Metabolic syndrome is a grouping of criteria that includes hypertension, glucose intolerance, truncal obesity and/or a high body mass index (BMI), insulin resistance, high very-low-density lipoproteins, high triglycerides, and low high-density lipoproteins. Metabolic syndrome is a problem in Hispanic children due to increasing obesity rates and a predisposition for insulin resistance in the Hispanic population. Omega-3 fatty acid supplementation has been shown to decrease triglycerides, body mass, insulin resistance, and hypertension while increasing HDL. Inflammatory markers are also reduced after omega-3 supplementation. More research is needed on the supplementation of omega-3 fatty acids in children before guidelines are written. Supplementation and overall intake levels of EPA and DHA can be determined through food frequency questionnaires. Research at this time indicates that supplementation with omega-3 fatty acids could be beneficial for Hispanic children who already partially met the criteria for metabolic syndrome, and is probably not harmful.

abstract: The prevalence of obesity and obesity-related disorders have increased world-wide. In the last decade, the intestinal microbiome has become a major indicator of metabolic and gastrointestinal health. Previous research has shown that high-fat diet (HFD) consumption can alter the microbial composition of the gut by increasing the abundance of gram-positive bacteria associated with the onset of obesity and type 2 diabetes. Although, the most common form of obesity and metabolic syndrome intervention is exercise and diet, these recommendations may not improve severe cases of obesity. Thus, an important relevance of my project was to investigate whether the intake of an organometallic complex (OMC) would prevent the onset of metabolic and gastrointestinal complications associated with high-fat diet intake. I hypothesized that the consumption of a HFD for 6 weeks would promote the development of metabolic and gastrointestinal disease risk factors. Next, it was hypothesized that OMC treatment would decrease metabolic risk factors by improving insulin sensitivity and decreasing weight gain. Finally, I hypothesized that HFD-intake would increase the abundance of gram-positive bacteria associated with gastrointestinal disease. My preliminary data investigated the effects of a 6-week HFD on the development of hepatic steatosis, intestinal permeability and inflammation in male Sprague Dawley rats. I found that a 6-week HFD increases hepatic triglyceride concentrations, plasma endotoxins and promotes the production of pro-inflammatory cytokines in the cecum wall. I then investigated whether OMC treatment could prevent metabolic risk factors in male Sprague-Dawley rats fed a HFD for 10 weeks and found that OMC can mitigate risk factors such hyperglycemia, liver disease, impaired endothelial function, and inflammation. Lastly, I investigated the effects of a 10-week HFD on the gastrointestinal system and found an increase in liver triglycerides and free glycerol and alterations of the distal gut microbiome. My results support the hypothesis that a HFD can promote metabolic risk factors, alter the gut microbiome and increase systemic inflammation and that OMC treatment may help mitigate some of these effects. Together, these studies are among the first to demonstrate the effects of a soil-derived compound on metabolic complications. Additionally, these conclusions also provide an essential basis for future gastrointestinal and microbiome studies of OMC treatment. / Dissertation/Thesis / Doctoral Dissertation Biology 2019

Hradecká M.: Natural compounds applicable for the treatment of metabolic syndrome, Diploma thesis 2018/2019, Charles University, Faculty of Pharmacy in Hradec Králové, Department of Pharmaceutical Botany, pp. 60. Occurence of metabolic syndrome is increasing worldwide in children and adults. The use of natural compounds is one of possibilities in the prevention and treatment of metabolic syndrome. These compounds may act complexly or affect individual risk factors associated with metabolic syndrome. Selected plants with these effects are incorporated into my diploma thesis (for example Allium sativum, Crataegus laevigata, Hibiscus sabdariffa, Persea americana, Rosmarinus officinalis, Silybum marianum and Vaccinium myrtillus). The alga Undaria pinnatifida and fungus Pleurotus sajor-caju are also mentioned. It is necessary to carry out other clinical studies, where the positive effect of mentioned constituents will be confirmed, which could be added to the list of phytopharmaceuticals used to prevent, slow down or treat the metabolic syndrome in the future. Keywords: natural compounds, metabolic syndrome

Second-generation antipsychotics (SGAs) are prescribed for treatment of psychosis. A major side effect of SGAs is an increased risk of metabolic syndrome (MetS) with symptoms of hypertension, hyperlipidemia, hyperglycemia, and truncal obesity. A clinic in the northeastern United States was not screening patients for MetS when being treated with SGAs. The purpose of this project was to educate staff on MetS risk factors, signs, symptoms, and patient management with a goal to improve their knowledge of MetS. Lewin's change theory provided a conceptual framework for the project. The project question explored the development and evaluation of an educational module on MetS increased staff knowledge. Educational content was guided by current literature and the American Psychiatric Association and American Diabetic Association practice guidelines. Five expert panel members, consisting of 3 psychiatrists, an advance practice nurse, and a registered nurse reviewed the education program and evaluated content using a Likert-type questionnaire. Expert panel evaluations indicated that the module content contained useful clinical information on MetS screening for patients on SGAs. After panel review, the program was presented to 7 clinic staff. Pretest and posttest questionnaires asked 10 multiple choice questions and results were compared. Questions on SGA side effects, MetS complications, prevalence, baseline assessment measures, lab work, and needed collaboration were answered correctly by 6 of the participants pretest and all questions after receiving the education program. The project has the potential to promote positive social change through staff education on MetS screening for patients, thus improving patient outcomes.

