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.

During their lifetime, Black/African Americans have a higher likelihood of developing the diabetes mellitus metabolic disorder than other racial and ethnic groups in the United States. While research indicates that socioeconomic status, diet, and obesity factor into race disparities, the epigenetics field additionally identifies historical and contemporary racism as contributors to race disparities. This study is a qualitative analysis that examines a sample of health science research articles that use an epigenetics approach to understand diabetes among Black/African Americans. I analyzed the extent and mechanisms through which articles subtly reproduce dominant stereotypes of Black/African Americans and diabetes through representations of culture, diet, and sugar consumption, among other factors. Moreover, our analysis shows how these articles recreate new scripts that view biological differences as a product of historical and ongoing racism. The result of this analysis indicates three categories: 1) presentations of race as a social construction and racism as a cause of biological outcomes; 2) utilization of cultural perspectives that reify racial categories and point to social environments within households/neighborhoods and diet as a cause; 3) advocating for a multidisciplinary approach in medicine to foster collaborative change within minority communities. These results further emphasize the importance for sociologists and other research scholars to become more educated in the field of epigenetics. Furthermore, by becoming more educated on epigenetics, this can allow sociologists to further contribute to the field.

Celiac disease (CD), an autoimmune disorder affecting millions of Americans, poses significant obstacles leading to a normal life. With no known cure, adherence to a strict glutenfree diet (GFD) is essential. However, the cost and limited availability of gluten-free alternatives can burden individuals with CD. Additionally, factors such as socioeconomic status, nutrient deficiencies, and the nature of the disease may contribute to mental health issues. This study aimed to investigate the influence of adherence to a GFD on depression in CD patients. The prevalence of depression among individuals with CD from diverse backgrounds was examined, along with the analysis of macro- and micronutrient distribution and the impact of the GFD. Data from the National Health and Nutrition Examination Survey spanning three cycles (2009-2014) were extracted, including 70 CD patients and 271 participants reporting general gluten issues. The dataset was analyzed using SAS v9.4 (SAS Institute, Inc., Cary, NC) with the three cycles merged using a unique identifier sequential number. Sample weights were applied to mitigate bias in national estimates due to unequal probability of selection, while oversampling was utilized to enhance the study’s reliability when examining subgroups or minorities. Survey weight and sampling design considerations were incorporated into the SAS syntax to safeguard participants’ privacy, as managed by the National Center for Health Statistics. Multiple linear regression analysis revealed no significant association between depression and adherence to the GFD or CD; however, ethnicity showed significance. Celiac disease exhibited a prevalence of 0.12% among White individuals, 3-6 times higher than other ethnic groups, and was twice as prevalent in females compared to males. Notably, deficiencies in macro- and micronutrients among CD and GFD cases were observed. Carbohydrate intake exhibited a negative association with GFD consumers and those with CD, while individuals adhering to a GFD showed an association with decreased polyunsaturated fat consumption, yet within adequate intakes. Deficiencies in micronutrients such as thiamin, vitamins B12, D, and E, and calcium were also observed within GFD group, while a low sodium intake was observed among CD group. This study provides insights into the complex interplay between diet, mental health, and CD management.

This dissertation thesis is focused on development and optimization of high- performance liquid chromatography (HPLC) and tandem mass spectrometry (LC-MS/MS) methods, and its utility for diagnosis of inherited metabolic diseases. The first thematic part describes a comprehensive laboratory approach to diagnostics of patients with hereditary xanthinuria by determination of specific markers and enzyme activity. For this purpose HPLC method with diode array detection for measurement of hypoxanthine, xanthine, allopurinol and oxypurinol in urine and plasma and HPLC method with fluorimetric detection for analysis of pterin and isoxanthopterin in plasma were employed. These methods were successfully applied in clinical practice to ascertain two patients with hereditary xanthinuria type I. The second thematic part aims at developing and clinical application of new LC-MS/MS method for simultaneous determination of total homocysteine (tHcy), methionine (Met) and cystathionine (Cysta) in dried blood spots (DBS) and plasma. The results demonstrated the clinical utility of this method for detection of patients with homocystinuria and possibility to distinguish between defects in the remethylation and transsulfuration pathways of homocysteine metabolism. Due to ease of DBS collection and sample transportation...

