Molecular, Genetic, and Biochemical Nutrition Commons^™

Retinoic Acid, Insulin, And Cycloheximide Alter Glycogen Homeostasis In Differentiating L6 Myoblasts, Aaron Armstrong

Doctoral Dissertations

Glycogen synthesis in skeletal muscle (SM) is responsible for the majority of post-prandial glucose disposal in healthy individuals. In type 2 diabetes mellitus (T2DM), compromised skeletal muscle glycogen synthesis contributes to hyperglycemia. L6 rat SM cells can develop insulin resistance with prolonged insulin stimulation and provide an in vitro model for mechanistic dysfunction in glycogen homeostasis. SM glycogen is synthesized by glycogen synthase (GS) in response to insulin stimulation. Canonically, insulin signaling increases GS activity through inhibition of its Ser641 regulator glycogen synthase kinase-3β (GSK3β) by protein kinase B (AKT). Proximal insulin signaling activates AKT via Ser473 phosphorylation which proceeds …

Switching Palmitoyl And Oleoyl Positions In Sn-2 And Sn-3 Of A Triacylglycerol Led To Differential Body Weight Gain Rates And Hepatic Gene Expressions In Mice Fed A High-Fat Diet, Xinge Hu

Masters Theses

Alterations of triacylglycerol (TAG) are associated with metabolic diseases such as obesity and diabetes. The fatty acyl groups in a TAG molecule determine its characteristics from melting temperature to digestion and absorption. We hypothesize that the TAG fatty acyl position affects the body weight (BW) gain and lipid metabolism in mice fed a high-fat diet (HFD, 36 % w/w diet). Six-week-old male C57BL/6J mice were randomly assigned to 3 dietary groups, 1,2-dipalmitoyl-3-oleoylglycerol (PPO), 1,3-dipalmitoyl-2-oleoylglycerol (POP), and chow control. The food intake and BW were measured daily during 6 weeks of treatment. The PPO group had significantly higher food intake, caloric …

Metabolism In The Colonocyte: Where Bacteria And Diet Meet, Bohye Park

Doctoral Dissertations

The host-microbiome interaction and the functions of microbial-derived metabolites, including butyrate, are important in colon health. Butyrate is the preferred energy source in colonocytes and has multiple physiological functions in the colon. A metabolic shift in colonocytes toward increased glucose utilization from butyrate oxidation is followed by several critical genetic modifications in cancerous colonocytes. Moreover, it has been suggested that the gut-microbiota composition is influenced by environmental factors, such as diets and the host's physiological status. Therefore, an understanding of the role of colonocyte metabolism toward impacting the host-microbiota commensal relationship would be an important step in understanding the functional …

The Studies Of Effects Of Vitamin A Status On Type 2 Diabetes In Zucker Diabetic Fatty Rats And Retinoic Acid On Glucose Transporter 4 Expression In L6 Cells, Tiannan Wang

Doctoral Dissertations

The epidemic of metabolic diseases such as diabetes has become a public health concern. Previous research data from our lab have shown that vitamin A (VA) status and retinoic acid (RA), a metabolite of VA, contribute to the glucose and lipid metabolism in the body and cells. As the skeletal muscle contributes to metabolic homeostasis, the effects of VA signaling system on its glucose metabolism are worth to be investigated. Here in this dissertation, the following two projects were carried out to study the VA’s role in the control of metabolism. (1) The effects of VA status on the development …

Effects Of N-3 Pufa-Derived Epoxides Combined With Seh Inhibition On Brown Adipose Tissue And Brown Adipocytes In Obesity, Yang Yang

Doctoral Dissertations

Brown adipose tissue (BAT) has become a promising target for obesity treatment and prevention. However, effective dietary factors to promote BAT mass and function have not been identified. 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) and 19,20-epoxydocosapentaenoic acid (19,20-EDP) are two prominent epoxy fatty acids (EpFAs) produced from n-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), respectively. EpFAs are quickly metabolized to less active diols by soluble epoxide hydrolase (sEH). In this dissertation, the effects of an sEH inhibitor (t-TUCB) (which stabilizes EpFAs) alone or combined with n-3 EpFAs on thermogenic activity in the BAT and brown adipocytes in …

Novel Insights Into The Role Of Pyruvate Kinase M2 In Podocyte Homeostasis And Function, Mohammed Alquraishi

Doctoral Dissertations

Background: Renal diseases are major health concerns and among the top ten leading causes of death in the US. A large number of these diseases are characterized by deterioration in glomerular structure and function, leading to reduced filtration capacity and proteinuria. Glomerulus podocytes are epithelial cells that maintain glomerular integrity and act as a defense mechanism against proteinuria. Recent advances in renal research suggested a novel role of glycolysis and its related enzymes, pyruvate kinase M2 (PKM2) in particular, in the progression of renal diseases. However, the precise role of PKM2 in podocyte homeostasis and its contribution to glomerular function …

Roles Of Select Cytochrome P450 Epoxygenases In Brown Adipogenesis, Katherine Marie Graham

Masters Theses

Brown adipose tissue (BAT) has recently emerged as a novel target for obesity treatment and prevention. Cytochrome P450 (CYP) epoxygenases, primarily CYP2J and CYP2C isoforms, produce epoxy fatty acids (EpFAs), which have been suggested to play important roles in the regulation of white adipogenesis and obesity. However, adipocyte-specific expression of CYP epoxygenases has not been extensively analyzed, and the roles of CYP epoxygenases in brown adipogenesis remain unexplored. In this study, we examined mRNA levels of Cyp2j and Cyp2c isoforms during murine and human brown and white adipocyte differentiation and in various adipose tissue depots of high-fat diet (HFD)-fed and …

The Effects Of Retinoic Acid And Insulin On Glycogenesis In Hl1c Hepatoma Cells, Addison J. Bond, Guoxun Chen Dr.

