Browsing by Author "Gentile, Christopher, committee member"
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Item Open Access A single session of sprint interval training increases total daily energy expenditure(Colorado State University. Libraries, 2014) Sevits, Kyle, author; Melby, Chris, advisor; Bell, Christopher, advisor; Gentile, Christopher, committee member; Browning, Ray, committee member; Melanson, Ed, committee memberBackground: Sprint interval training (SIT) is known to elicit favorable physiological adaptations, including improved insulin sensitivity and glucose tolerance. Its utility for weight maintenance is unclear. Presumably any effects would be mediated by increased energy expenditure during both the exercise itself, and during recovery. Therefore, the objective of this study is to determine the effects of a single bout of SIT on 24-hour energy expenditure (EE). Methods: 24-hour EE was determined in 12 healthy men (age: 26 ± 2 years; body mass index: 23.6 ± 0.5 kg/m2; mean ± SE). After three days of controlled diet and maintenance of energy balance, subjects were studied in a whole-room indirect calorimeter for two consecutive days. One of these days (random order) began with a single bout of SIT (5 x 30 second "all-out" exertions on a cycle ergometer against a resistance equivalent to 7.5% body mass, separated by 4 minutes of loadless cycling). Subjects spent the other day in the calorimeter without exercising. Results: An acute bout of SIT increased 24-hour EE in all subjects by an average of 226 ± 15 kcal during an otherwise sedentary day (Control: 2189 ± 58 vs. SIT: 2415 ± 62 kcal/day; P < 0.001). There was also a non-significant (P = 0.054) decrease in fat balance on the exercise day (control = -9.7 ± 7.9 g/day vs. SIT = -20.6 ± 8.2 g/day). Conclusions: Our data provide support for SIT as a time-efficient exercise to increase total daily energy expenditure and may aid in the maintenance of health.Item Open Access Acute beet juice ingestion improves estimates of insulin sensitivity in obese adults(Colorado State University. Libraries, 2014) Beals, Joseph William, author; Bell, Christopher, advisor; Hickey, Matthew, committee member; Gentile, Christopher, committee memberPoor glucose regulation is strongly associated with low nitric oxide (NO) bioavailability; a characteristic that may be improved with stimulation of NO generating pathways. For example, endothelial nitric oxide synthase null mice demonstrate improved glucose metabolism following sodium nitrate ingestion. Dietary nitrates are sequentially reduced in the oral and gastric cavities to NO, a process that is attenuated by rinsing with an antibacterial mouthwash. We hypothesized that acute dietary nitrate consumption will improve glucose tolerance. 9 sedentary, healthy, obese adults (2 male; body mass index: 33.7 ± 4.0 kg/m2: age: 45±7 years; mean ± SE) were studied. Using a randomized crossover design, four oral glucose tolerance tests were performed (equal carbohydrate load). To assess the influence of dietary nitrate, subjects consumed either 500mL of beet juice + 25g glucose, or 500mL of water + 75g glucose, with and without prior antibacterial mouthwash use. Beet juice was selected because it is rich in nitrate. Venous blood samples were collected for the determination of glucose and insulin concentrations. Neither the circulating glucose nor insulin responses were influenced by beet juice and/or mouthwash (P>0.05). However, the Matsuda Index, an estimate of insulin sensitivity, was greater for beet juice compared with beet juice preceded by mouthwash (104.6 ± 11.7 vs. 83.5 ± 11.1; P<0.05). These preliminary data suggest that acute dietary nitrate ingestion may promote insulin sensitivity in obese adults.Item Open Access Mechanism and subpopulation specificity of mitochondrial reactive oxygen species release in the post-ischemic hyperthyroid myocardium(Colorado State University. Libraries, 2012) de Mooy, Anthony Brett, author; Chicco, Adam J., advisor; Frye, Melinda, advisor; Gentile, Christopher, committee memberHyperthyroidism (HT) augments release of reactive oxygen species (ROS) from cardiac mitochondria following myocardial ischemia/reperfusion (I/R). The present study examined the mechanisms of this phenomenon and determined whether subsarcolemmal (SSM) and intermyofibrillar mitochondria (IFM) are differentially affected. Male SD rats received 10 daily injections of thyroid hormone (30ug/kg i.p.; HT) or vehicle (CON) before hearts were excised and exposed to a 20/25 min global I/R protocol ex vivo. Following I/R, ROS release was assessed in freshly isolated SSM and IFM using the Amplex Red assay with a variety of substrate and inhibitor combinations to examine sites and mechanisms of release. ROS release from SSM exceeded IFM