A tontura é um sintoma que acomete a população mundial, sendo observada maior prevalência em idosos devido ao processo de deterioração funcional dos sistemas auditivo e vestibular com o envelhecimento e também devido à alta sensibilidade destes sistemas a problemas clínicos situados em outras partes do corpo humano, comumente relacionados à etiologia vascular e metabólica. A Reabilitação Vestibular (RV) tem se mostrado uma importante e efetiva estratégia no tratamento de indivíduos com desordens do equilíbrio corporal, proporcionando uma acentuada melhora na qualidade de vida. O objetivo deste trabalho foi avaliar prospectivamente o efeito da RV como forma de tratamento das labirintopatias de origem vascular e metabólica sobre a qualidade de vida de indivíduos idosos. O estudo foi delineado como um ensaio clínico prospectivo, longitudinal, observacional, com a participação de 40 indivíduos idosos de ambos os gêneros, com faixa etária entre 60 e 84 anos, divididos em 2 grupos conforme o diagnóstico médico, tontura de origem vascular ou metabólica. Os pacientes passaram por anamnese, aconselhamento, avaliação da qualidade de vida (escala de quantificação da tontura e Dizziness Handicap Inventory brasileiro) e a RV propriamente dita que se baseou no protocolo de Cawthorne e Cooksey. A análise estatística dos dados foi feita através do teste t-Student, para comparações de amostras pareadas, usando um teste de hipótese bilateral; os coeficientes de Pearson e de Spearman foram usados no estudo de correlações. Observou-se que o idoso portador de labirintopatia de origem metabólica ou vascular, possui idade média de 70,2 anos, diagnóstico prevalente no grupo metabólico de diabetes mellitus e no grupo vascular de hipertensão arterial sistêmica. Pelas escalas utilizadas podemos observar que os aspectos avaliados por meio do DHI (físico, emocional, funcional e geral) e escala de quantificação de tontura, melhoraram após a intervenção terapêutica pela Reabilitação Vestibular nos idosos portadores de labirintopatias de origem vascular e metabólica. Contudo não se observou diferença significativa nas escalas do DHI e quantificação da tontura pós RV entre os grupos metabólico e vascular. Observou-se ainda, neste estudo, correlação significativa entre a escala de quantificação da tontura com o DHI pré e pós-tratamento. Pelas questões abordadas no DHI houve um incremento na qualidade de vida de todos os idosos em estudo. O período de terapia mediante RV variou de quatro a dez sessões terapêuticas. Assim, levando em consideração os dados epidemiológicos do envelhecimento no Brasil e sabendo que a grande parte dos idosos com afecções otoneurológicas tem origem vascular e metabólica, conclui-se que a RV baseada nos protocolos de Cawthorne e Cooksey pode ser utilizada de modo benéfico nesta população, trazendo inclusive impacto positivo na qualidade de vidas destes indivíduos. / The dizziness is a symptom that attacks the world-wide population, being observed bigger predominance in old due to the process of functional deterioration of the hearing and vestibular systems with the aging and also due to the high sensibility of these systems to clinical problems situated in other parts of the human body, usually related to vascular and metabolic etiology. The Vestibular Rehabilitation (VR) has shown an important and effective strategy in the individuals\' treatment with disorders of the physical balance, providing an accented improvement in the quality of life. The objective of this work was evaluate prospectively the effect of the RV as form of treatment of the labyrinth disease of vascular and metabolic origin in the quality of life of geriatric patients. The study was outlined like a clinical prospective test, longitudinal, observed, with the participation of 40 old individuals of both genders, with age group between 60 and 84 years divided in 2 groups according to the medical diagnosis,dizziness of vascular or metabolic origin. The patients passed over medical examinations, anamnesis, advising, evaluation of quality of life (scale of quantification of dizziness and Brazilian Dizziness Handicap Inventory) and the VR properly stated, what was based on the protocol of Cawthorne and Cooksey. The statistics analysis from the data was done through the t-Student test, to comparisons of parallels samples, using a test of bilateral hypothesis; the coefficients of Pearson and Spearman were used in the study of correlations. It was noticed that the old bearer of labyrinth disease of metabolic or vascular origin, has