PhD, University of Cincinnati, 2020, Medicine: Epidemiology (Environmental Health)

Background: Metabolic syndrome (MetS) affects ~10% of adolescents and is associated with development of diabetes and heart disease. The MetS severity z-score can be used to estimate MetS risk on a continuous scale. The most prevalent MetS component is abdominal obesity, commonly assessed using body mass index (BMI) or waist circumference. Sagittal abdominal diameter (SAD) also measures abdominal obesity and is highly correlated with visceral fat, which in turn is associated with disease risk. The purpose of this research was to examine the association of lifestyle factors with SAD and MetS z-score in typical US adolescents (Aim 1), and to explore the relationship between SAD and MetS z-score in adolescents undergoing weight loss surgery (Aim 2). Methods: Aim 1 was a cross-sectional analysis of adolescents from the National Health and Nutrition Examination Survey (NHANES) 2011-2016. Two 24-hour diet recall interviews were used to calculate Healthy Eating Index (HEI)-2015 scores indicating diet quality. Self-reported physical activity habits were used to determine adherence to national guidelines (= 60 min/day). In Aim 2, we examined data from Teen Longitudinal Assessment of Bariatric Surgery (TeenLABS) participants. Demographic, anthropometric (SAD, waist circumference, BMI), and lab data were analyzed from baseline (pre-surgery), and 6 months, 1 year, and 5 years post-surgery. In both studies, SAD was measured using NHANES procedures, MetS prevalence was defined using age-appropriate criteria, and MetS z-score was calculated according to sex- and race-specific formulas. In Aim 1, multivariable linear regression was used to evaluate the relationship of diet, SAD and physical activity with MetS z-score, and analysis was stratified by sex. For Aim 2, the association between SAD and MetS z-score was evaluated using a linear mixed model, adjusted for pre-defined covariates. Results: Aim 1 included 1,214 adolescents, with 49.2% female and mean age 15.4 years. Fe (open full item for complete abstract)

Committee: Jane Khoury Ph.D. (Committee Chair); Ranjan Deka Ph.D. (Committee Member); Thomas Inge M.D. Ph.D. (Committee Member); Todd Jenkins Ph.D. (Committee Member) Subjects: Epidemiology

PHD, Kent State University, 2025, College of Arts and Sciences / School of Biomedical Sciences

Cardiovascular disorders remain the leading cause of morbidity and mortality worldwide, with atherosclerosis as the predominant underlying pathology. In individuals with Metabolic Syndrome (MetS), which encompasses conditions such as obesity, diabetes, dyslipidemia, and hypertension, the development of atherosclerosis is accelerated. Vascular smooth muscle cells (VSMCs) play a pivotal role in atherosclerotic plaque formation through phenotypic switching—a process influenced by various extracellular factors, including TSP1. TSP1, a matricellular glycoprotein, has emerged as a key mediator of vascular inflammation, remodeling, and cell behavior. However, its precise role in VSMC differentiation and atherosclerosis in the context of MetS remains unclear. The significance of my dissertation lies in addressing the critical knowledge gap surrounding TSP1's role in VSMC phenotypic modulation within atherosclerotic lesions, particularly under the compounded metabolic stresses of MetS. The goal of this study was to elucidate the effect of TSP1 on VSMC behavior and plaque development. We specifically investigated the link between TSP1 expression, atherosclerosis, and SMC differentiation in MetS and the regulatory role of smooth muscle-specific TSP1 in SMC phenotypic changes in diabetes and the molecular pathways involved. We found that agouti KKAy+/-ApoE-/- mice (MetS) exhibited pronounced metabolic disturbances, including significant increases in body weight, non-fasted blood glucose levels (>250 mg/dL), and plasma lipid levels (cholesterol and triglycerides) compared to non-agouti KKAy-/-ApoE-/- controls (non-MetS). Male MetS mice demonstrated severe glucose intolerance, although insulin sensitivity was unaffected across groups. Male MetS mice exhibited significantly greater lipid burden and plaque area in the aortic root associated with upregulation of TSP1 and lesser testosterone levels compared to non-MetS males. However, female MetS mice did not display the same les (open full item for complete abstract)

Committee: Priya Raman (Advisor); Mohammad Yunus Ansari (Committee Member); Jessica Ferrell (Committee Member); Vahagn Ohanyan (Committee Member) Subjects: Biomedical Research; Pharmacology

Doctor of Philosophy in Regulatory Biology, Cleveland State University, 2024, College of Arts and Sciences