in CON and HT hearts by 25-50% following I/R (P < 0.01). Surprisingly, HT augmented ROS release from SSM, but decreased ROS release from IFM (P < 0.05 for both). Blocking electron flow from respiratory complex 1 to 3 abolished the effect of HT on SSM, but not IFM. Inhibition of uncoupling proteins with GDP abolished the HT-induced reduction in IFM, but had little effect in SSM. Maximally uncoupling mitochondria with FCCP abolished effects of HT in IFM and SSM. Collectively, results indicate that 1) complex 3 in SSM is the primary source of mitochondrial ROS release following I/R in HT, and 2) enhanced activity of uncoupling proteins limits ROS release from IFM under these conditions.Item Open Access Mechanisms of impaired red blood cell ATP release in older adults: implications for altered vascular control with age(Colorado State University. Libraries, 2018) Racine, Matthew L., author; Dinenno, Frank A., advisor; Amberg, Gregory, committee member; Chicco, Adam, committee member; Gentile, Christopher, committee memberThe following dissertation is comprised of a series of experiments with the overall aim of determining the mechanisms of impaired ATP release from red blood cells (RBCs) of healthy older adults in response to hemoglobin deoxygenation and identifying a potential role of this impairment in the declines in vascular control of peripheral blood flow with advancing age. Advancing age is the primary risk factor for cardiovascular disease (CVD), which is the leading cause of death in societies today and is strongly associated with arterial dysfunction. Furthermore, impairments in vascular control and the subsequent regulation of tissue blood flow and oxygen delivery contribute to vascular pathologies such as atherosclerosis and ischemic disease, as well as the age-associated declines in functional capacity, exercise tolerance, and overall quality of life. Thus, understanding the mechanisms of the age-related impairments in vascular control and identifying potential therapeutic targets holds significant potential for reducing the healthcare burden associated with a rapidly aging population. Accordingly, the ultimate goal of this dissertation is to determine if an in vivo pharmacological approach can be utilized to treat the age-related declines in RBC ATP release, thereby restoring circulating ATP responses and subsequent vascular control during the physiological stimuli of hypoxia and exercise in healthy older adults. The key novel findings of this dissertation are that (i) age-associated declines in RBC deformability are the primary mechanism of impaired deoxygenation-induced ATP release from RBCs of healthy older adults; (ii) primary (healthy) aging is not associated with a global decline in RBC function given that inhibition of cyclic AMP hydrolysis by phosphodiesterase 3 did not improve deoxygenation-induced ATP release from RBCs of older adults and that the cellular responses to Gi protein activation remained intact with age; and (iii) that systemic Rho-kinase inhibition via administration of fasudil improves the age-related impairments in vascular control and circulating ATP during systemic hypoxia and exercise, which may be related to enhanced RBC ATP release and NO bioavailability. These findings are the first to identify a role for Rho-kinase inhibition in improving these physiological responses in healthy older adults and are therefore clinically significant for aging population in which impaired vascular control contributes to elevations in cardiovascular disease risk and declines in exercise tolerance, functional independence and overall quality of life.Item Embargo Metabolic support of preimplantation embryo growth and viability(Colorado State University. Libraries, 2024) Fresa, Kyle Joseph, author; Carnevale, Elaine, advisor; Chicco, Adam, advisor; Tesfaye, Dawit, committee member; Krisher, Rebecca, committee member; Gentile, Christopher, committee memberEarly embryo metabolism involves essential and dynamic biological reactions that support viability, growth, and pregnancy establishment. Embryo metabolism not only serves to provide energy through ATP synthesis, but also facilitates the production of macromolecules such as proteins, nucleotides, and lipids. The ways in which embryos balance catabolic and anabolic activity during the preimplantation stage are not well understood; however, understanding these processes may lead to improved fertility treatments, embryo culture, and pregnancy outcomes. The studies described in this dissertation utilize innovative methods, such as stable isotope tracer analysis to track carbon and nitrogen flux through various pathways, oxygen microsensors to determine individual embryo respiration under various conditions, and proteomic analysis to determine the impacts of