average age of 70,2 years, prevalent diagnosis in the metabolic group of diabetes mellitus and in the vascular group of arterial high blood pressure. For the used scales we can notice that the aspects evaluated through the DHI (physical, emotional, functional and general) and the scale of quantification of dizziness, improved after the therapeutic intervention by the Vestibular Rehabilitation in the geriatric patients with labyrinth disease of vascular and metabolic origin. Nevertheless significant difference in the scales of the DHI and quantification of dizziness after VR was not observed between the metabolic and vascular groups. Significant correlation was still observed in this study between the scales of quantification of dizziness with the DHI before and after treatment. For the questions boarded in the DHI there was a growth in the quality of life of all the old ones in study. The total time of treatment by means of VR varies of 4-10 therapeutic sessions. So, taking into account the epidemiologist data of the aging in Brazil and knowing that great part of the old ones with vestibular affections has vascular and metabolic origin, it is concluded that the VR based on the protocols of Cawthorne and Cooksey, can be used inbeneficial way in this population, also bringing positive impact in the capacity of life of these individuals.

Foi realizado o estudo prospectivo de uma amostra da população portadora de Síndrome de Down que procurou o Departamento de Genética do Hospital Infantil Darcy Vargas,no período de 1959 a 1996. Dos 2816 portadores de Síndrome de Down que compareceram a este Serviço, neste período , a amostra estudada consistiu de 518 pacientes que mantiveram períodos de retomo ambulatorial conforme previsto pelo Protocolo de segmento clínico adotado. O objetivo do estudo foi caracterizar a incidência de colecistopatia litiásica em pacientes portadores de Síndrome de Down . Para desenvolver este estudo, após o diagnóstico citogenético e clínico da Síndrome de Down, procurou-se correlacionar faixa etária dos genitores, uso de anticoncepcionais e principalmente promover a utilização de exames subsidiários específicos que permitiram melhores condições diagnósticas e definição de mecanismos fisiopatológicos eventuais relacionados à colilitiase. Verificou-se a presença de cálculos de vesícula biliar em 27 pacientes ( 3,28%) comparando-se à incidência descrita na população como um todo (0,07%). Estes dados caracterizam a prevalência de cálculos de vesícula biliar em portadores de Síndrome de Down ( a distribuição das probabilidades da frequência de cálculo de vesícula biliar em Sindrome de Down está dentro do intervalo de 95%, entre 3,6% e 7,7%). As correlações realizadas vieram a excluir,na amostra estudada, algumas etiologias comumente descritas para colelitíase e provavelmente vincula o fenômeno da colelitíase a mecanismos fisioembriopatológicos ligados à hipotonia e estase do conteúdo da vesícula biliar( e/ou redução na velocidade do seu esvaziamento). Em consequência torna-se importante propor uma investigação rotineira para esta patologia, com ênfase nos mecanismos fisiopatológicos, prováveis responsáveis pela incidência aumentada na população com Síndrome de Down. / The purpose of this study has been the prospective analysis of the Down syndrome population received by the Genetic Department of \"Hospital Infantil Darcy Vargas\", in the period from 1959 to 1996. The Department has received 2816 Down Syndrome patients\' in this period, and this study has selected 518 patients, clinical and cytogenetically diagnosed, which were studied following the specific clinical protocol, in periodical evaluations. The incidence of cholelithiasis was verified and it has been analysed the possible relationships among this disease and parentaI age, contraceptive use and clinical features leading to the discussion of eventual aetiologic mechanisms causing gallstones. It was verified 27 patients affected by Down Syndrome and presenting cholelithiasis in the survey of 518 patients ( 3.28 %) compared to the frequency of 7/10000 in the non Down population ( 0.07% ). The statistical analysis has shown that the distribution of the frequency probabilities have been between 3.6% and 7.7%, These studies have verified that the aetiology of the gallstones in the Down syndrome patients could be related to the hypotonic characteristic of the patients, leading to cholestasis, It is very important the suggestion of routine evaluation for this pathology, related to the eventual aetiologic features.