Eukaryotic initiation factor 2A (eIF2A) is a highly conserved 65 kDa eukaryotic protein that functions in minor initiation pathways, which affect the translation of only a subset of messenger ribonucleic acid (mRNAs), such as internal ribosome entry site (IRES)-containing mRNAs and/or mRNAs harboring upstream near cognate/non-AUG start codons. These non-canonical initiation events are important for regulation of protein synthesis during cellular development, differentiation and/or the integrated stress response. Selective eIF2A knockdown in cellular systems was shown to inhibit translation of such mRNAs, which rely on alternative initiation mechanisms for their translation. However, there existed a gap in our understanding of how eIF2A functions in mammalian systems in vivo (on the organismal level) and ex vivo (in cells). To address this question we have developed the eIF2A-total body knockout (KO) mouse model. Using this model, we presented evidence implicating eIF2A in the biology of aging and metabolic syndrome. We discovered that eIF2A-KO mice have reduced life span and that eIF2A plays an important role in maintenance of lipid homeostasis, the control of glucose tolerance and insulin resistance. We also showed the eIF2A KO affects male and female mice differently, suggesting that eIF2A may affect sex-specific pathways. The metabolic syndrome phenotype has three main etiological categories: obesity and disorders of adipose tissue (particularly increased size of adipocytes); glucose intolerance and insulin resistance; and a constellation of independent factors of hepatic, vascular, and immunologic origin and all of these features were observed in the eIF2A-KO mice. Increased adipocyte size is, in particular, well known to be positively correlated with impaired insulin sensitivity and glucose tolerance leading to metabolic syndrome. To specifically check whether the absence of eIF2A in adipose tissue is responsible for metabolic abnormalities observed in the tota (open full item for complete abstract)

Committee: Anton Komar (Committee Chair); Barsanjit Mazumder (Committee Member); Roman Kondratov (Committee Member); William Baldwin III (Committee Member); Merlin Gnanapragasam (Committee Member); William Merrick (Committee Member) Subjects: Biology; Molecular Biology; Physiology

Master of Science, The Ohio State University, 2008, Graduate School

Committee: Not Provided (Other) Subjects:

Doctor of Philosophy in Clinical-Bioanalytical Chemistry, Cleveland State University, 2024, College of Liberal Arts and Social Sciences

Metabolic syndrome (MetS) is a complex condition characterized by a cluster of metabolic abnormalities including obesity, dyslipidemia, insulin resistance, and hypertension. These abnormalities significantly increase the risk of health disorders such as cardiovascular diseases and type 2 diabetes. However, the molecular mechanisms underlying MetS are not fully understood. Recent evidence shows that Ribonuclease L (RNase L), an antiviral protein, is emerging in MetS. RNase L is an interferon inducible enzyme involved in innate immunity during viral infection. In this study, we investigated the role of RNase L in MetS using RNase L wildtype and knockout mice and cells. The findings revealed that RNase L deficiency did not influence food intake but significantly impacted glucose clearance post-glucose challenge, leading to insulin resistance in KO mice. Subsequent investigation of how RNase L affects insulin signaling unveiled a pronounced decrease in insulin responsiveness in RNase L knockout cells. Additionally, we employed the LC/MS proteomic method to identify a potential target of RNase L, which may elucidate the molecular mechanism underlying the involvement of RNase L in insulin signaling. These results highlight the intricate role of RNase L in MetS and underscore RNase L as a conceivable therapeutic target for this disorder.

Committee: Aimin Zhou (Advisor); Crystal Weyman (Committee Member); Xue-Long Sun (Committee Member); Michael Kalafatis (Committee Member); Bin Su (Committee Member) Subjects: Biochemistry; Cellular Biology; Health Sciences; Molecular Biology

Doctor of Philosophy, The Ohio State University, 2024, Psychology

Perceived discrimination is a psychosocial stressor defined as the experience of unfair treatment based on race, sex, religion, or other characteristics. Experiences of discrimination have been associated with negative physical and psychological health outcomes. Though less frequently studied, discrimination has also been linked to adverse cognitive outcomes. Discrimination is particularly important to study as chronic stress may accelerate preexisting vulnerabilities, thereby exacerbating negative health outcomes. The goal of this project is to clarify the role of discrimination in two important contexts: racial disparities in cognitive health and age-related cognitive decline. The current study will examine the association between discriminatory experiences and cognitive functioning in a sample of healthy adults from the Midlife in the United States (MIDUS) dataset. Moreover, I will leverage the comprehensive biological and psychological information available through MIDUS to explore the mediating impact of inflammatory markers, metabolic syndrome, and allostatic load, as well as the moderating impact of psychosocial factors on these relationships. I will test these relationships by pursuing three specific studies. Study 1 investigates whether perceived discrimination mediates the relationship between self-reported race and cognitive functioning. Study 2 describes the relationship between perceived discrimination and cognition across the lifespan. Additionally, this study will explore the role of moderating social factors on the relationship between discrimination and cognition. Study 3 then clarifies the role of health mediators in these relationships. The implications of these results are threefold. First, they will provide a more comprehensive understanding of the relationship among these factors; second, they will highlight who may be at increased risk for cognitive decline following experiences of discrimination; and third, these results may enable researcher (open full item for complete abstract)

