No description available.

No description available.

No description available.

The global incidence of overweight and obese individuals has skyrocketed in the past few decades resulting in a new health epidemic. In 1980, 5% of males and 8% of females were categorized as obese; by 2008 these values doubled equating to half a billion adults worldwide. This surge of overweight and obese individuals has driven a dramatic increase in people afflicted with metabolic disorders. As such, the term "metabolic syndrome" (MetS) has been coined to describe several interrelated metabolic risk factors which often present in concert. Specifically, metabolic syndrome refers to the presence of at least three of the following five conditions: central obesity, elevated triglycerides, diminished high density lipoprotein (HDL) cholesterol, hypertension, and insulin resistance (IR). MetS is a major health concern due to its ability to increase the likelihood of cardiovascular disease (CVD), diabetes, and other life-threatening ailments. In light of this growing medical epidemic, we have concentrated our efforts in evaluating the role of microRNA-155 (miR-155) in MetS development. MicroRNAs are a newly defined class of small, non-coding RNA which contain the unique ability to regulate gene expression through RNA interference. As a result of this ability, microRNAs can mediate a wide variety of cellular processes. In order to evaluate the function of miR-155 in MetS, we established a novel miR-155-/-/ApoE-/- (DKO) mouse model. Coupling this model with the use of normal rodent or high fat diets allowed us to investigate how states of caloric balance and surplus affected the manifestation of the individual MetS components. We found that male and female DKO mice fed a high fat diet had significantly augmented body masses of 18% and 10% respectively, when compared to ApoE-/- counterparts on the same diet. Evaluation of this phenotype with body composition analysis revealed an 18% and 46% increase in body fat percentage among the male DKO mice on normal and high fat diets, respectively. This trend was also observed in female DKO mice, albeit to a lesser extent. This phenotype was further substantiated by the observation of augmented gonadal white adipose tissue pad mass within male and female DKO mice fed either chow. This equated to a 43% and 112% increase in male mice and a 45% and 57% augmentation in female mice for normal and high fat chow diets, respectively. In light of our findings, we also evaluated how miR-155 impacted glucose and insulin sensitivity. We found levels of insulin to be augmented by 181% and 148% in male DKO mice on normal and high fat diets, respectively. Furthermore, we found these mice to be euglycemic. These observations suggest that DKO mice are IR but capable of compensating for their insensitivity with elevated insulin production. Due to the tight association between MetS and the development of non-alcoholic fatty liver disease (NAFLD) as well as CVD, we felt it prudent to investigate the manifestation of these conditions. We found elevated hepatic mass of 40% and 13% in male and female DKO mice on high fat chow. Furthermore, hepatic discoloration was seen in these mice prompting us to perform in-depth histological evaluation which revealed widespread steatosis, a hallmark of NAFLD. Meanwhile, investigation of atherosclerosis, the key underlying cause of most CVDs, unexpectantly revealed diminished development. Due to the complex nature of atherosclerosis it is tough to explain the exact reason for this observation. Independent reports have shown that miR-155 plays a critical role in the development, maturation, or activation of B-cell, T-cells, macrophages, and dendritic cells. As a result, decreased immune cell infiltration may be the root cause for the observed decline in atherosclerosis. Taking into account our observations of obesity, IR, and NAFLD in conjunction with independent findings of blood pressure mitigation by miR-155, we feel confident in reporting that miR-155 is a vital factor in preventing MetS and NAFLD development. Despite this, we surprisingly found atherosclerosis development to be diminished in these mice suggesting a pro-inflammatory role in atherogenesis. This duality highlights the complex and ambiguous nature of miRNAs. In light of this, further evaluations should be conducted to gain additional insight into these pathologies and hopefully the development of novel therapeutics. / Pharmacology

Equine Metabolic Syndrome (EMS) is a unique condition of horses characterized by adiposity, insulin resistance, and an increased risk of laminitis. Reducing insulin resistance may decrease the incidence of laminitis in horses with EMS. Pioglitazone, a thiazolidinedione class of anti-diabetic drug, has proven efficacy in humans with type 2 diabetes, a syndrome of insulin resistance sharing some similarities with EMS. The ability of pioglitazone to influence insulin sensitivity in an endotoxin-infusion model of induced insulin resistance was investigated. Our hypothesis was that piogltiazone would preserve insulin sensitivity in a model of induced insulin resistance. The specific aims were to investigate the pharmacokinetics and pharmacodynamics of pioglitazone in an endotoxin infusion model of insulin resistance. 16 normal adult horses were enrolled. Pioglitazone was administered to 8 horses (1 mg/kg, PO, q24h) for 14 days, and 8 horses served as their controls. Liquid chromatography with tandem mass spectroscopy was used to quantitate plasma concentration of pioglitazone. A frequently sampled intravenous glucose tolerance test with minimum model analysis was used to compare indices of glucose and insulin dynamics prior to, and following, endotoxin infusion in horses treated with pioglitazone and their controls. Parameters of clinical examination and lipid metabolism were compared prior to, and following, endotoxin administration. Pioglitazone administered orally at 1 mg/kg q 24 h resulted in plasma concentrations lower, and more variable, compared to those considered therapeutic in humans. No significant effect of drug treatment was detected on clinical parameters or indices of insulin dynamics or lipid homeostasis following endotoxin challenge. / Master of Science

