore are considered metabolic. To identify neuronal activation, we stained for cells expressing c-fos. We found that intracerebroventricular leptin activates hypothalamic neurons, however c-fos positive neurons were not retrogradely labelled raphe-projecting sympathetic metabolic neurons.

Diversos estudos têm demonstrado que a atividade coordenada das células epiteliais com o estroma é fundamental no crescimento e diferenciação em situações fisiológicas e patológicas, inclusive no câncer. Vários relatos acentuam a importância do compartimento estromal nos tumores malignos e indicam fortemente que interações contínuas entre o carcinoma e as células estromais (resultando em regulamento e modulação recíproca) são condições prévias para desenvolvimento e progressão de carcinomas. Comparativamente, pouca informação está disponível sobre as características e o papel do estroma durante o processo carcinogênico e a maioria dos dados são baseados em estudos isolados. Nos animais tratados com o carcinógeno Dimetilhidrazina foi identificado na mucosa colônica o aparececimento de “Focos de Estroma Ativado" (FEA) que diferem do foco inflamatório esporádico encontrado na mucosa normal dos animais controles devido à imuno-expressão aumentada de células CD34, CD68, α-actina de músculo liso (ASMA), COX-2 positivas e densidade microvascular. Além disso, o FEA cercou um número aumentado de criptas colônicas em fissão que freqüentemente apresentavam células epiteliais com núcleos hipercromáticos. Este último achado pode sugerir correlação entre as alterações estromais e epiteliais dentro dos FEA. Embora esses achados sejam novos, são consistentes com observações prévias que o estroma tem um papel significante na carcinogênese. Juntamente com dados da literatura, este trabalho sugere que, no cólon, a “field cancerization" epitelial pode ser acompanhada através de alterações estromais e isto pode apontar novos marcadores de transformação neoplásica. / There has been considerable that the activity of epithelial cells with their stroma is fundamental in controlling growth and differentiation in normal and pathological situations, including cancer. A number of reports stress the importance of the stromal compartment in malignant tumors and strongly indicate that continuous interactions between the carcinoma and stromal cells (resulting in their reciprocal regulation and modulation) are prerequisites for carcinoma development and progression. Comparatively, less information is available about the features and role of the stroma for the carcinogenic process. In animals treated with the carcinogen Dimethyl-hydrazine we identified the appearing of mucosal “Activated Stromal Foci" (ASF) that differ from the sporadic inflammatory foci found in the normal mucosa of the control animals because of the presence of increased immune-expression of CD34, CD68, α-smooth muscle actin (ASMA), COX-2 positive cells and microvessel density. Furthermore, the ASF surrounded a increased number of colonic crypts in fission when compared to areas of normal stroma. This last finding suggests that stromal activation and epithelial changes may be correlated. These findings are novel but expected and consistent with previous observations that the stroma has a significant role in carcinogenesis. Taken together with literature data, our findings suggest that in the colon, the epithelial field cancerization may be accompanied by stromal changes and this may point to the finding of new markers of neoplastic transformation.

Diversos estudos têm demonstrado que a atividade coordenada das células epiteliais com o estroma é fundamental no crescimento e diferenciação em situações fisiológicas e patológicas, inclusive no câncer. Vários relatos acentuam a importância do compartimento estromal nos tumores malignos e indicam fortemente que interações contínuas entre o carcinoma e as células estromais (resultando em regulamento e modulação recíproca) são condições prévias para desenvolvimento e progressão de carcinomas. Comparativamente, pouca informação está disponível sobre as características e o papel do estroma durante o processo carcinogênico e a maioria dos dados são baseados em estudos isolados. Nos animais tratados com o carcinógeno Dimetilhidrazina foi identificado na mucosa colônica o aparececimento de “Focos de Estroma Ativado” (FEA) que diferem do foco inflamatório esporádico encontrado na mucosa normal dos animais controles devido à imuno-expressão aumentada de células CD34, CD68, α-actina de músculo liso (ASMA), COX-2 positivas e densidade microvascular. Além disso, o FEA cercou um número aumentado de criptas colônicas em fissão que freqüentemente apresentavam células epiteliais com núcleos hipercromáticos. Este último achado pode sugerir correlação entre as alterações estromais e epiteliais dentro dos FEA. Embora esses achados sejam novos, são consistentes com observações prévias que o estroma tem um papel significante na carcinogênese. Juntamente com dados da literatura, este trabalho sugere que, no cólon, a “field cancerization” epitelial pode ser acompanhada através de alterações estromais e isto pode apontar novos marcadores de transformação neoplásica. / There has been considerable that the activity of epithelial cells with their stroma is fundamental in controlling growth and differentiation in normal and pathological situations, including cancer. A number of reports stress the importance of the stromal compartment in malignant tumors and strongly indicate that continuous interactions between the carcinoma and stromal cells (resulting in their reciprocal regulation and modulation) are prerequisites for carcinoma development and progression. Comparatively, less information is available about the features and role of the stroma for the carcinogenic process. In animals treated with the carcinogen Dimethyl-hydrazine we identified the appearing of mucosal “Activated Stromal Foci” (ASF) that differ from the sporadic inflammatory foci found in the normal mucosa of the control animals because of the presence of increased immune-expression of CD34, CD68, α-smooth muscle actin (ASMA), COX-2 positive cells and microvessel density. Furthermore, the ASF surrounded a increased number of colonic crypts in fission when compared to areas of normal stroma. This last finding suggests that stromal activation and epithelial changes may be correlated. These findings are novel but expected and consistent with previous observations that the stroma has a significant role in carcinogenesis. Taken together with literature data, our findings suggest that in the colon, the epithelial field cancerization may be accompanied by stromal changes and this may point to the finding of new markers of neoplastic transformation.

Obesity is America’s fastest growing health threat. Although a primary health risk factor, obesity increases the probability of secondary health consequences such as stroke, diabetes mellitus and heart disease. Siberian hamsters offer a convenient model to study obesity, as they exhibit a photoperiod-driven reversal of obesity during the fall-winter months (i.e., short-days-SD). SD responses in the Siberian hamster, amongst others, include decreased adiposity and gonadal regression. The duration of the dark period is faithfully transmitted into a neuroendocrine melatonin (MEL) signal; that codes seasonal information. The brain communicates with body fat (white adipose tissue- WAT) via the sympathetic nervous system (SNS). The central MEL binding sites, however, necessary for the body fat/lipid mobilization responses during SDs are not precisely known, although melatonin receptor (MEL 1aR) mRNA has been co-localized with sympathetic outflow neurons of WAT in several forebrain areas. This dissertation aims to identify and to characterize the contribution of central sites that are important in seasonal responses in Siberian hamsters. Thus, I asked: Which specific brain sites are both sufficient and necessary to stimulate SD-like decreases in body, WAT and testes mass? Furthermore, I tested if SD-induced decreases in body fat mass are accompanied by increased energy expenditure, specifically brown adipose tissue (BAT) thermogenesis. It is hoped that the identification of brain sites and mechanisms involved in the effortless reversal of obesity in these animals can be applied to treatment opportunities of human obesity.