Committee: Jasmeet Hayes (Committee Chair); Jesse Walker (Committee Member); Baldwin Way (Committee Member); Scott Hayes (Committee Member) Subjects: Clinical Psychology

Master of Science, The Ohio State University, 2023, Veterinary Clinical Sciences

Equine metabolic syndrome is a collection of clinical and clinicopathologic findings including insulin dysregulation (ID), regional adiposity or obesity, and laminitis. Insulin dysregulation and hyperinsulinemia are associated with development of hyperinsulinemia-associated laminitis (HAL), resulting in significant welfare and financial implications. Previous research in our laboratory identified attenuation of activated 5'-adenosine monophosphate-activated protein kinase (AMPK) concentrations and increased downstream activation of mechanistic target of rapamycin (mTOR) signaling in digital lamellar tissue of horses with laminitis. Therapy with other AMPK agonists has been investigated alone and in combination (such as metformin and aspirin), yielding variable efficacy in altering ID. Since mTOR is upregulated in laminitis, resveratrol (RES) may also be an attractive therapeutic target for HAL. The purpose of this investigation was to evaluate the effects of combination treatment with RES (10 mg/kg PO q12hr), metformin (MET; 30 mg/kg PO q12hr), and aspirin (ASP; 20 mg/kg PO q24hr) on experimentally-induced ID. We hypothesized that co-administration of AMPK agonists would improve insulin and glucose dynamics in experimentally-induced equine ID. ID was induced in 33 healthy adult light-breed horses using dexamethasone (0.08 mg/kg by mouth every 24 hours). Horses were randomly assigned to one of 5 treatment groups: RES, MET/ASP, RES/ASP, RES/MET/ASP, and placebo (CON). Frequently-sampled insulin-modified IV glucose tolerance tests (FSIGTT) and oral sugar tests (OST) were performed at baseline, after 7 days of dexamethasone administration (ID), and after ID plus 7 additional days of AMPK agonist treatment. Minimal Model analysis was performed to calculate AIRg (acute insulin response to glucose), insulin sensitivity (SI), glucose effectiveness (Sg), and disposition index (DI) from the FSIGTT [insulin] and [glucose] data. Area under the curve of [insulin] (AUCins) and (open full item for complete abstract)

Committee: Teresa Burns (Committee Chair); Ramiro Toribio (Committee Member); Laura Hostnik (Committee Member) Subjects: Endocrinology

Doctor of Philosophy, The Ohio State University, 2023, Biomedical Sciences

Gene therapy refers to the use of genetic material to treat disease through gene addition, gene correction/alteration, or gene knockdown. The goal of the technique is to address the root causes of disease rather than symptoms alone. Gene therapy holds promise for treating a wide range of diseases, including many genetic disorders and certain types of cancer. Gene therapy was first conceptualized in the 1970s and 1980s following advances in our knowledge of genetic material. The first clinical trials were rightly met with skepticism due to lack of concern for patient safety and regulatory bodies. Ultimately, the first attempts came too soon and resulted in various adverse events and widely publicized patient deaths. The field slowed in the 1990s and early 2000s as we began to understand the basic science of gene therapy vectors and expand a so-called “toolkit” of vectors to increase safety and efficacy. Subsequent clinical trials proved more promising and resulted in the approval of the first gene therapies. Currently, gene therapy remains a clinical reality, though more work is needed to expand the number of therapeutics and indications. Adeno-associated viral (AAV) vectors are one tool within the gene therapy toolkit. AAVs are thought to be relatively safe for gene transfer due to their largely non-integrative nature and tendency to trigger mild immunogenic responses. Certain challenges remain in the field to maximize the utility of AAVs as vectors, including the need for cell-specific targeting, appropriate levels of the therapeutic construct, and the ability to evade immunogenic responses. The development of recombinant AAVs (rAAVs) through engineering of the transgene cassette and viral capsid can address many of these concerns, as both can dictate cellular transduction, transgene expression levels, and immune responses. Other areas of optimization include the use of different administration routes and dosing schedules. The combination of all the above will be (open full item for complete abstract)

Committee: Lei Cao (Advisor); Dana McTigue (Committee Member); Takeshi Kurita (Committee Member); Allison Bradbury (Committee Member) Subjects: Endocrinology; Neurobiology; Neurosciences

