Childhood obesity and subsequent poor health implications continue to be a critical health concern and recent literature suggests academics may also be under greater strain among these individuals. This study examined the relationship between metabolic health and academic achievement in students “at risk” for drop. Fifteen adolescences participated in an educational camp aimed at developing knowledge of core curriculum by developing design projects. Metabolic health was assessed via biochemical measurements of blood lipid and glucose, resting blood pressure, and anthropometric measurements of height, weight, and waist circumference. Variables were examined individually and as a combined risk score. Academic achievement measurements were results were obtained from district testing. Little association was found between academic achievement and metabolic health. BMI was greater than the 85th percentile for sample. Participants partook in 32.4 minutes/day of moderate-vigorous physical activity during camp. Slight variation between Pre-and Post- measures of academics suggests presence of confounding variables.

Development of type 2 diabetes (T2D) is preceded by prediabetes, which is a metabolically "atypical" state associated with chronic low-grade inflammation, overweight and obesity, lack of exercise, and detrimental changes to the gut microbiome. Dietary intake and exercise are modifiable lifestyle factors for reducing T2D risk; however, several questions remain unanswered related to the efficacy and role of prebiotics and exercise, and their respective influences on gut microbiome composition, intestinal permeability, insulin sensitivity and metabolic flexibility. Sedentary to recreationally active overweight and obese adults 40-75 years old at-risk for T2D were recruited (n=22) and randomized to either supplementation with inulin, a prebiotic dietary fiber, (10g/d) or maltodextrin while consuming a controlled diet for six weeks. At baseline and week 6, participants completed a stool collection, a 4-sugar probe test, an intravenous glucose tolerance test (IVGTT), and high-fat meal challenge with skeletal muscle biopsies to evaluate changes in the gut microbiome composition, intestinal permeability, insulin sensitivity and metabolic flexibility, respectively. There were no baseline group differences (all p>0.05). Following the intervention, Bifidobacteria operational taxonomic units increased in the intervention group ([placebo: Δ 9.5 ± 27.2 vs inulin: 96.3 ± 35.5][p=0.03]). There were no other group differences over time in any other outcome variables with the exception of changes in metabolic flexibility. Secondarily, a systematic review of literature was conducted to determine the influence of exercise engagement on gut microbiome composition. Overall, exercise interventions appeared to diversify taxa within the Firmicutes phylum, and specifically in several taxa associated with butyrate production and gut barrier function. Due to unclear risk of bias in all studies and low quality of evidence, additional research is needed using well- designed trials. In summary, the respective influences of prebiotics and exercise on human gut microbiome composition and their subsequent effects on metabolic function and disease risk are not well understood. / PHD

High-throughput transcriptomic profiling has become a ubiquitous tool to assay an organism transcriptome and to characterize gene expression patterns in different cellular states or disease conditions, as well as in response to molecular and pharmacologic perturbations. Refinements to data preparation techniques have enabled integration of transcriptomic profiling into large-scale biomedical studies, generally devised to elucidate phenotypic factors contributing to transcriptional differences across a cohort of interest. Understanding these factors and the mechanisms through which they contribute to disease is a principal objective of numerous projects, such as The Cancer Genome Atlas and the Cancer Cell Line Encyclopedia. Additionally, transcriptomic profiling has been applied in toxicogenomic screening studies, which profile molecular responses of chemical perturbations in order to identify environmental toxicants and characterize their mechanisms-of-action. Further adoption of high-throughput transcriptomic profiling requires continued effort to improve and lower the costs of implementation. Accordingly, my dissertation work encompasses both the development and assessment of cost-effective RNA sequencing platforms, and of novel machine learning techniques applicable to the analyses of large-scale transcriptomic data sets. The utility of these techniques is evaluated through their application to a toxicogenomic screen in which our lab profiled exposures of adipocytes to metabolic disrupting chemicals. Such exposures have been implicated in metabolic dyshomeostasis, the predominant cause of obesity pathogenesis. Considering that an estimated 10% of the global population is obese, understanding the role these exposures play in disrupting metabolic balance has the potential to help combating this pervasive health threat. This dissertation consists of three sections. In the first section, I assess data generated by a highly-multiplexed RNA sequencing platform developed by our section, and report on its significantly better quality relative to similar platforms, and on its comparable quality to more expensive platforms. Next, I present the analysis of a toxicogenomic screen of metabolic disrupting compounds. This analysis crucially relied on novel supervised and unsupervised machine learning techniques which I specifically developed to take advantage of the experimental design we adopted for data generation. Lastly, I describe the further development, evaluation, and optimization of one of these methods, K2Taxonomer, into a computational tool for unsupervised molecular subgrouping of bulk and single-cell gene expression data, and for the comprehensive in-silico annotation of the discovered subgroups.