Indiana University-Purdue University Indianapolis (IUPUI) / Coronary microvascular function is markedly impaired by the onset of the metabolic syndrome and may be an important contributor to the increased cardiovascular events associated with this mutlifactorial disorder. Despite increasing appreciation for the role of coronary K+ channels in regulation of coronary microvascular function, the contribution of K+ channels to the deleterious influence of metabolic syndrome has not been determined. Accordingly, the overall goal of this investigation was to delineate the mechanistic contribution of K+ channels to coronary microvascular dysfunction in metabolic syndrome. Experiments were performed on Ossabaw miniature swine fed a normal maintenance diet or an excess calorie atherogenic diet that induces the classical clinical features of metabolic syndrome including obesity, insulin resistance, impaired glucose tolerance, dyslipidemia, hyperleptinemia, and atherosclerosis. Experiments involved in vivo studies of coronary blood flow in open-chest anesthetized swine as well as conscious, chronically instrumented swine and in vitro studies in isolated coronary arteries, arterioles, and vascular smooth muscle cells. We found that coronary microvascular dysfunction in the metabolic syndrome significantly impairs coronary vasodilation in response to metabolic as well as ischemic stimuli. This impairment was directly related to decreased membrane trafficking and functional expression of BKCa channels in vascular smooth muscle cells that was accompanied by augmented L-type Ca2+ channel activity and increased intracellular Ca2+ concentration. In addition, we discovered that impairment of coronary vasodilation in the metabolic syndrome is mediated by reductions in the functional contribution of voltage-dependent K+ channels to the dilator response. Taken together, findings from this investigation demonstrate that the metabolic syndrome markedly attenuates coronary microvascular function via the diminished contribution of K+ channels to the overall control of coronary blood flow. Our data implicate impaired functional expression of coronary K+ channels as a critical mechanism underlying the increased incidence of cardiac arrhythmias, infarction and sudden cardiac death in obese patients with the metabolic syndrome.