Master of Science (MS), Wright State University, 2022, Pharmacology and Toxicology

Pancreatic islet β-cell plays an essential role in insulin release and hence glucose homeostasis. The maintenance of glucose homeostasis depends on β-cell ability to cope with enough insulin to fulfill metabolic and physiological demands. Adequate insulin release is the result of highly complex and dynamic interplays between acute changes in β- cell electrical activity, exocytosis and chronic adaptations in cellular function, volume, mass and proliferation. All of this appears modulated, to some extent, by the functional presence of Slc12a2 symporters, also known as Na+K+2Cl– cotransporter-1 (Nkcc1), which accumulates intracellular Cl– above its electrochemical equilibrium. Recent studies from our laboratory showed that mice lacking Nkcc1 in β-cell (Nkcc1βKO) develop a cluster of metabolic phenotypes reminiscent of the metabolic syndrome i.e., hyperglycemia, hyperinsulinemia, glucose intolerance, insulin resistance, steatohepatitis and overweight. The present study is aimed at determining the potential relationship between those phenotypes and pancreas morphometric parameters including islet size, β-cell number, volume, mass and neogenesis. The results presented here indicate that elimination of Nkcc1 from β-cell negatively impact those parameters, even before the onset of overweight and its metabolic complications. Therefore, we propose that Nkcc1 plays a potential causative role in the development of metabolic syndrome.

Committee: Mauricio Di Fulvio Ph.D. (Advisor); Courtney Sulentic Ph.D. (Committee Member); Khalid Elased Pharm.D., Ph.D. (Committee Member) Subjects: Biology; Pharmacology

Doctor of Philosophy, The Ohio State University, 2020, Ohio State University Nutrition

Early studies of energy expenditure highlighted the reciprocal relationship between increases in energy metabolism and life expectancy. A growing body of literature emphasizes that individuals suffering from metabolic and chronic diseases have higher energy demands to fight illness in addition to the energy necessary for homeostatic maintenance. Two conditions of metabolic dysregulation, cancer cachexia and metabolic syndrome illustrate this phenomenon. Each condition exhibits 5 shared pathological characteristics which contribute to metabolic disease progression: dysregulated energy balance, insulin resistance, mitochondrial dysfunction, dysregulated lipid storage and adipocyte function, and chronic inflammation. The goal of this research was to identify bioactive dietary components that improve the pathologies associated with cancer cachexia and metabolic syndrome. The first objective of this research was to evaluate the therapeutic effect of dietary naringenin in mice with C-26 adenocarcinoma-induced cachexia. Cancer cachexia is characterized by the loss of skeletal muscle with or without the loss of adipose tissue that results in functional impairment impacting quality of life and overall survival. Naringenin is a flavonoid most commonly found in citrus fruits and tomatoes that has a wide range of positive effects in pre-clinical models, including improving insulin-mediated metabolism while reducing inflammation and tumor growth. Therefore, we hypothesized that a diet supplemented with naringenin would prevent the progression of cancer cachexia by inhibiting body weight loss, improving insulin sensitivity, and decreasing inflammation in a mouse model of cancer cachexia. We examined the effects of 2% dietary naringenin on changes in food intake, body weight, body composition, muscle function, insulin tolerance, and inflammatory status in the Colon 26 mouse model. Naringenin-fed tumor-bearing mice exhibited body weight loss and decreased food intake earlier th (open full item for complete abstract)

Committee: Martha Belury Ph.D. RD (Advisor); Kichoon Lee Ph.D. (Committee Member); Tonya Orchard Ph.D. RD (Committee Member); Noah Weisleder Ph.D. RD (Committee Member) Subjects: Biology; Health Sciences; Nutrition

Master of Science, The Ohio State University, 2020, Human Ecology: Human Nutrition

