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Systemic Insulin Sensitivity And Skeletal Muscle Akt Signaling In Rats Artificially Selected For Low And High Aerobic Capacity, Kyle Levi Fulghum

MSU Graduate Theses

The mechanism(s) linking physical inactivity, obesity, and type-II diabetes are unclear. I hypothesized low intrinsic aerobic capacity is associated with reduced systemic insulin sensitivity via skeletal muscle insulin signaling. After 34 generations of selective breeding, high aerobic capacity (HCR) rats exhibited an 8-fold increase in running distance vs low aerobic capacity (LCR) rats (n=14 per group). LCR rats had higher rates of weight gain vs HCR (p<0.05) though food consumption was constant (p=0.86) over a 12-week study. Rats were divided into 4 groups: 1) LCR-Sham Surgery, 2) LCR-Catheterization, 3) HCR-Sham Surgery or 4) HCR-Catheterization (n=7 per group). Euglycemic-hyperinsulinemic clamps on catheterized rats tested insulin sensitivity while sham LCR and HCR were used for basal tissue analysis. Plasma insulin levels did not differ during the clamps, but LCR required lower glucose infusion rates than HCR (p<0.05). Upon insulin stimulation, both absolute and normalized phospho-Akt(Ser473) of soleus muscle were significantly increased in HCR above basal group (p<0.05), but not in LCR. No difference was observed between insulin-stimulated phospho-Akt(Ser473) of HCR and LCR groups . These data support that LCR is linked to a reduction in insulin sensitivity in vivo without impairments of insulin-stimulated skeletal muscle phospho-Akt(Ser473) vs HCR rats.

Normal Glycolytic Enzyme Activity Is Critical For Hypoxia Inducible Factor-1a Activity And Provides Novel Targets For Inhibiting Tumor Growth, Geoffrey Grandjean Phd

Dissertations & Theses (Open Access)

Normal Glycolytic Enzyme Activity is Critical for Hypoxia Inducible Factor-1α Activity and Provides Novel Targets for Inhibiting Tumor Growth

By Geoffrey Grandjean

Advisory Professor: Garth Powis, D. Phil

Unique to proliferating cancer cells is the observation that their increased need for energy is provided by a high rate of glycolysis followed by lactic acid fermentation in a process known as the Warburg Effect, a process many times less efficient than oxidative phosphorylation employed by normal cells to satisfy a similar energy demand ^[1]. This high rate of glycolysis occurs regardless of the concentration of oxygen in the cell and …

Bioenergetics Modeling To Assess Aquatic Invasive Species Trophic Impact, Nickolas John Kosmenko

Electronic Theses and Dissertations

Energy requirements of aquatic invasive species (AIS) relative to native species may help explain differences in trophic impact, as species requiring more energy must consume more food, depleting resources more quickly. Variables relating to energy use were compared between co-existing invasive and native fish species in invaded habitats. Most comparisons (8/12) demonstrated higher rates in invasive species (1-46% greater), suggesting high trophic impact is a characteristic of AIS and should be of consideration in management. Bioenergetic mass-balance principles indicate energy consumed by a fish is offset by metabolic (~40%), waste (~30%), and growth (~30%) demands. Since routine metabolic rate data …

Effect Of Dietary Lysine On Plasma Amino Acid Profile And Selected Metabolites Of Late-Stage Finishing Pigs, Naresh Regmi

Theses and Dissertations

The objective of this study was to evaluate the effects of dietary lysine on plasma concentrations of amino acid (AAs) and other metabolites of finishing pigs. Eighteen crossbred late-stage finishing pigs (9 barrows and 9 gilts) were assigned to three dietary treatments, Diets I (lysine-deficient), II (lysineequate), and III (lysine-excess), according to a randomized complete block design with gender as block. After 4 weeks on trial, jugular vein blood were collected and centrifuged for plasma samples, which were analyzed for concentrations of 24 AAs using HPLC method and 6 selected metabolites related to major nutrient metabolism using ACE Alera Clinical …

Identifying And Characterizing Yeast Pas Kinase 1 Substrates Reveals Regulation Of Mitochondrial And Cell Growth Pathways, Desiree Demille

Theses and Dissertations

Glucose allocation is an important cellular process that is misregulated in the interrelated diseases obesity, diabetes and cancer. Cells have evolved critical mechanisms for regulating glucose allocation, one of which is sensory protein kinases. PAS kinase is a key sensory protein kinase that regulates glucose allocation in yeast, mice and man; and is a novel therapeutic target for the treatment of metabolic diseases such as obesity, diabetes and cancer. Despite its importance, the molecular mechanisms of PAS kinase function are largely unknown. Through large-scale protein-interaction studies, we have identified 93 novel binding partners for PAS kinase which help to expand …