Metabolic syndrome (MetS) and abdominal obesity (AbOb) increase the risk of developing cardiovascular disease and diabetes. Energy restriction (ER), highprotein (PRO) intake and high-intensity interval training (HIT) can independently improve MetS and AbOb. However, ER reduces metabolically active lean body mass (LBM) in addition to body fat (BF). Purpose: To determine the effects of a 16-wk ER diet with 2 levels of PRO (15% or 25% of energy), plus HIT, on MetS risk factors, AbOb, and body composition in women. Methods: Sedentary, premenopausal women (age=35±10y) with AbOb (waist circumference [WC] ≥80cm) were randomized to a 16-wk ER diet (-300kcals/d) with 15% (15PRO; n=17) or 25% (25PRO; n=18) of energy from PRO, plus 45min/d, 3d/wk HIT and 45min/d, 2d/wk continuous moderate-intensity exercise (CME) (-200kcals/d). Diet and physical activity (PA) were assessed using 4-d weighed food and PA records, respectively; diet and exercise compliance were assessed monthly with multiple-pass 24-h recalls and weekly tracking logs. Body weight (BW), WC, DXA-assessed body composition (BF [%], BF [kg], trunk fat [kg], and LBM [kg]), blood lipids (total cholesterol [TC], high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], triglycerides [TG]), glycemic markers (fasting plasma glucose [FPG], insulin, and homeostatic model assessment for insulin resistance [HOMA-IR], beta cell function [HOMA-%β] and insulin sensitivity [HOMA-%S]) and resting blood pressure (BP) (systolic BP [SBP]; diastolic BP [DBP]) were assessed pre/post-intervention. Repeated measures analysis of variance and two sample t-tests were used at analyze the date. Results are reported as means±standard deviations. Results: There were significant time, but not group, differences in BW (-5.1±2.6kg, p=0.0141), WC (- 7.3±3.6cm, p<0.0001), TC (-18.1±17.4mg/dL, p<0.0001), LDL-C (12.2± 16.2mg/dL, p<0.0001), TG (-25.3±56.2mg/dL, p=0.0064), insulin (-2.1±4.2mg/dL, p=0.0048), HOMA-IR (-0.2±0.5, p=0.0062), HOMA-%β (-12.1±35.2%, p=0.0497), HOMA-%S (28.5±78.4%, p=0.0357), and SBP (-3±9mmHg, p=0.214). There were significant group x time differences in DBP (15PRO=-5±8mmHg, 25PRO=- 2±8mmHg; p=0.0024). There were no time or group differences in FPG or HDLC. There were significant time, but not group, effects on changes in BW (-5.1kg± 2.6, p<0.0001), BF (-3.3±1.6%, p<0.0001), and LBM (-0.6kg±1.5, p=0.0283). The 15PRO group lost more absolute whole BF (-5.2kg vs. -3.9kg, p=0.0355) and trunk fat (-3.1kg vs. -2.2kg) vs. the 25PRO group. Conclusion: Both diets significantly improved BW, AbOb, MetS risk factors, glycemic control, and BF (%); LBM (kg) loss was similar in both groups. Compared to the 15PRO diet had significantly greater absolute BF-kg and trunk fat-kg losses. Increased PRO intake did not improve AbOb or MetS risk beyond ER and HIT/CME. The impact of HIT/CME and the greater (-1.3kg) changes in BW in the 15PRO group may have contributed significantly to the changes in absolute BF and trunk fat. More research is needed to separate the impact of HIT/CME and weight loss from the impact of PRO during ER. / Graduation date: 2013 / Access restricted to the OSU Community at author's request from March 28, 2013 - March 28, 2014

Objetivo: Avaliar o efeito da sibutramina na perda de peso de adolescentes obesos e as mudanças ocorridas nos parâmetros da síndrome metabólica com a perda de peso. Pacientes e métodos: O estudo foi duplo cego placebo controlado tipo cross-over com duração de 13 meses. Os pacientes receberam placebo ou sibutramina por 6 meses e vice-versa, nos 6 meses seguintes. Foram incluídos no estudo 73 adolescentes obesos de ambos os sexos com idades entre 10 e 18 anos. Os exames laboratoriais e exames de imagem foram realizados antes, no período de wash-out e ao final dos 13 meses de acompanhamento. Foram dosados: Colesterol total e frações, triglicérides, Leptina, proteína C reativa, transaminases e teste de tolerância à glicose oral. Os exames de imagem realizados foram: ultrassom de abdômen, Ecocardiograma, Eletrocardiograma, idade óssea. Resultados: A porcentagem de pacientes que perderam 10% do peso inicial no placebo foi de 46% e no grupo sibutramina foi de 75%. Quando usaram o placebo, o peso em média se elevou em1,61 kg, DP 4,46 e o IMC reduziu-se em média 0,24 kg/m2 DP 1,57 enquanto que os pacientes que receberam a sibutramina, o peso reduziu-se em média 4,47 kg e DP 5,87 e o IMC reduziu-se em média 2,38 kg/m2 e DP 2,36 com p < 0,001. Apesar da sibutramina reduzir o peso, IMC e medida de circunferência abdominal as mudanças metabólicas laboratoriais não foram observadas no período de tempo avaliado. Conclusão:A sibutramina induziu significantemente mais perda de peso em adolescentes obesos comparado ao placebo, sem efeitos colaterais significativos. Embora tivesse havido perda de peso, no período observado, não houve diferenças estatisticamente significantes nos parâmetros metabólicos / Objective: Evaluate the effect of sibutramine on weight loss and changes in the parameters of the metabolic syndrome due to weight loss in obese adolescents. Patients and methods: This was a randomized double blind crossover study with duration of 13 months. The study included 73 obese adolescents of both sexes aged between 10 and 18 years (with BMI > 2DP registered at the outpatient clinic of the Pediatric endocrinology Department of Hospital das Clínicas, São Paulo, Brazil, between 2007 and 2010. Patients were randomized to receive either placebo followed by sibutramine (6 months each) or sibutramine followed by placebo (6 months each). Anthropometric measurements, laboratory tests and imaging studies were performed at baseline, during the wash-out period and at the end of the 13 months follow-up. Total cholesterol, HDL, triglycerides, leptin, C-reactive protein, transaminases and oral glucose tolerance were tested. The following Imaging studies were performed: abdominal ultrasound, echocardiogram, EKG, bone age X-ray. Results: The percentage of patients who lost at least 10% of initial weight while taking the placebo was 46% and while taking sibutramine was 75%. While on placebo, average weight increased by 1.61 kg (SD 4.46). BMI decreased by 0.24 kg/m2 (SD 1.57) as a consequence of growth. While on sibutramine, weight decreased on average by 4.47 kg (SD 5.87) and mean BMI decreased by 2.38 kg/m2 (SD 2.36, p <0.001). Changes in BMI, waist circunference, or metabolic changes were not found statistically significant. Conclusion: Sibutramine induced significantly more weight loss in obese adolescents compared to placebo, without significant side effects. Although there was weight loss, in the study period there were no statistically significant differences in metabolic parameters