Metabolic syndrome (MetS) and its associated risk factors are a major public health issue in the United States. Those with MetS often experience dysregulated metabolic responses which provoke oxidative stress and decrease nitric oxide bioavailability, which causes impaired vascular endothelial function (VEF) and is related to increased cardiovascular disease (CVD) risk. One approach to mitigating this has been limiting carbohydrate intake to decrease postprandial rises in blood glucose, however low-carbohydrate diets tend to lack important food sources of nutrients (such as fruits and vegetables) and be high in fat (especially saturated fat). Therefore, there is a need to identify dietary patterns which reliably decrease CVD risk. Potatoes are of research interest because epidemiological studies have suggested negative effects on cardiometabolic health. However, these studies have largely ignored the way in which potatoes are often consumed and cannot identify causal relationships. Resistant starch has been suggested to improve glycemic control and thus vascular endothelial function (VEF) and is present in cooked and cooled potatoes at about 5% by weight. The objective of this thesis was to establish evidence that incorporation of potatoes into a dietary pattern based on the Dietary Guidelines for Americans (DGA) enhances cardiometabolic health in persons with MetS by improving metabolic and vascular responses. The hypothesis was that the inclusion of potatoes, as part of a DGA-based dietary pattern, would attenuate postprandial hyperglycemia (PPH)-mediated impairments in VEF. The approach entailed a two-arm, randomized controlled, cross-over trial in which the diet of MetS adults was rigorously controlled for two weeks to deliver a DGA-based meal pattern containing potatoes (17.5 g/day RS) or an energy-matched bagel (control; <1 g/day RS). Fasting glucose and insulin were assessed at the beginning (day 0) and end (day 14) of each intervention. Postprandial glycemia (open full item for complete abstract)

Committee: Richard Bruno (Advisor); Alejandro Relling (Committee Member); Carolyn Gunther (Committee Member) Subjects: Nutrition

Doctor of Philosophy, The Ohio State University, 2019, Nutrition Program, The Ohio State University

Biofilm infected chronic wounds are a major healthcare challenge. Biofilm infected chronic wounds appear visually closed, but remain functionally open because of lack of barrier function of the repaired skin. These defectively closed wounds show high recurrence rate which significantly increase the healthcare cost. Cutaneous lipids play a key role in maintaining barrier function of the skin. Ceramides are major (50%) epidermal lipids. Ceramide levels are regulated by ceramidases, transcription factor, peroxisome proliferator activator delta (PPARδ) and its target gene lipid transporter, ABCA12. However, the role of ceramides in would healing remain largely unknown. I hypothesize that biofilm infection depletes cutaneous ceramide levels in wounds that compromises skin barrier function. I tested this hypothesis in a porcine pre-clinical wound healing model that closely resembles human wound healing. Full thickness burn wounds (2”x2”) were created on pigs and followed up to 56 days post-wounding with or without infection of Pseudomonas aeruginosa or Pseudomonas ceramidase mutant strains. Analyses of wound closure by digital planimetry, skin barrier function by measuring trans epidermal water loss (TEWL), ceramide levels by lipidomics and immunohistochemistry (IHC), PPARδ and ABCA12 expression by IHC, quantitative RT-PCR and western blot was performed. I found five hundred fold increases in bacterial ceramidases in biofilm-infected pig wound tissues causing depletion of long chain ceramides in the wounds. Depletion of cutaneous ceramides downregulated PPARδ resulting in compromised ABCA12-dependent transport of lipid molecules to stratum corneum. Such disruption of ceramide homeostasis causes compromised barrier function of the repaired skin. Further depletion of ceramide was rescued by bacterial ceramidase inhibitor ceramidastin. These effects were absent in biofilm-infection caused by ceramidase mutant of Pseudomonas. This study showed that microbial ceramidase deplet (open full item for complete abstract)

Committee: Ouliana Ziouzenkova PhD (Advisor); Chandan Sen PhD (Committee Co-Chair); Cameron Rink PhD (Committee Member); Irene Hatsu PhD (Committee Member) Subjects: Microbiology; Nutrition; Surgery

Master of Science in Exercise and Health Studies, Miami University, 2019, Exercise and Health Studies

The ratio of adiponectin-to-leptin (A/L) is strongly correlated with risk of chronic disease19, 29, 36. Limited research has been conducted examining the relationship between physical activity and A/L. Thus, the PURPOSES of this study are to evaluate the associations between A/L and habitual physical activity, metabolic syndrome criteria (MSF), and HOMA-IR. METHODS: The proposed project examined the relationship between adiponectin and leptin with habitual physical activity levels and HOMA – IR in healthy adults (age: 58 years or older). Habitual physical activity data were obtained objectively (7-day accelerometry; OPA) and subjectively (CHAMPS; SPA). Serum hormone levels was measured through ELISA of blood samples. Partial correlations and hierarchical linear regression analyses were also performed. RESULTS: A/L and adiponectin were directly, while leptin was indirectly associated with SPA, except when adjustment for BMI was performed. Leptin was also indirectly associated with OPA prior to BMI adjustment. A/L was predictive of HOMA-IR and MSF, although leptin and adiponectin included separately in a model predicted greater variance. CONCLUSION: Our results supported all hypotheses, although it appears that leptin has the strongest relationship with measures of physical activity and the hormones added as separate entities in a model are more predictive of HOMA-IR and MSF compared to A/L.