metabolic disturbances on embryo viability. The overarching hypothesis of this dissertation is that embryo viability is dependent on efficient and tightly regulated metabolic activity, and disturbances to metabolic function ultimately lead to reduced developmental potential. To test this hypothesis, a series of projects were conducted to 1) evaluate the importance of phosphoenolpyruvate carboxykinase (PEPCK) during early development, 2) uncover the function of PEPCK to support catabolic and anabolic activity in early embryos, and 3) determine the impacts of delayed embryo development on embryo metabolism and pathway regulation. These projects revealed important insights into the impact of embryo metabolism on development, including the discovery of a novel, PEPCK-mediated pathway that embryos utilize to balance energy production and biosynthesis. Furthermore, the impact of delayed embryo development was demonstrated to alter embryo metabolic activity and pathway regulation, including increased aerobic activity and altered protein expression. These findings improve our understanding of metabolic activity and regulation during preimplantation development, highlighting the impact of metabolic activity to promote ATP production, biosynthesis, developmental kinetics, and ultimately survival. The experimental outcomes presented in this dissertation provide a foundation for targeted approaches to improve embryo development and reproductive success.Item Open Access Predictors of learning outcomes among students in nutrition science courses at Colorado State University(Colorado State University. Libraries, 2018) Peth, James Anthony, author; Melby, Christopher, advisor; Balgopal, Meena, advisor; Foster, Michelle, committee member; Gentile, Christopher, committee member; Hickey, Matthew, committee memberOverview This dissertation is a summary of exploratory research to assess predictors of learning outcomes (academic background, conceptions of subject, motivations for studying, and approaches to learning) among students taking two undergraduate nutrition science courses at CSU—Human Nutrition (Course 1) and Integrative Nutrition & Metabolism (Course 2). It was comprised of three studies. Introduction There is a global need for experts trained in nutrition with an integrationist approach to health sciences and equipped to understand complex issues in health and disease. Yet, many students in nutrition sciences courses are not learning at a mastery level and often lack the knowledge and ability to integrate what they have learned to apply it to more advanced courses and their careers. Key factors influencing a student's approach to learning and performance outcomes in a course include their academic background, motivations for learning the subject, conceptions of the subject, and approaches to learning. Pilot data from preliminary research performed during a course re-design project at Colorado State University (CSU) indicate many students begin nutrition science courses with inadequate prior knowledge from prerequisite courses, lack autonomous motivations, exhibit fragmented conceptions of the science of nutrition, and adopt surface, rather than deeper, more meaningful approaches to learning. Methods Exploratory mixed-methods research was performed to assess academic background, motivations for studying nutrition, conceptions of the discipline, and approaches to learning among students in Course 1 (Human Nutrition) and Course 2 (Integrative Nutrition & Metabolism). It was comprised of three studies. The first was an analysis of academic and demographic data for 1,739 students, who had completed Course 1 only (n=1,377) or both Course 1 and Course 2 (n=362) between 2010-2016, to identify and evaluate relationships with in-class exam performance. Studies 2-3 were analyses of semi-structured interviews with students who had completed Course 1 only (n=12) or both Course 1 and Course 2 (n=27) between 2012-2015. Each student reflected on their experiences before and after the course(s) they completed, including their motivations for studying nutrition, conceptions of nutrition as a discipline, and approaches to learning. Transcripts were inductively coded and discrete categories of motivations, conceptions, and approaches were developed using phenomenography. Transcripts were re-analyzed using focused coding, and each student was categorized for each domain. Statistical tests were conducted to evaluate the strength of relationships among academic background variables, motivations, conceptions, approaches, and learning outcomes. Results Pre-course GPA, grades in prerequisite courses, and scores on a prior knowledge test for Course 1 were positively correlated with in-class exam performance. Pre-course GPA was the best predictor for both