Objetivo: Avaliar o efeito da sibutramina na perda de peso de adolescentes obesos e as mudanças ocorridas nos parâmetros da síndrome metabólica com a perda de peso. Pacientes e métodos: O estudo foi duplo cego placebo controlado tipo cross-over com duração de 13 meses. Os pacientes receberam placebo ou sibutramina por 6 meses e vice-versa, nos 6 meses seguintes. Foram incluídos no estudo 73 adolescentes obesos de ambos os sexos com idades entre 10 e 18 anos. Os exames laboratoriais e exames de imagem foram realizados antes, no período de wash-out e ao final dos 13 meses de acompanhamento. Foram dosados: Colesterol total e frações, triglicérides, Leptina, proteína C reativa, transaminases e teste de tolerância à glicose oral. Os exames de imagem realizados foram: ultrassom de abdômen, Ecocardiograma, Eletrocardiograma, idade óssea. Resultados: A porcentagem de pacientes que perderam 10% do peso inicial no placebo foi de 46% e no grupo sibutramina foi de 75%. Quando usaram o placebo, o peso em média se elevou em1,61 kg, DP 4,46 e o IMC reduziu-se em média 0,24 kg/m2 DP 1,57 enquanto que os pacientes que receberam a sibutramina, o peso reduziu-se em média 4,47 kg e DP 5,87 e o IMC reduziu-se em média 2,38 kg/m2 e DP 2,36 com p < 0,001. Apesar da sibutramina reduzir o peso, IMC e medida de circunferência abdominal as mudanças metabólicas laboratoriais não foram observadas no período de tempo avaliado. Conclusão:A sibutramina induziu significantemente mais perda de peso em adolescentes obesos comparado ao placebo, sem efeitos colaterais significativos. Embora tivesse havido perda de peso, no período observado, não houve diferenças estatisticamente significantes nos parâmetros metabólicos / Objective: Evaluate the effect of sibutramine on weight loss and changes in the parameters of the metabolic syndrome due to weight loss in obese adolescents. Patients and methods: This was a randomized double blind crossover study with duration of 13 months. The study included 73 obese adolescents of both sexes aged between 10 and 18 years (with BMI > 2DP registered at the outpatient clinic of the Pediatric endocrinology Department of Hospital das Clínicas, São Paulo, Brazil, between 2007 and 2010. Patients were randomized to receive either placebo followed by sibutramine (6 months each) or sibutramine followed by placebo (6 months each). Anthropometric measurements, laboratory tests and imaging studies were performed at baseline, during the wash-out period and at the end of the 13 months follow-up. Total cholesterol, HDL, triglycerides, leptin, C-reactive protein, transaminases and oral glucose tolerance were tested. The following Imaging studies were performed: abdominal ultrasound, echocardiogram, EKG, bone age X-ray. Results: The percentage of patients who lost at least 10% of initial weight while taking the placebo was 46% and while taking sibutramine was 75%. While on placebo, average weight increased by 1.61 kg (SD 4.46). BMI decreased by 0.24 kg/m2 (SD 1.57) as a consequence of growth. While on sibutramine, weight decreased on average by 4.47 kg (SD 5.87) and mean BMI decreased by 2.38 kg/m2 (SD 2.36, p <0.001). Changes in BMI, waist circunference, or metabolic changes were not found statistically significant. Conclusion: Sibutramine induced significantly more weight loss in obese adolescents compared to placebo, without significant side effects. Although there was weight loss, in the study period there were no statistically significant differences in metabolic parameters