Committee: Kyle Timmerman Dr. (Advisor); Kevin Ballard Dr. (Committee Member); Ronald Cox Dr. (Committee Member) Subjects: Behavioral Sciences; Biology; Health; Health Care; Health Sciences; Kinesiology; Physiology

Doctor of Philosophy, The Ohio State University, 2019, Nutrition Program, The Ohio State University

The diagnosis and treatment of chronic diseases, including metabolic syndrome, in the United States (U.S.) and worldwide continues to challenge our healthcare system. Despite efforts to reduce the prevalence of metabolic syndrome and the clustering of components that make up metabolic syndrome, there have been no significant reductions in prevalence when last reported in 2006. Notably as age increases, the prevalence of metabolic syndrome increases. While the increasing prevalence has been noted, there are no real treatments for metabolic syndrome or the individual components of metabolic syndrome, rather management of symptoms as the disease continues to progress. This research study identifies the current state of metabolic syndrome in post-menopausal women and men >55 years of age in the U.S. based on data from National Health and Nutrition Examination Survey (NHANES), providing an update to previous research in a traditionally high-risk sub-group. This research study also examines dietary soy intake and phytoestrogen excretion paving the way for translational research using a functional food to potentially impact metabolic syndrome in this high-risk population. Based on NHANES data from 2009-2014, the prevalence of metabolic syndrome in post-menopausal women and men >55 years of age in the U.S. is 41.8%. Consistent with previous research, the prevalence in adults age 60-69 years (43.3%) and >70 years (43.5%) were highest compared to <60 years (37.3%). A diagnosis of metabolic syndrome increases the risk of chronic diseases including type 2 diabetes mellitus, hyperlipidemia, stage 1 hypertension, stage 2 hypertension, a cardiovascular disease event and obesity. Average dietary soy intake was 0.04 + 0.01 oz with a maximum intake of 1.54 oz and 15.4% of the study population consuming greater than 0 oz of dietary soy. Correlation of average daily dietary soy intake and urinary phytoestrogen metabolites was significant (ρ=0.16, p<0.01). No significant differenc (open full item for complete abstract)

Committee: Susan Olivo-Marston (Advisor); Martha Belury (Committee Member); Randall Harris (Committee Member); Yael Vodovotz (Committee Member) Subjects: Nutrition

Doctor of Philosophy, The Ohio State University, 2019, Kinesiology

The metabolic pathways responsible for the synthesis, transport and utilization of ketones are ancient and served an important evolutionary role for humans during prolonged periods of food deprivation. Today, this beneficial metabolic program is largely silenced owing to the abundance of carbohydrate-dense food present in the food supply. However, when dietary carbohydrate is restricted and protein consumed in moderation, the ketogenic metabolic machinery awakens. After just a few days circulating ketones increase by an order of magnitude and over several weeks there is a profound shift away from away from glucose as the primary energy substrate to the preferred use of fatty acids and ketones. We refer to this metabolic process as keto-adaptation. The de-emphasis on insulin-dependent glucose uptake into cells and concomitant increase in fat oxidation has important implications in the management of insulin resistance and its secondary manifestations (e.g, cancer, obesity, metabolic syndrome, type-2 diabetes), which are all functionally carbohydrate intolerant conditions. Given the majority of adults in the U.S. are suffering from some degree of insulin resistance; the health implications of keto-adaptation are profound. In a definitive break from traditional groupthink, chronic disease patients are now experimenting with diets low in carbohydrate in an effort to improve their health, body composition, and disease state. This chapter will explore the rationale for the construct of keto-adaptation as a tool for achieving general well-being and improved health related outcomes.

Committee: Jeff Volek (Advisor); Maryam Lustberg (Committee Member); Brian Focht (Committee Member); William Kraemer (Committee Member) Subjects: Kinesiology

Master of Science, The Ohio State University, 2018, Allied Medicine

Approximately 93 million adults and over 13 million children and adolescents across the U.S. are considered overweight or obese.1 Healthcare expenditures are shown to be 81% greater in obese adults versus those of normal-weight.2 Obesity has been linked to several chronic health conditions and severe disease risks. These health concerns include risk for cardiovascular disease, type 2 diabetes, some cancers, and metabolic syndrome.3 The prevalence of type 2 diabetes and hypertension has steadily increased in the United States and the prevalence of metabolic syndrome is estimated at more than 30%.4UUnderstanding the trends in metabolic syndrome and examining those who are at an increased risk for metabolic conditions is paramount.4 Therefore, it is essential that accurate and reliable tools are used and implemented to assess patients at risk for metabolic syndrome. Currently body mass index (BMI), waist circumference (WC), and dual-energy x-ray absorptiometry (DXA) are believed to be appropriate screening measures. Expanding on the work of Hamagawa et al.5, and Suzuki et al.6, this work adds evidence for providing a cost effective, portable, accurate, and non-ionizing approach to assess an individuals' abdominal adiposity. This approach uses diagnostic medical sonography (DMS) as a tool for assessing abdominal adiposity in hopes of this method being adopted to help determine an individual's risk for metabolic conditions. Participants provided several anthropometric measures as well as imaging data, to determine if sonographic measures of abdominal fat could be an accurate screening technique for gauging the risk for heart disease, stroke, and diabetes. Measurements were taken on a GE Logiq i laptop ultrasound unit to indirectly asses the participants' subcutaneous fat and visceral fat. These measures were then compared to corresponding measures of BMI, WC, and DXA (android percent body fat, subscores). Additionally, a mesenteric fat thickness measurement was taken (open full item for complete abstract)