courses, explaining 51.9% and 43.9% of the score variance in Course 1 and Course 2, respectively. Alone, demographic variables were poor predictors of performance. First-generation status was negatively correlated with performance. Among students interviewed, 100% indicated having an intrinsic interest in learning nutrition before Course 1. However, when taking upper-level nutrition science Courses 1 and 2, 100% suggested being driven to some extent by extrinsic rewards, and only 53.8% and 63% of students suggested having autonomous motivations for studying the specific material covered in Courses 1 and 2, respectively. At the start of Course 1, 87.2% of students had a fragmented conception of nutrition as a discipline; 76.9% adopted a surface approach to learning. Most (82.4%) of the students with a fragmented conception of nutrition science adopted a surface approach to learning. For Course 2, 52% began with a coherent conception of nutrition as a science, and most (81.5%) adopted a deep approach to learning in the course. Statistically significant relationships were identified among motivations, conceptions, and approaches to learning for Course 1. In both Course 1 and 2, coherent conceptions, autonomous motivations, and deep approaches were associated with significantly higher mean grades. Conclusions and Implications Previous academic achievement and prior knowledge provide students a critical foundation for success in upper-level courses in nutrition science. Students develop more coherent conceptions of nutrition as a science, autonomous motivations for learning nutrition, and deep approaches to learning nutrition as they progress through their courses, attempting to meet academic demands. These developmental changes are associated with positive learning outcomes. Efforts should be made to support and increase students' development of cognitive prerequisites, such as prior knowledge from foundational sciences, coherent conceptions of nutrition as a science, and autonomous motivations and deep approaches for learning nutrition earlier in their academic program.Item Open Access Role of the endothelium in modulating sympathetic vasoconstriction in contracting skeletal muscle of young and older adults(Colorado State University. Libraries, 2016) Hearon, Christopher M., author; Dinenno, Frank A., advisor; Amberg, Gregory, committee member; Chicco, Adam, committee member; Gentile, Christopher, committee memberAerobic capacity is a powerful independent predictor of all-cause mortality in healthy and disease populations. Healthy (primary) ageing is associated with a decline in maximal aerobic capacity, exercise intolerance and elevated risk for ischemic cardiovascular disease. Specifically, ageing is characterized by impaired regulation of vascular tone during exercise, due in part to lower vasodilatory signaling and elevated sympathetic vasoconstrictor activity in the peripheral vasculature. Impaired regulation of peripheral vascular tone results in attenuated blood flow and oxygen delivery to contracting skeletal muscle during exercise and is a primary contributor to the age-associated decline in aerobic capacity. The overall aim of this dissertation is to determine the vascular signaling mechanisms responsible regulating sympathetic vasoconstrictor signaling during exercise in young healthy adults and translate these findings to improve vascular function during exercise in older adults. The regulation of blood flow and oxygen delivery during exercise depends on the proper integration of local vasodilatation and neural sympathetic vasoconstriction. In healthy humans, the integration of these competing signals results in attenuation of sympathetic vasoconstriction, or “sympatholysis”, to ensure adequate blood flow to contracting skeletal muscle. The signaling mechanisms responsible for sympatholysis in healthy humans are unknown. To date, the only exogenous vasodilator shown to mimic exercise in its ability to attenuate sympathetic vasoconstriction in humans is adenosine triphosphate (ATP). The first aim of this dissertation is to determine if smooth muscle cell hyperpolarization (via activation of inwardly-rectifying potassium (KIR) channels), the primary vasodilatory pathway of ATP, is responsible for ATP-mediated attenuation of sympathetic vasoconstriction. In contrast to smooth muscle specific signaling, vasodilatory stimuli such as ATP and exercise can act through endothelium-dependent pathways. The second aim of this dissertation tests the hypothesis that endothelium-dependent signaling is capable of attenuating sympathetic vasoconstriction during exercise in young healthy humans. With age, impaired endothelial function and elevated sympathetic vasoconstrictor activity results in impaired functional sympatholysis. The third