Made available in DSpace on 2016-01-26T12:51:31Z (GMT). No. of bitstreams: 1 janinehatsumimiyamoto_dissert.pdf: 287223 bytes, checksum: 94be79897234bdddd89d8d839f550e34 (MD5) Previous issue date: 2012-01-25 / Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from insulin secretion defects, in its peripheral action, or both. Clinical manifestations of diabetes are broad and can range from asymptomatic glucose intolerance to acute complications as diabetic ketoacidosis or complications of slow evolution, such as neurological and vascular changes. Vascular changes affect virtually every body's blood vessels, large and small ones, constituting macro-and microangiopathy, respectively. The main clinical expressions of microangiopathy are diabetic nephropathy and retinopathy. The macroangiopathy is represented by early atherosclerosis, more severe and more frequent than that observed in non-diabetic population. The non-establishment or definition of a glycemic threshold in diabetic patients and the persistence of this relationship in non-diabetics suggest that glucose is a continuous variable risk, as well as other cardiovascular risk factors. The diabetic dyslipidemia is characterized by an increase in LDL small and dense particles, the reduction in HDL-cholesterol and high triglycerides levels. Diabetes or pre-diabetes, low HDL-cholesterol, high triglycerides and arterial hypertension are risk factors, when linked to central obesity, form the metabolic syndrome and 1.5-fold increase in overall mortality and 2.5 in cardiovascular mortality. Given the above, the purpose of the study was to assess the prevalence of metabolic syndrome according to the definition of the National Cholesterol Education Program Adult Treatment Panel III in patients with type 2 diabetes mellitus, its association and components with coronary disease. A total of 610 patients with type 2 diabetes mellitus were retrospectively analyzed, concerning age, gender, clinical and metabolic characteristics. The prevalence of metabolic syndrome was 78.4%. The comparative analysis between the groups with and without metabolic syndrome was significantly associated with coronary artery disease (p=0.032). By means of logistic regression, waist circumference (p=0.79) and fasting glucose (p=0.13) were not significant. The arterial hypertension (p=0.01) and dyslipidemia (p=0.005) showed significant association with coronary artery disease. Therefore, we can conclude that the metabolic syndrome is highly prevalent in patients with type 2 diabetes mellitus; it has shown an association with coronary heart disease and among its components, arterial hypertension and dyslipidemia indicate a significant association. / Diabetes Mellitus constitui um grupo de doenças metabólicas caracterizado por hiperglicemia resultante de defeitos na secreção de insulina, na sua ação periférica ou em ambas. As manifestações clínicas do diabetes são amplas e podem compreender desde intolerância assintomática à glicose até complicações agudas como a cetoacidose diabética ou complicações de evolução lenta, tais como alterações vasculares e neurológicas. As alterações vasculares atingem praticamente todos os vasos do organismo, pequenos e grandes, constituindo a micro e a macroangiopatia, respectivamente. As principais expressões clínicas da microangiopatia são a retinopatia e a nefropatia diabética. A macroangiopatia é representada pela aterosclerose mais precoce, mais grave e mais frequente que a observada na população não diabética. O não estabelecimento ou definição de um limiar glicêmico em diabéticos e a persistência desta relação em não-diabéticos sugerem que a glicemia é uma variável contínua de risco, da mesma forma que outros fatores de risco cardiovascular. A dislipidemia diabética caracteriza-se pelo aumento de partículas de LDL pequenas e densas, pela redução do HDL colesterol e valores elevados de triglicérides. Diabetes ou pré-diabetes, baixo valor de HDL colesterol, triglicérides elevado e hipertensão são fatores de risco que, ligados à obesidade central, formam a síndrome metabólica e aumentam em 1,5 vezes a mortalidade geral e em 2,5 vezes, a cardiovascular. Diante do exposto, o propósito do estudo foi avaliar a prevalência de síndrome metabólica de acordo com a definição do National Cholesterol Education Program Adult Treatment Panel III em pacientes com diabetes mellitus tipo 2 e a sua associação e a dos seus componentes com a doença coronariana. Um total de 610 pacientes com diabetes mellitus tipo 2 foram analisados, retrospectivamente, quanto à idade, sexo e características clínicas e metabólicas. A prevalência de síndrome metabólica foi de 78,4%. A Análise comparativa entre os grupos com e sem síndrome metabólica mostrou associação significativa com a doença coronariana (p=0,032). Por meio de regressão logística, a circunferência abdominal (p=0,79) e a glicemia de jejum (p=0,13) não foram significativas. A hipertensão arterial (p=0,01) e a dislipidemia (p=0,005) evidenciaram associação significativa com a doença coronariana. Portanto, podemos concluir que a síndrome metabólica tem alta prevalência em pacientes com diabetes mellitus tipo 2; mostrou associação com doença coronariana e entre os seus componentes, a hipertensão arterial e a dislipidemia denotaram associação significativa.