Committee: Kevin Evans (Advisor); Colleen Spees (Committee Member); Randee Hunter (Committee Member) Subjects: Health Care; Medicine; Radiology

Doctor of Philosophy (PhD), University of Toledo, 2018, Biomedical Sciences (Molecular Medicine)

Insulin resistance has long been considered to play a crucial role in the pathophysiology of metabolic syndrome that is the leading cause of mortality and morbidity worldwide. Metabolic diseases consist of a group of metabolic abnormalities that increase the risk of health problems, such as type 2 diabetes (T2D) and cardiovascular disease. Nonalcoholic fatty liver disease (NAFLD) is associated with obesity and metabolic syndromes. It is the fastest growing cause of liver dysfunction. Its progressive form nonalcoholic steatohepatitis (NASH) is associated with hepatic fibrosis that can develop into cirrhosis. In addition, there is a growing body of evidence that among risk factors that promote atherosclerosis, metabolic syndrome is a potent predictor of cardiovascular events. Insulin resistance seems to play a major role in the pathophysiology of atherosclerosis in relation with metabolic syndrome. Given that patients with NAFLD/NASH are at a high risk to develop atherosclerosis; these two diseases may share some pathology. However, precise molecular mechanisms underlying the pathogenesis and progression of these diseases are not well understood. Thus studying the molecular link between them would pinpoint sites of more effective pharmacologic interventions. The carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), a protein that is markedly reduced in the liver of patients with NASH, promotes insulin clearance to regulate insulin action. Whether or not CEACAM1 links hyperinsulinemia to NAFLD/NASH and atherosclerosis still needs to be determined. CEACAM1 enhances the rate of uptake of the insulin-receptor complex into the clathrin-coated vesicles of hepatocytes. It also plays a major role in mediating the negative acute effect on fatty acid synthase (Fasn) activity. As such, CEACAM1 regulates insulin and lipid metabolism. Mice with global null mutation of CEACAM1 (Cc1–/–) display hyperinsulinemia resulting from impaired insulin clearance, insulin resist (open full item for complete abstract)

Committee: Sonia Najjar PhD (Committee Chair); Guillermo Vazquez PhD (Committee Member); Jennifer Hill PhD (Committee Member); Rajesh Gupta MD (Committee Member); David Kennedy PhD (Committee Member); Steven Haller PhD (Committee Member) Subjects: Biomedical Research

Doctor of Philosophy, The Ohio State University, 2018, Biomedical Sciences

Cardiometabolic disease, a condition characterized by an abnormal metabolic phenotype, presents a major public health burden, as it is a chronic condition that affects over 30% of American adults. Currently it is believed that cardiometabolic disease is caused by chronic over-nutrition and lack of exercise, although the exact path of disease development is still incompletely understood. Recent improvements in the treatment of cardiometabolic disease and its downstream conditions, cardiovascular disease and diabetes, indicate the beneficial effects of early detection and aggressive treatment. Strategies to detect changes in multiple organ systems due to cardiometabolic disease could be used for earlier diagnosis and provide information for targeted therapies to prevent severe downstream consequences. This work seeks to develop multimodality techniques to evaluate the effects of cardiometabolic disease and produce reliable biomarkers that may be used to better inform understanding and treatment of disease. First, it presents a standardized magnetic resonance spectroscopy technique to quantify mitochondrial oxidative phosphorylation capacity in skeletal muscle. The spectroscopy technique is then used to evaluate the effects of cardiac rehabilitation exercise training in patients with and without metabolic abnormalities. Second, a novel multi-energy computed tomography method for quantification of myocardial fibrosis is described. The pre-clinical development of the computed tomography method and clinical validation of the technique are presented. Together, the techniques developed and described in this work present a multimodality, multiorgan approach to characterize cardiometabolic health and disease.