Mong, Lok Yee. / Thesis submitted in: December 2007. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2008. / Includes bibliographical references (leaves 124-145). / Abstracts in English and Chinese; some text in appendix also in Chinese. / Acknowledgements --- p.i / Abstract (English version) --- p.iii / Abstract (Chinese version) --- p.v / Table of Contents --- p.vii / List of Tables --- p.ix / List of Figures --- p.xi / List of Abbreviations --- p.xiii / Chapter Chapter 1 - --- Introduction / Chapter 1.1 --- Childhood obesity: a worldwide epidemic --- p.1 / Chapter 1.2 --- Health consequences of childhood obesity --- p.3 / Chapter 1.3 --- Determinants of childhood obesity --- p.5 / Chapter 1.4 --- Hormonal dysregulation and obesity --- p.9 / Chapter 1.5 --- Project objectives and long term significance --- p.14 / Chapter Chapter 2 - --- Research Plan and Methodology / Chapter 2.1 --- Study cohort / Chapter 2.1.1 --- Subject recruitment --- p.15 / Chapter 2.1.2 --- Ethics --- p.16 / Chapter 2.1.3 --- Measurements and blood sample collections --- p.16 / Chapter 2.1.4 --- Subgroup for dietary assessment --- p.18 / Chapter 2.1.5 --- Cohort re-visits in 2006 --- p.19 / Chapter 2.2 --- Genetic study / Chapter 2.2.1 --- Sample size estimation and research subjects --- p.21 / Chapter 2.2.2 --- DNA samples --- p.22 / Chapter 2.2.3 --- Candidate genes --- p.24 / Chapter 2.2.4 --- SNP tagging and prioritizing --- p.25 / Chapter 2.2.5 --- Genotyping methods & quality control --- p.28 / Chapter 2.2.6 --- Statistical analysis --- p.31 / Chapter 2.3 --- Dietary assessment / Chapter 2.3.1 --- Three-day 24-hour dietary recalls --- p.36 / Chapter 2.3.2 --- Lifestyle questionnaire --- p.37 / Chapter 2.3.3 --- Data management --- p.38 / Chapter 2.3.4 --- Statistical methods --- p.39 / Chapter Chapter 3 - --- Results Page / Chapter 3.1 --- Study cohort --- p.41 / Chapter 3.2 --- Genetic study / Chapter 3.2.1 --- Subjects --- p.41 / Chapter 3.2.2 --- SNPs selection --- p.41 / Chapter 3.2.3 --- Factor analysis of adiposity in the study population --- p.44 / Chapter 3.2.4 --- Genotyping and association testing in stage1 --- p.50 / Chapter 3.2.5 --- Genotyping and association testing in stage2 --- p.52 / Chapter 3.2.6 --- Association of the CART gene with adiposity --- p.55 / Chapter 3.2.7 --- Association of the GHR gene with adiposity --- p.60 / Chapter 3.2.8 --- Association of the GHRHR gene with adiposity --- p.69 / Chapter 3.2.9 --- Association of the IGFBP3 gene with adiposity --- p.75 / Chapter 3.2.10 --- Association of the POMC gene with adiposity --- p.83 / Chapter 3.2 --- Dietary assessment / Chapter 3.3.1 --- Nutrient intakes of the subgroup in2004 --- p.87 / Chapter 3.3.2 --- Nutrient intakes of the subgroup in2006 --- p.92 / Chapter 3.3.3 --- Lifestyle pattern of the cohort in2006 --- p.97 / Chapter Chapter 4 - --- Discussion / Chapter 4.1 --- The role of GH-related genes with adolescent adiposity --- p.102 / Chapter 4.2 --- Nutrient intakes and lifestyle pattern of the adolescents --- p.120 / Chapter 4.3 --- Conclusion of this study --- p.123 / References --- p.124 / Appendices / Chapter A --- Information of the SNPs selected --- p.146 / Chapter B --- Comparison of SNPs minor allele frequency (MAF) among two genotyping stages and HapMap data --- p.154 / Chapter C --- Hardy-Weinberg Equilibrium (HWE) of SNPs in two genotyping stages --- p.162 / Chapter D --- Factor score coefficient matrix --- p.170 / Chapter E --- Association of SNPs with factors scores --- p.172 / Chapter F1 --- Consent form (English version) --- p.207 / Chapter F2 --- Consent form (Chinese version) --- p.209 / Chapter G1 --- 24-hour dietary recall forms (English version) --- p.211 / Chapter G2 --- 24-hour dietary recall forms (Chinese version) --- p.218 / Chapter H --- Food photo booklet --- p.225 / Chapter I1 --- Lifestyle questionnaire (English version) --- p.236 / Chapter I2 --- Lifestyle questionnaire (Chinese version) --- p.238