A tontura é um sintoma que acomete a população mundial, sendo observada maior prevalência em idosos devido ao processo de deterioração funcional dos sistemas auditivo e vestibular com o envelhecimento e também devido à alta sensibilidade destes sistemas a problemas clínicos situados em outras partes do corpo humano, comumente relacionados à etiologia vascular e metabólica. A Reabilitação Vestibular (RV) tem se mostrado uma importante e efetiva estratégia no tratamento de indivíduos com desordens do equilíbrio corporal, proporcionando uma acentuada melhora na qualidade de vida. O objetivo deste trabalho foi avaliar prospectivamente o efeito da RV como forma de tratamento das labirintopatias de origem vascular e metabólica sobre a qualidade de vida de indivíduos idosos. O estudo foi delineado como um ensaio clínico prospectivo, longitudinal, observacional, com a participação de 40 indivíduos idosos de ambos os gêneros, com faixa etária entre 60 e 84 anos, divididos em 2 grupos conforme o diagnóstico médico, tontura de origem vascular ou metabólica. Os pacientes passaram por anamnese, aconselhamento, avaliação da qualidade de vida (escala de quantificação da tontura e Dizziness Handicap Inventory brasileiro) e a RV propriamente dita que se baseou no protocolo de Cawthorne e Cooksey. A análise estatística dos dados foi feita através do teste t-Student, para comparações de amostras pareadas, usando um teste de hipótese bilateral; os coeficientes de Pearson e de Spearman foram usados no estudo de correlações. Observou-se que o idoso portador de labirintopatia de origem metabólica ou vascular, possui idade média de 70,2 anos, diagnóstico prevalente no grupo metabólico de diabetes mellitus e no grupo vascular de hipertensão arterial sistêmica. Pelas escalas utilizadas podemos observar que os aspectos avaliados por meio do DHI (físico, emocional, funcional e geral) e escala de quantificação de tontura, melhoraram após a intervenção terapêutica pela Reabilitação Vestibular nos idosos portadores de labirintopatias de origem vascular e metabólica. Contudo não se observou diferença significativa nas escalas do DHI e quantificação da tontura pós RV entre os grupos metabólico e vascular. Observou-se ainda, neste estudo, correlação significativa entre a escala de quantificação da tontura com o DHI pré e pós-tratamento. Pelas questões abordadas no DHI houve um incremento na qualidade de vida de todos os idosos em estudo. O período de terapia mediante RV variou de quatro a dez sessões terapêuticas. Assim, levando em consideração os dados epidemiológicos do envelhecimento no Brasil e sabendo que a grande parte dos idosos com afecções otoneurológicas tem origem vascular e metabólica, conclui-se que a RV baseada nos protocolos de Cawthorne e Cooksey pode ser utilizada de modo benéfico nesta população, trazendo inclusive impacto positivo na qualidade de vidas destes indivíduos. / The dizziness is a symptom that attacks the world-wide population, being observed bigger predominance in old due to the process of functional deterioration of the hearing and vestibular systems with the aging and also due to the high sensibility of these systems to clinical problems situated in other parts of the human body, usually related to vascular and metabolic etiology. The Vestibular Rehabilitation (VR) has shown an important and effective strategy in the individuals\' treatment with disorders of the physical balance, providing an accented improvement in the quality of life. The objective of this work was evaluate prospectively the effect of the RV as form of treatment of the labyrinth disease of vascular and metabolic origin in the quality of life of geriatric patients. The study was outlined like a clinical prospective test, longitudinal, observed, with the participation of 40 old individuals of both genders, with age group between 60 and 84 years divided in 2 groups according to the medical diagnosis,dizziness of vascular or metabolic origin. The patients passed over medical examinations, anamnesis, advising, evaluation of quality of life (scale of quantification of dizziness and Brazilian Dizziness Handicap Inventory) and the VR properly stated, what was based on the protocol of Cawthorne and Cooksey. The statistics analysis from the data was done through the t-Student test, to