Committee: Subha V. Raman MD (Advisor); Orlando P. Simonetti PhD (Committee Member); Elliot Crouser MD (Committee Member); Brandon Biesiadecki PhD (Committee Member) Subjects: Biomedical Research; Health

Doctor of Philosophy, The Ohio State University, 2017, Biomedical Sciences

The ability of pathogenic viruses to alter host metabolism has been recently characterized. Infection by the human adenovirus serotype 36 (AD36) promotes obesity in animal models and correlates to increased adiposity in humans, yet improves glycemic control. Based on in vitro studies, the E4ORF1 protein is responsible for both the adipogenic and insulin sparing properties of AD36 infection via insulin independent Akt activation. We generated a recombinant adeno-associated viral (rAAV) vector to express AD36E4ORF1. Through intravenous delivery we expressed AD36E4ORF1 in the livers of diabetic, insulin resistant, and wild-type mice. Hepatic AD36E4ORF1 improved glucose tolerance and attenuated hyperglycemia in obese diabetic Db -/- mice without improving insulin sensitivity. AD36E4ORF1 also reduced hyperinsulinemia and improved glucose tolerance in insulin resistant mice with diet induced obesity (DIO). Liver specific glucose uptake was increased without improving insulin sensitivity. Confirming the findings of previous in vitro studies, Akt activity was not only increased but also required for AD36E4ORF1 mediated glucose uptake. AD36E4ORF1 expression is a model of insulin independent AKT activation and provides a novel therapeutic mechanism to improve glycemic control in cases of insulin resistance. Next, we looked at how environmental factors might contribute to healthy aging and prevention of metabolic syndrome. Animals housed in a larger, more complex enriched environment (EE) are provided with increased somatosensory stimulation, physical exercise, and enhanced social interactions. Together, these stimuli increase expression of brain derived neurotrophic factor (BDNF) in the hypothalamus, activating a hypothalamic sympathoneural-adipocyte axis (HSA). In young animals, HSA activation has been shown to improve glycemic control and overall health but its impact in older animals has not been previously characterized. Middle-aged 10 month old female mice were h (open full item for complete abstract)

Committee: Lei Cao Ph.D. (Advisor); Denis Guttridge Ph.D. (Committee Member); Courtney DeVries Ph.D. (Committee Member); Kay Huebner Ph.D. (Committee Member) Subjects: Biomedical Research

PHD, Kent State University, 2017, College of Arts and Sciences / School of Biomedical Sciences

Cardiovascular disease is the major cause of morbidity and mortality in obesity and Metabolic Syndrome (MetS). Elevated serum leptin levels or hyperleptinemia, hallmark of obesity, contribute to increased risk of atherosclerosis in MetS patients. Despite clinical correlations, underlying molecular mechanisms of hyperleptinemia-induced atherosclerosis are incompletely understood. Our laboratory previously reported that leptin has a direct regulatory effect on the expression of a potent proatherogenic matricellular protein thrombospondin-1 (TSP-1), suggesting TSP-1 is a potential link between hyperleptinemia and atherosclerosis. In aim 1 of this dissertation, we investigated the transcriptional mechanisms that mediate leptin-induced upregulation of TSP-1 expression in primary cultures of human aortic smooth muscle cells (HASMC). We found that leptin upregulates TSP-1 transcription via formation of a single transcriptional complex between the nuclear factors IRF-1 and CREB on the TSP-1 gene promoter. Our study in aim 2 provides the first evidence that TSP-1 plays a direct role in leptin-induced atherosclerosis. Using `en face' lesion assays, ultrasound imaging and aortic root histology, we demonstrated that while exogenous leptin increased atherosclerotic lesion formation in ApoE-/- mice, TSP-1-/-/ApoE-/- mice developed fewer lesions in response to leptin. Leptin-treated TSP-1-/-/ApoE-/- mice were protected against increased cellular complexity in aortic root lesions compared to leptin-treated ApoE-/- mice. Also, leptin-treated TSP-1-/-/ApoE-/- mice revealed attenuated VSMC proliferation in aortic vessels compared to leptin-treated ApoE-/-. Overall, data in aim 2 demonstrated that knockout of TSP-1 in ApoE-/- mice protects against leptin-induced atherosclerosis. The goal of aim 3 was to investigate the role of TSP-1 in development of atherosclerosis in MetS. We generated a mouse model of combined MetS and atherosclerosis (KKAy+/-/ApoE-/-) by crossing obese d (open full item for complete abstract)

Committee: Priya Raman (Advisor); William M. Chilian (Committee Member); Charles K. Thodeti (Committee Member); Feng Dong (Committee Member); Derek S. Damron (Committee Member) Subjects: Biology; Molecular Biology; Physiology