Elucidating The Impact Of Roseophage On Roseobacter Metabolism And Marine Nutrient Cycles, Nana Yaw Darko Ankrah

Doctoral Dissertations

As the most abundant biological entities in marine environments, viruses are an important component of marine food webs. The activity of viruses contributes significantly to the mortality of marine microorganisms, ultimately influencing biological function and chemical composition of aquatic systems by impacting species composition and flow of carbon, nitrogen and other nutrients. Despite the growing recognition that viral activity contributes to marine biogeochemical cycles, the extent to which virus infection reshapes host metabolism and the effect of this alteration on the composition of host lysate remains poorly understood. Additionally, the degree to which natural bacterioplankton communities metabolise the released lysate …

Influx And Efflux Of Adenine Nucleotides From Erythrocytes Regulate Oxygen Transport And Systemic Metabolism, William G. O'Brien Iii

Dissertations & Theses (Open Access)

Erythrocytes are responsible for ensuring a sufficient supply of oxygen to meet activity demands. The mammalian erythrocytes primarily modulate their oxygen-carrying capacity by varying the levels of organic phosphates, such as 2,3-BPG. In other organisms, such as fish, ATP instead of 2,3-BPG is used to modulate their erythrocyte’s oxygen binding ability. Here, using a series of genetically modified mice, we investigated a previously unrecognized pathway of adenine nucleotide influx and efflux that modulates erythrocyte’s oxygen binding ability and controls systemic metabolism. Our studies show that the loss of AMPD3 and CD73, two important enzymes in regulating AMP levels intra- and …

Role Of Crebh In Endotoxin Mediated Modulation Of Hepatic Metabolism, Aditya Prakash Dandekar

Wayne State University Dissertations

Bacterial endotoxins can induce a variety of physiological changes in the host. This effect is not only restricted to inflammatory changes but also comprises metabolic changes in the host body. Lipopolysaccharide (LPS), one of the key components of the bacterial cell walls, is capable of triggering host metabolic changes. Hyperlipidemia usually accompanies with high endotoxin levels as well as inflammation. Lipid metabolism disorders are one of the common hallmarks of a patient with sepsis or high levels of endotoxin through diet. Previously, we have identified an endoplasmic reticulum (ER) anchored liver-specific transcription factor CREBH (cAMP-responsive element-binding protein, hepatocyte-specific), which is …

The Role Of Crebh In Hepatic Energy Regulation Under Metabolic Stress, Roberto Mendez

Wayne State University Dissertations

Lipid metabolism is tightly regulated by nuclear receptors, transcription factors, and cellular enzymes in response to nutritional, hormonal, and stress signals. Hepatocyte specific, cyclic AMP responsive element-binding protein (CREBH) is a transcription factor that is preferentially expressed in the liver and localized in the endoplasmic reticulum (ER) membrane. CREBH is known to be activated by ER stress, inflammatory stimuli, and metabolic signals to regulate hepatic acute-phase response, lipid metabolism, and glucose metabolism. In my thesis research, I have characterized the roles and mechanisms of CREBH in these functions, as well as the overall phenotype of CrebH-null mice. I demonstrated that …

Tick-Flavivirus Interactions: Discovery Of Host Proteins That Are Affected In Virus Infection, Jeffrey Michael Grabowski

Open Access Dissertations

Grabowski, Jeffrey M. Ph.D., Purdue University, August 2015. Tick-Flavivirus Interactions: Discovery of Host Proteins That Are Affected in Virus Infection. Major Professors: Catherine A. Hill and Richard J. Kuhn.