Pulses (i.e. beans, lentils, and chickpeas) are enriched in plant-based proteins and non-digestible carbohydrates (e.g. fibre) that may beneficially impact intestinal and metabolic health. The objectives of this thesis were to determine if i) consumption of diet supplemented with kidney beans would improve biomarkers of intestinal and metabolic health, ii) dark-colored beans would provide additional health benefits compared to light-colored beans, and iii) background diet composition would impact the health effects of kidney bean consumption. Study 1: 5-week-old male C57Bl/6 mice were fed either a basal diet (BD; 20% casein, wt/wt), or isocaloric diets supplemented with 15% cooked white kidney beans or dark red kidney beans for 9 weeks (n=12/group); Study 2: 5-week-old male C57Bl/6 mice were fed either a high-fat diet (HF; 60% kcals from fat) or HF diet supplemented with 15% cooked white kidney beans or dark red kidney beans. In both studies, consumption of diets supplemented with beans improved microbiota community structure and activity, as indicated by increased abundance of short-chain fatty acid (SCFA) producing bacteria (Prevotella and S24-7) and intestinal SCFA concentrations, with dark kidney beans inducing the greatest effects. Furthermore, biomarkers of colonic inflammation, barrier integrity, and metabolic health were beneficially impacted by kidney bean consumption, however, the effects were greater in mice consuming low-fat vs. high-fat diets. In conclusion, this thesis demonstrated that while kidney bean consumption led to improvements in intestinal and metabolic health, the results were influenced by seed coat color and the nutrient composition of the background diet.

No description available.

Inactivity reduces insulin action. Energy surplus causes similar reductions to insulin action. Unless energy intake is reduced to match low energy expenditure during inactivity, a concurrent energy surplus may account for the lower insulin action. This study evaluated the effect of inactivity (sitting) with and without energy surplus on insulin action. Fourteen young (26.1 ± 4.5 years (M ± SD)), lean (23.7 ± 7.1% fat), fit (VO 2peak = 49.1 ± 3.3 ml*kg -1 *min -1 ) men (n=7) and women (n=7) completed each of 3, 24-hour conditions: an active condition (i.e. high energy expenditure with energy intake matched to expenditure) = ACTIV; (2) reduced energy expenditure (inactivity) with no reduction in energy intake (i.e. energy surplus) = INACTIV; (3) inactivity with energy intake reduced to match low energy expenditure = INACTIV LO-CAL. Insulin action was measured during a glucose infusion the following morning. Data were analyzed using linear mixed-effects models with planned contrasts. Compared to ACTIV, insulin action, defined as whole-body rate of glucose disappearance ( R d ) scaled to steady-state plasma insulin, was reduced 39% in INACTIV ( p < 0.001) and by 18% in INACTIV LO-CAL ( p = 0.07). Insulin action was also higher in INACTIV LO-CAL compared to INACTIV ( p =0.04). These results suggest that 1 day of sitting elicits large reductions in insulin action. Energy surplus accounts for half of the decline in insulin action, suggesting other factors are involved in the metabolic response to inactivity.