Metabolic Syndrome (MetS) is a collective term for a cluster of disorders, including dysglycemia, central obesity, dyslipidemia, hypertension, and eventual end organ damage. The combination of these disorders increases the risk of many kinds of end organ damages, including coronary heart disease, kidney failure, and cirrhosis. MetS is highly prevalent in the United States, affecting one third of the U.S. population in a 2009 estimate. The Lyon strains are three rat strains selectively inbred from the same colony of outbred rats for different blood pressure levels. The Lyon Hypertensive (LH) strain, in addition to its essential hypertension phenotype, also harbors many disorders found in MetS. The Lyon Normotensive (LN) rat strain is completely devoid of these symptoms, while Lyon Low-pressure (LL) is obese but is resistant to other traits of MetS. Rat chromosome 17 (RNO17) has previously been linked with many of MetS' phenotypes in Lyon Hypertensive (LH). In this project, we are using a mixture of genetical genomics and systems biology methods to identify genetic elements that may cause the LH phenotype. Divergent haplotype blocks between the Lyon strains were first identified by the analysis of the distribution of observed strain differences (OSD) calculated from the result of genome resequencing. Divergent haplotype regions totaling less than 16% of the rat genome that contain more than 95% of the identified SNPs in each of the three pairwise comparisons between the Lyon strains have been identified; in particular, there are 14 divergent haplotype blocks between LH and LN spanning 7.7% of RNO17 that harbor more than 97% of SNPs identified on RNO17. Twenty-five genes in these regions were thus identified as potential genetic determinants for MetS. Phenotypic QTLs (pQTL) and expression QTLs (eQTL) mapping from a cohort of male LH × LN F2 rats were performed by putting the cohort on a 15-week phenotyping protocol and genome-wide genotyping. Total liver RNA from 36 individuals from the cohort were sequenced to provide expression data for eQTL mapping. We have mapped 22 pQTLs that are statistically linked to 15 traits, with RNO17 linked to 15 traits associated with blood pressure, leptin and body weight. We have also identified 1,200 eQTLs from this cohort, including 11 eQTLs with cis-linkage with one or more genes. On RNO17, we have identified two SNPs between 29-39 Mb which are significantly linked to the expression of 85 genes; the only gene with cis-linkage with these SNPs, RGD1562963, was hence identified as a putative master regulator. Transcriptome analyses were then performed on the Lyon parental animals; the total liver and kidney of RNA from 6 each of LH, LL and LN strains that were subjected to the same 15-week phenotyping protocol were sequenced for differential expression analysis, gene coexpression network analysis and quantitative trait transcript analysis. Differential expression analysis identified 4 genes on RNO17's divergent haplotype regions: Cul2 and the aforementioned RGD1562963 for liver, Amph and Bambi for kidney. Quantitative trait transcript analyses have shown significant correlations between the expressions of these four genes with one or more of the traits of the animals treated, validating their status as potential genetic determinants for MetS. However, out of the 84 genes that RGD1562963 potentially regulates, only two other genes (Cul2 and Supt4h1) have significant correlations with one or more traits. Gene coexpression network analyses have shown a relationship between genes on the TGF-β pathway and the differentially expressed genes in the kidney, supporting our speculation on the hyperactivity of the TGF-β system in the etiology of the LH phenotypes. An LH-17LN consomic strain was also generated by introgressing an LN copy of RNO17 onto the LH genomic background to validate in vivo the role of RNO17 in the etiology of MetS symptoms in LH. We have observed that the consomic strain has significantly decreased body weight, adiposity, blood pressure, and inter-week blood pressure differences that may be a surrogate for salt sensitivity. Thus, the role of RNO17 on the LH genotype is validated. In summary, we have been able to identify, by in vivo and in silico methods, that RNO17 is related to the MetS traits in LH; that 4 genes, Amph, Bambi, Cul2, and RGD1562963, are potential genetic contributors to RNO17's effects; and that their effects may include, but are not limited to, the activation of TGF-Β signals.

Thesis (M.Sc. (Biochemistry))--North-West University, Potchefstroom Campus, 2007.