aim is to determine if augmentation of endothelium-dependent signaling during exercise improves age-associated impairments in functional sympatholysis. The primary findings of this dissertation are that 1) similar to exercise, the ability of ATP to attenuate sympathetic vasoconstriction is independent of smooth muscle cell hyperpolarization via activation of KIR channels, 2) activation of endothelium-dependent signaling during exercise significantly enhances the ability of contracting skeletal muscle to attenuate sympathetic vasoconstriction, and 3) that augmentation of endothelium-dependent signaling during exercise significantly improves functional sympatholysis in older adults. These findings are the first to identify endothelium-dependent modulation of sympathetic vasoconstriction in humans, and identifies vascular signaling pathways capable of improving the regulation of vascular tone during exercise in older adults. These findings are clinically significant for patient populations and disease states characterized by impaired functional sympatholysis including ageing, hypertension, and heart failure.Item Open Access The role of fatty acids on endoplasmic reticulum proteostasis in non-alcoholic fatty liver disease(Colorado State University. Libraries, 2017) Estrada, Andrea Lee, author; Pagliassotti, Michael, advisor; Miller, Benjamin, committee member; Foster, Michelle, committee member; Frye, Melinda, committee member; Gentile, Christopher, committee memberNon-alcoholic fatty liver disease (NAFLD) is currently a significant health concern in both adults and children. NAFLD is a disease characterized by accumulation of fat in the liver (steatosis) in the absence of chronic alcohol consumption. In some individuals, steatosis progresses to non-alcoholic steatohepatitis (NASH), which is characterized by steatosis, inflammation, apoptosis and fibrosis, and can ultimately lead to end-stage liver disease. The underlying causes of NAFLD are unclear, although recent evidence has implicated the endoplasmic reticulum (ER) in both the development of steatosis and progression to NASH. Disruption of ER homeostasis or "ER stress" has been observed in the livers and adipose tissue of humans with NAFLD and/or obesity. Downstream signaling events that arise from ER stress include lipid biogenesis, insulin resistance, inflammation, fibrosis and apoptosis, all of which are hallmark features of NAFLD and NASH. Elevated circulating free fatty acids are a characteristic feature of humans with NAFLD and are positively correlated with disease severity. Our laboratory has demonstrated that in rodents, selective elevation of circulating free fatty acids induces ER stress in liver and adipose tissue. In addition, ER stress is exacerbated when the composition of fatty acids includes levels of saturated fats comparable to what is encountered in the typical western diet. We, and others, have also demonstrated that saturated fatty acids provoke ER stress in cultured hepatocytes, pancreatic beta cells, and various other cell types. These data have led to the hypothesis that the composition of fatty acids presented to and stored within the liver is an important determinant of ER homeostasis. ER stress is characterized by an accumulation of unfolded proteins within the lumen of the ER. Therefore, the presence of ER stress in NAFLD implies that there is an imbalance between the protein load presented to the ER, and the ability of the ER to process, degrade and/or remove these proteins. The overall aim of this thesis was to examine how saturated fatty acids disrupt ER homeostasis in the liver. We explored in vivo hepatic protein synthesis in response to acute dietary intervention, namely using diets high saturated fat and sucrose, which promote hepatic steatosis and insulin resistance in rats. We utilized the saturated fat, palmitate in controlled delivery to H4IIE liver hepatocytes in order to assess protein synthesis and components of protein degradation. Lastly, we examined the roles of calcium homeostasis and protein palmitoylation in response to palmitate treatment in H4IIE liver hepatocytes. We found that diets high in saturated fat did not affect hepatic protein synthesis in rats. In agreement with this observation, H4IIE hepatocyte treatment with palmitate did not selectively stimulate cellular protein synthesis. Provision of palmitate increased protein ubiquitination, this result was observed independent of proteasome activity or total cellular protein degradation. Lastly, we found that palmitate-induced ER stress was characterized by a reduction in sarcoendoplasmic reticulum ATPase (SERCA) activity. Our data suggest that saturated fatty acid-induced ER stress is mediated via reduced SERCA activity, and subsequent disruption in protein handling.