With age comes a decline in the dynamic regulation of a balanced and functional mitochondrial proteome (proteostasis) that leads to an increase in oxidative stress and macromolecule damage, with a decline in ATP production. Compromised protein networks and reduced available energy leaves an organism susceptible to accelerated aging and the onset of age-related disease. Since mitochondrial respiratory complexes are composed of protein subunits from both mitochondria and nuclear genomes, their assembly relies on the coordination of mitochondrial and cytoplasmic translation machinery. Disruption of mitochondrial translation generates an imbalance in the ratio of mitochondrial (mtDNA) to nuclear DNA (nDNA) encoded proteins, which is called a mitonuclear protein imbalance. In response to the protein imbalance, a retrograde stress signal is sent from the mitochondria to the nucleus, invoking the mitochondrial unfolded protein response (UPRᵐᵗ) to resolve the mitoproteostatic stress. In a young healthy cell, the UPRᵐᵗ upregulates protein folding chaperones and proteases to resolve the consequences of a mitonuclear protein imbalance. In the early stages of aging, the UPRᵐᵗ appears to be upregulated in response to age-related mitochondrial proteostatic stress. In aged senescent cells however, the UPRᵐᵗ response is blunted. There is cross-species evidence that induction of the UPRᵐᵗ through moderate-intensity exercise or through genetic disruption of the mitochondrial translation machinery will act as a hormetic - resulting in health benefits in the long term. Caenorhabditis elegans longevity models demonstrate that a reduction in mitochondrial ribosomal protein (Mrp) gene expression or disturbed mitochondrial translation will function as a hormetic. The disruption of the mitochondrial ribosome leads to a mitonuclear protein imbalance, invokes the nematode UPRᵐᵗ, which then robustly extends C. elegans lifespan and health span. To determine whether the hormetic effects of mild mitochondrial ribosome disruption can be recapitulated in a mammalian model, this thesis tests a C57/BL6/NTaconic mouse model altered in the germline to have reduced Mrpl54 expression through heterozygous mutation. Mice were metabolically tested at ages 6-, 18-, and 24-months and followed through their natural lifespan to determine whether reduction in the expression of a critical Mrp (Mrpl54) impacts lifespan or metabolic health span. While Mrpl54 mRNA expression was ~50% of wildtype in all Mrpl54⁺ᐟ⁻ tissues tested, there were no differences observed in metabolic health with age or lifespan in either male or female mice. Cultured Mrpl54⁺ᐟ⁻ primary myoblasts had lower absolute levels of nDNA- and mtDNA-encoded respiratory complex subunits relative to wildtype; however, the ratio between nDNA- and mtDNA-encoded protein subunits remained like wildtype. Further testing of the model revealed that Mrpl54⁺ᐟ⁻ males had weaker grip strength by age 12-months, which was also found in the data from multiple heterozygous Mrp (Mrp⁺ᐟ⁻) mouse models available at the International Mouse Phenotyping Consortium. 12-month-old Mrpl54⁺ᐟ⁻ males displayed reduced tetanic force and better fatigue recovery in ex vivo skeletal muscles, and the transmission electron micrographs of skeletal muscle sarcomeres revealed an early aging phenotype. Unlike the C. elegans reduced Mrp longevity model, reduced expression of a critical Mrp did not result in lifespan or metabolic health span benefits in a mouse model. In contrast, the Mrpl54⁺ᐟ⁻ male model showed evidence of premature skeletal muscle aging. While the results of this research do not support the role of Mrpl54 reduced expression in mammalian lifespan or health span extension, they do point to a premature aging phenotype for certain muscle parameters that may be relevant to people living with heterozygous mitochondrial protein mutations. Typically, these individuals are regarded as carriers and free of phenotype associated with their mitochondrial protein mutation. The results in this thesis suggest that those with a heterozygous mitochondrial protein gene mutation may manifest a phenotype as they grow older and are less resilient to external or internal challenges.

Studies have identified metabolic health factors to be a major concern in Mexican-Americans, including Mexican immigrants to the United States (U.S.). Acculturation stress has been hypothesized to be a factor in the development of many health-related concerns in this population. Specifically, previous studies have shown that acculturation stress contributes to health concerns, including metabolic health concerns (e.g., diabetes, metabolic syndrome). The primary purpose of this study was to examine the relationship between cultural orientation, a measure of acculturation designed to provide more information than traditional acculturation measures, and metabolic health outcomes. Specific acculturation-related stressors (social support, job-related stress, and depression) were hypothesized mediators in this relationship among a convenience sample of 98 foreign-born Mexicans living in Utah County, Utah controlling for age, gender, socio-economic status (SES), and years in the U.S. Data were collected twice with a three year interval to examine change over time. Changes in these constructs were examined through the use of Growth Modeling with Bayesian estimation. The Acculturation Rating Scale for Mexican-Americans (ARSMA-II) was used to measure Anglo Cultural Orientation and Mexican Cultural Orientation. Standard blood analyses were used to measure metabolic health outcomes, which included glycosylated hemoglobin (HbA1c), insulin, and glucose. The Interpersonal Support Evaluation List (ISEL-12) was used to measure social support, the Job Content Questionnaire (JCQ) was used to measure job-related stress, and the Center for Epidemiological Studies-Depression Scale (CES-D) was used to measure depression. No change was identified in Anglo Cultural Orientation or Mexican Cultural Orientation over time in the majority of subjects. A positive relationship between Anglo Cultural Orientation and HbA1c was found, as was a negative relationship between Mexican Cultural Orientation and HbA1c. Mediation analyses showed a mediation effect of depression on the relationship between Anglo Cultural Orientation and glucose. Implications of findings, limitations, and directions for future research are discussed.