comparisons of parallels samples, using a test of bilateral hypothesis; the coefficients of Pearson and Spearman were used in the study of correlations. It was noticed that the old bearer of labyrinth disease of metabolic or vascular origin, has average age of 70,2 years, prevalent diagnosis in the metabolic group of diabetes mellitus and in the vascular group of arterial high blood pressure. For the used scales we can notice that the aspects evaluated through the DHI (physical, emotional, functional and general) and the scale of quantification of dizziness, improved after the therapeutic intervention by the Vestibular Rehabilitation in the geriatric patients with labyrinth disease of vascular and metabolic origin. Nevertheless significant difference in the scales of the DHI and quantification of dizziness after VR was not observed between the metabolic and vascular groups. Significant correlation was still observed in this study between the scales of quantification of dizziness with the DHI before and after treatment. For the questions boarded in the DHI there was a growth in the quality of life of all the old ones in study. The total time of treatment by means of VR varies of 4-10 therapeutic sessions. So, taking into account the epidemiologist data of the aging in Brazil and knowing that great part of the old ones with vestibular affections has vascular and metabolic origin, it is concluded that the VR based on the protocols of Cawthorne and Cooksey, can be used inbeneficial way in this population, also bringing positive impact in the capacity of life of these individuals.

Sepsis is a leading cause of death among critically ill patients that results in metabolic alterations including hypercatabolism, lipoatrophy, and muscle wasting, contributing to the development of cachexia. Septic cachexia is associated with loss of body weight, fat mass, and lean mass and dysregulated immune function. There are currently no efficacious treatment strategies for septic cachexia, and nutritional interventions have limited success in preventing hypercatabolic wasting. Pyocyanin is a virulence factor produced by sepsis-causing Pseudomonas aeruginosa that has been shown to activate the aryl hydrocarbon receptor (AhR), increase inflammation, and produce reactive oxygen species. Thus, pyocyanin represents a novel mechanistic target in the development of septic cachexia. In Aim 1, we hypothesized that pyocyanin reduces adipocyte differentiation and activates AhR in vitro and in vivo. In vitro, pyocyanin reduced differentiation of 3T3-L1 cells to adipocytes and promoted expression of proinflammatory cytokines. These effects were associated with activation of AhR. We established an in vivo model of pyocyanin-induced cachexia using repeat intraperitoneal exposure to pyocyanin in male and female C57BL/6J mice. Acutely, pyocyanin reduced differentiation of stem cells isolated from adipose stromal vascular tissue and augmented expression of proinflammatory cytokines. Chronically, pyocyanin reduced body weight and fat mass, which was associated with adipose-specific AhR activation. Pyocyanin had sexually dimorphic effects on lipolysis and adipocyte inflammation. These data suggest a role of pyocyanin in adipose cachexia associated with sepsis. In Aim 2, we hypothesized that pyocyanin activates adipocyte AhR to promote adipose tissue wasting and cachexia. To test this hypothesis, we used a mouse model of adipocyte-specific deficiency of AhR and chronically administered pyocyanin to male and female mice. In male mice with adipocyte AhR deficiency, effects of pyocyanin to promote adipose wasting and cachexia were attenuated. In contrast, female adipocyte AhR deficient mice had an augmented response to pyocyanin to decrease body weight. Results suggest divergent mechanisms of pyocyanin to regulate adiposity and body weight through adipocyte AhR between male and female mice. These data support a role for pyocyanin in the development of adipose cachexia associated with Pseudomonas aeruginosa sepsis that is partially regulated by adipocyte AhR. Targeting pyocyanin’s effects on adipocytes represents a potentially novel therapeutic approach for septic cachexia that could mitigate septic cachexia, a condition associated with increased risk of mortality in this population.