Development And Application Of Pseudoreceptor Modeling, Gregory Lee Wilson

Open Access Dissertations

Quantitative Structure-Activity Relationship (QSAR) methods are a commonly used tool in the drug discovery process. These methods attempt to form a statistical model that relates descriptor properties of a ligand to the activity of that ligand compound towards a specific desired physiological response. QSAR methods are known as a ligand-based method, as they specifically use information from ligands and not protein structural data. However, a derivation of QSAR methods are pseudoreceptor methods. Pseudoreceptor methods go beyond standard QSAR by building a model representation of the protein pocket. However, the ability of pseudoreceptors to accurately replicate natural protein surfaces has not …

Carnitine And O-Acylcarnitines In Pseudomonas Aerguinosa: Metabolism, Transport, And Regulation, Jamie Meadows

Graduate College Dissertations and Theses

Pseudomonas aeruginosa is found in numerous environments and is an opportunistic pathogen affecting those who are immunocompromised. Its large genome encodes tremendous metabolic and regulatory diversity that enables P. aeruginosa to adapt to various environments. We are interested in how P. aeruginosa senses and responds to the host-derived compounds, carnitine and acylcarnitines. Acylcarnitines can be hydrolyzed to carnitine, where the liberated carnitine and its catabolic product glycine betaine can be used as osmoprotectants, for induction of the virulence factor phospholipase C, and as sole carbon, nitrogen, and energy sources. P. aeruginosa is incapable of de novo synthesis of carnitine and …

The Metabolomic Effects Of Metformin On Colon Cancer, Jennifer W. Harris

Theses and Dissertations--Clinical and Translational Science

Metformin is an oral biguanide that is prescribed to over 120 million people worldwide for the treatment of conditions including type II diabetes mellitus, polycystic ovarian syndrome, and gestational diabetes. This hypoglycemic agent is rapidly emerging as a potential cost-effective anti-oncogenic agent. Over the past decade multiple epidemiologic studies have consistently associated metformin with decreased cancer incidence and cancer-related mortality. More recently numerous preclinical and clinical studies have demonstrated anti-cancer effects of metformin, leading to the proposal of numerous clinical trials to better understand this drug and its mechanism of action.

Previously experts believed metformin primarily targeted AMP-activated protein kinase …

Impaired Glucose Metabolism In The Absence Of Skeletal Muscle Brain And Muscle Arnt-Like-Protein 1 (Bmal1), Brianna D. Harfmann

Theses and Dissertations--Physiology

Metabolism is a critical physiological function that works to generate energy for cells, store substrates and maintain homoeostasis. Alterations in normal metabolism can have a severe effect on physiology, leading to metabolic disease. Skeletal muscle is a key metabolic tissue, taking up ~80% of postprandial glucose. Therefore it contributes considerably to glucose metabolism: glucose uptake, oxidation and homeostasis. To address the role of the skeletal muscle clock in insulin sensitivity and glucose tolerance, our lab generated an inducible skeletal muscle specific Bmal1^-/- mouse (iMSBmal1^-/-). 5 weeks post-recombination we observed impairment in both insulin- and AICAR-stimulated skeletal …

Metabolic Characterization Of Mpnst Cell Lines, Christopher A. Waker

Browse all Theses and Dissertations

Malignant transformation is the process by which cells develop cancer properties. While many causes for malignant transformation are known (i.e. common genetic mutations and/or exposure to toxins or viruses), the basic requirements that allow a cell to stay alive with altered nutrient and energy requirements are just now being studied. In some tumor types malignant cells undergo changes that result in metabolic differences compared to normal cells. These can include defects in mitophagy resulting in an accumulation of dysfunctional mitochondria and/or a metabolic switch resulting in increased glycolysis, termed the Warburg effect. Increased tumor growth and metastasis have also been …

The Alpha-Glucosidase Inhibitor Acarbose As A Calorie Restriction Mimetic To Modify Metabolic Outcomes In Mice, Rachel Ann Brewer

All ETDs from UAB

Age-related diseases continue to be a leading cause of death. One of the only replicable methods proven to decrease age-related morbidity and mortality in multiple species is calorie restriction (CR). CR is difficult for human populations to implement, and has a number of associated risks and side effects. A CR mimetic could provide the healthspan- and lifespan-extending benefits of CR without the limitations. Acarbose (ACA), an α-glucosidase and α-amylase inhibitor approved to treat type 2 diabetes in humans, was recently identified as able to extend lifespan in healthy mice. The purpose of this research was to determine the effects of …

Energy Metabolism Of Platelets During Activation, Oxidative Stress And Storage, Saranya Ravi

All ETDs from UAB

The principal function of platelets is to regulate hemostasis, and dysfunction of platelet aggregation or activation can lead to either excessive thrombotic or hemorrhagic complications. It has been shown that the ability to generate ATP and exposure to oxidative stress can affect platelet thrombotic potential. While platelet metabolism has been extensively studied, the importance of substrate availability and metabolic plasticity in regulating aggregation under physiological or pathological conditions is not well understood. In this dissertation, we examined the reliance of platelets on different metabolic substrates, the importance of ATP production for aggregation in response to thrombin stimulation, metabolic stress following …