Obesity is today a problem that has reached epidemic proportions. One of the causes of obesity is the over-consumption of energy. Fat is the most energy-dense nutrient, where the quality seems to be more important for the development of the metabolic diseases than the quantity. The fatty acid composition in serum lipid fractions can be used to mirror the dietary fat quality. Stearoyl-CoA-desaturase (SCD) is an enzyme that converts saturated to monounsaturated fatty acids. A surrogate measure of SCD activity can be estimated as a fatty acid ratio; 16:1/16:0 (palmitoleic acid/palmitic acid) and 18:1/18:0 (oleic acid/stearic acid). The aim of this project was to investigate the intra-day variation in the SCD-ratio in humans eating a standardized diet. The results showed that triacylglycerol and nonesterified fatty acid fractions in serum lipids had a significant variance in the 16:1/16:0 ratio during the day, whereas 18:1/18:0 ratio in the same fractions did not exhibit the same pattern. In this study 16:1/16:0 ratio also seems to be a better marker than 18:1/18:0 ratio for estimating SCD activity. For further evaluation of the intra-day variation there need to be a more long-term study of the SCD-activity for a larger group of subjects.

Mexican-Americans are disproportionately burdened by metabolic syndrome, a medical condition characterized by the concurrence of clinical abnormalities that contributes to diabetes, obesity, and cardiovascular disease (CVD). This is alarming since Mexican-Americans constitute two-thirds of the US Latino population, the largest minority and fastest growing group in the US. Investigating acculturative stressors associated with immigration is crucial for eliminating health disparities, but few studies have examined the acculturative impact of Mexican migration to the United States or the relationship between acculturation and metabolic syndrome among Mexican-Americans. The purpose of this dissertation research was to investigate the associations between acculturation and metabolic syndrome among a bi-national sample of Mexicans and Mexican-Americans. Metabolic syndrome was assessed among a bi-national sample of individuals with diabetes using the definition outlined by the International Diabetes Federation, and acculturation was assessed by proxy measures (years lived in the US and generational status) and responses on the Acculturation Rating Scale for Mexican-Americans, version-II. Chi-square, analysis of variance, and logistic regression were used to determine relationships between country, gender, and acculturation status and metabolic syndrome and its biomarkers. The overall prevalence of metabolic syndrome was 79.7%, with 85.0% prevalence among Mexican-Americans and 75.7% among Mexicans (p=0.069). Mexican-Americans had higher blood pressure and central obesity, while Mexicans had higher triglycerides levels. The majority (81.2%) of Mexican-Americans was first generation and lived in the US for an average of 27.65 +/- 16.05 years. The mean acculturation score was -1.83 +/- 1.56, which indicated participants in this study were Mexican-oriented, or more closely associated to Mexican cultural influences than Anglo cultural influences. Higher acculturation scores were positively associated with fasting blood glucose and systolic blood pressure and lower acculturation was negatively associated with fasting blood glucose. Logistic regression analysis showed first generation Mexicans-Americans were more likely to develop metabolic syndrome than second generation Mexican-Americans (OR 7.399, 95% CI 1.464-37.401, p=0.015). Mexican and Mexican-American individuals with type 2 diabetes have a high prevalence of metabolic syndrome, which increases their risk for heart disease and other cardiovascular complications. Mexican-Americans are especially affected by central obesity and hypertension and Mexican immigrants appear to be impacted by negative lifestyle factors upon entering the United States. Acculturation is a complex process and the unclear relationship between acculturation and metabolic syndrome warrants further investigations.

The leading cause of death among women is coronary heart disease (CHD), a multifactorial disease with polygenic heritability estimated at 50%. Polymorphisms in the family with sequence similarity 5, member C’ ( FAM5C) gene have been associated with myocardial infarction (MI), and one single-nucleotide polymorphism (SNP) has partially accounted for linkage in an acute coronary syndrome subset. The linkage peak on FAM5C corresponds directly with a quantitative trait locus for the inflammatory biomarker monocyte chemoattractant protein 1, as well as a linkage peak to metabolic syndrome (MetS). Metabolic syndrome increases the risk of developing CHD, and MI has been positively associated with elevated inflammatory biomarkers. This study was designed as a descriptive pilot gene association study. The purpose was to investigate the variability of the FAM5C SNP (rs10920501) in a cohort of women with documented CHD. It also examined the association between the variability of the FAM5C SNP (rs10920501), MetS, inflammatory markers, and the association with early onset CHD in the presence or absence of MI. A subset of 91 women was derived from an earlier study of women randomized to either a gender-tailored or traditional cardiac rehabilitation program. The results indicated the T allele of FAM5C SNP rs10920501 has a strong protective effect in women with a history of MI. Women with a history of MI and the heterozygous (AT) genotype had a mean age of onset of CHD at 62 years, compared to the homozygous wild type (AA) with a mean age of onset at 55 years, (F (3, 34) = 5.00, p < .01). No women in this study with the homozygous variant (TT) had an MI, further demonstrating the protective effective of the T allele. The genotype of FAM5C SNP rs10920501 explains approximately seven percent of the variability of age of onset of CHD in women who have had an MI, while holding body mass index (BMI) and smoking history constant. There was no significant relationship between FAM5C SNP (rs109320501) and MetS or any inflammatory biomarkers in this sample. In conclusion, FAM5C remains a gene of interest in a complex disease process.

abstract / Pharmacology and Pharmacy / Doctoral / Doctor of Philosophy