Expansion of visceral adipose tissue correlates with the metabolic syndrome and increased cardiovascular risk. Hypertrophied visceral fat becomes inflamed, causing increased lipolysis, decreased triglyceride storage, and lipotoxicity in skeletal muscle and liver resulting in insulin resistance. Perivascular adipose tissue is a normal component of the adventitia of arteries in humans and animals. Whether or not perivascular adipose also becomes inflamed in obesity is an important question, as this may be an additional, direct mechanism by which obesity causes vascular inflammation and disease. Thus, for the first part of my thesis, we asked the question: does perivascular adipose in mice become inflamed with high fat feeding? In contrast to visceral adipose, macrophage gene expression was not increased in perivascular adipose in response to high fat diet, and this correlated with reduced F480 antigen positive cells as seen by immunohistochemistry and flow cytometry. Interestingly, perivascular adipose surrounding the thoracic aorta was similar to brown adipose tissue, a highly thermogenic fat depot, as shown by histology and DNA microarrays. Moreover, inter-scapular brown adipose was also resistant to diet induced inflammation in comparison to visceral adipose. These findings suggest that brown adipose in the perivascular niche may serve to protect the vasculature from diet induced inflammation, or from cold exposure, or both; whether or not brown perivascular adipose tissue exists in humans has yet to be determined. In the second part of my thesis, we evaluated the role of perivascular adipose tissue in the apolipoprotein E knockout mouse, which exhibits severe hyperlipidemia and atherosclerosis, but is resistant to diet induced obesity and glucose intolerance. We tested the hypothesis that in this model of severe atherosclerosis, inflammation of perivascular adipose does occur. However, we were surprised to find that macrophage specific gene expression, as determined by either microarray analysis or quantitative polymerase chain reaction, was not increased in either the perivascular or the visceral adipose of high fat diet fed apolipoprotein E knockout mice. While the visceral adipose of wild type mice had extensive alterations in gene expression in response to high fat diet, in particular, enrichment of inflammatory gene expression and broad down regulation of peroxisome proliferator activated receptor gamma target genes, apolipoprotein E knockout visceral adipose did not. Importantly, the apolipoprotein E knockout visceral adipose instead showed increased expression of genes encoding enzymes in fatty acid oxidation pathways. High fat diet fed apolipoprotein E knockout visceral adipose was also characterized by smaller adipocyte size. We conclude that, 1) inflammation in thoracic perivascular adipose does not occur in conjunction with diet induced obesity in normal animals nor with atherosclerosis in apolipoprotein E knockout mice, 2) thoracic perivascular adipose tissue is essentially identical to brown adipose tissue in mice, thus potentially protecting the vasculature from the cold, and 3) apolipoprotein E knockout mice remain lean on a high fat diet, despite hyperlipidemia and atherosclerosis, and the decreased adiposity correlates with decreased adipocyte size and adipose inflammation but increased oxidation of fatty acids. Consistent with previous work showing apolipoprotein E controls adipocyte uptake and deposition of triglyceride, its absence prevents adipocyte hypertrophy and resultant inflammation of visceral adipose tissue. Thus limiting adipocyte acquisition of fatty acids may be advantageous, provided that compensatory mechanisms to prevent sustained hyperlipidemia and peripheral organ lipotoxicity can be activated.