Metabolic And Oxidative Regulation Of Neuronal Autophagy And Survival, Matthew Dodson

All ETDs from UAB

Neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease and Huntington's disease are all characterized by metabolic dysfunction, increased oxidative damage to proteins and organelles, formation of proteinaceous inclusions, decreased autophagic and proteasomal function, and eventual neuronal and glial cell death. While our understanding of the mechanisms that underlie many of these pathologies is constantly growing, their exact cause, onset, interplay and progression still remain unclear. The gap between the description of disease pathologies and understanding the fundamental mechanisms of disease pathogenesis, progression and potential therapeutics to mitigate disease progression is still large. Based on the observation that altered glucose utilization, …

Strategies For Preventing Age And Neurodegenerative Disease-Associated Mitochondrial Dysfunction, Vedad Delic

USF Tampa Graduate Theses and Dissertations

Mitochondrial dysfunction plays a pivotal role in the development of aging phenotypes and aging-associated neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and Amyotrophic lateral sclerosis (ALS). Strategies that restore mitochondrial dysfunction may rescue the deficits of central metabolism in these disorders and improve cell survival. For example, we found that modulating the mTOR signaling pathway in a tissue culture model of aging-induced mitochondrial DNA mutation enhanced mitochondrial function as evidenced by increased oxygen consumption. Our previous melatonin studies also led us to hypothesize that caloric restriction and the hormone melatonin would reverse brain mitochondrial dysfunction in animal …

Exploring The Role Of Intracellular Aminopeptidases In Staphylococcus Aureus Pathogenesis, Devon Nicole Marking

USF Tampa Graduate Theses and Dissertations

Staphylococcus aureus is a remarkably pathogenic bacterium that is widely prevalent among the human population. It is the leading agent of skin and soft tissue infections, and is also responsible for causing an array of severe and life threatening diseases. The invasiveness of the pathogen, coupled with increasing antibiotic resistance seen for S. aureus infections, makes this bacterium a prominent public health concern. The extended pathogenicity of S. aureus is largely due to its repertoire of virulence factors, which are typically characterized by being bound to the cell wall, or secreted into the extracellular environment. Previously, our lab identified a …

The Role Of Intermembrane Space Redox Factors In Glutathione Metabolism And Intracellular Redox Equilibrium, Hatice Kubra Ozer

Theses and Dissertations

The mitochondrial intermembrane space (IMS) is a unique subcellular compartment that houses key thiol-dependent redox pathways such as protein transport, mitochondrial respiration, and detoxification of ROS (reactive oxygen species). These pathways are all dependent on cysteine-rich proteins, thus maintaining thiol-disulfide balance in this organelle is crucial for cellular functions. An IMS protein import pathway called the Mia40-Erv1 disulfide relay system uses disulfide bond formation for the import and retention of substrate proteins in the IMS. Erv1 is also suggested to be involved in maturation of cytosolic Fe-S cluster proteins and regulation of iron homeostasis in S. cerevisiae. However, these studies …

Selection And Basis For 2,4-D (2,4-Dicholorphenoxyacetic Acid) Tolerance In Red Clover (Trifolium Pratense), Tara L. B. Lewis

Theses and Dissertations--Plant and Soil Sciences

A red clover (Trifolium pratense) population (UK), from a cross between the cultivar Kenland and a 2,4-D tolerant population (Florida), was recurrently selected for 2,4-D tolerance with evaluations after the 6^th, 7^th, and 8^th selection cycles. All UK populations were more 2,4-D tolerant than Kenland. The 2,4-D tolerance following the 6^th selection cycle was similar to the Florida population and tolerance was increased following 7 and 8 cycles of selection by removing plants showing 2,4-D injury and doubling the rate of 2,4-D used for selection.

Yield and forage quality were evaluated in …

A Comparison Of Obesity Interventions Using Energy Balance Models, Marcella Torres

Theses and Dissertations

An energy balance model of human metabolism developed by Hall et al. is extended to compare body composition outcomes among standard and proposed obesity interventions. Standard interventions include a drastic diet or a drastic diet with endurance training. Outcomes for these interventions are typically poor in clinical studies. Proposed interventions include a gradual diet and the addition of resistance training to preserve lean mass and metabolic rate. We see that resistance training, regardless of dietary strategy, achieves these goals. Finally, we observe that the optimal obesity intervention for continued maintenance of a healthy body composition following a diet includes a …