Chancellor’s Honors Program Projects

No abstract provided.

Pkm2 Influences The Metabolic Fate Of Butyrate In Colorectal Cancer Cells, Megan Louise Pence

Chancellor’s Honors Program Projects

No abstract provided.

Butyrate, A Major Bacterial-Derived Metabolite: Understanding Of Butyrate Metabolism In Cancerous Colonocytes, Anna Han

Doctoral Dissertations

The prohibitory effects of dietary fiber in colorectal cancer have been identified, although the detailed mechanism of this beneficial effect remain unclear. Butyrate, a fermentation metabolite of fiber, has anti-cancer properties by inhibiting cell proliferation and increasing cell apoptosis in cancer cells. A major mechanism, whereby butyrate exerts anti-cancer effects in colorectal cancer, is its role as an HDAC inhibitor. Moreover, it has been suggested that the metabolic fate of butyrate is significantly related to its role as an HDAC inhibitor. Therefore, understanding butyrate metabolism in cancerous colonocytes sheds important light on how butyrate has its selective and inhibitory effects …

Beneficial Effects Of Naringenin And Indomethacin On White And Brown Adipocytes, Jamie Ann Kearns

Masters Theses

As obesity continues to grow and medical costs in the United States are estimated at $147 billion annually, novel ways to prevent and treat obesity are needed. One approach is to promote thermogenesis to improve energy balance by increasing the activities of thermogenic brown and beige adipocytes.

Naringenin, a citrus flavanone, has been shown to act as anti-inflammatory and lipid lowering agent as well as activate PPARgamma. However, it is unclear whether it can activate thermogenic activity in white adipocytes, i.e., promote formation of beige adipocytes. Indomethacin (INDO) is an FDA approved drug used to treat pain related to inflammation …

Long-Term Treatment With Insulin And Retinoic Acid Increased Glucose Usage In L6 Muscle Cells Via Glycogenesis, Matthew Ray Goff

Doctoral Dissertations

Skeletal muscle glucose metabolism can affect whole body glucose homeostasis significantly. Vitamin A (VA) plays a role in a number of physiological functions including glucose metabolism. However, its role in skeletal muscle glucose metabolism has not been well established. Insulin controls glucose metabolism in the skeletal muscle via the regulations of glucose uptake, glycogenesis, and glycolysis. We hypothesize that insulin and VA signaling pathways may converge to regulate glucose metabolism in skeletal muscle. Here, the effects of retinoic acid (RA) alone and in combination with insulin on glucose utilization in rat L6 muscle cells were studied. L6 cells were treated …

Brown And Beige Adipocytes: Effects Of Inflammation And Nutritional Intervention, Jiyoung Bae

Doctoral Dissertations

Recent findings of brown adipocytes and brown-like or beige adipocytes, capable of dissipating energy as heat, in adult humans have promised new hope for obesity treatment and prevention. Understanding of the regulation of brown and beige adipocytes will provide novel strategies to reach the goal. Pattern recognition receptors (PRR) are responsible for inflammation in adipose tissue, which leads to adipose dysfunction and obesity associated chronic diseases. It has been shown that PRR activation induces inflammation, leading to insulin resistance in white adipocytes and white adipose tissue (WAT). However, the roles of PRR activation in brown adipocytes and brown adipose tissue …

Exploring Novel Environmental Link To Obesity: Role Of Parabens In Adipogenesis In Vitro And In Vivo, Pan Hu

Doctoral Dissertations

Parabens are a group of alkyl esters of p-hydroxybenzoic acid that include methylparaben, ethylparaben, propylparaben, butylparaben, and benzylparaben. Paraben esters and their salts are widely used as preservatives in cosmetics, toiletries, food, and pharmaceuticals. Humans are exposed to parabens through the use of such products from dermal contact, ingestion, and inhalation. The extent of the exposure is reflected by the frequent detection of these compounds in urine samples in the general population. Moreover, parabens have been detected in human serum, milk, placental tissues and breast tumor tissues. Parabens have been shown to preserve estrogenic/antiandrogenic effects, and can activate peroxisome proliferator-activated …

Calcium And Leucine Modulation Of Airway Inflammation, Patricia Louise Brown

Doctoral Dissertations

Over the past several decades the prevalence of obesity and asthma have increased in a parallel fashion. Recent studies reported a positive relationship between the two disorders that may in fact be causal. Although the link between obesity and asthma has become widely recognized, the underlying pathophysiological connection is not elucidated. Increased markers of inflammatory and oxidative stress are present in obesity and asthma suggesting the link is immunological. The systemic inflammation observed in obesity may potentially initiate adverse affects in the airways. Previous studies have shown that consumption of dairy foods (rich in calcium and leucine) suppress 1,25-dihydroxycholecalciferol (calcitriol) …

Role Of Vitamin A Status And Its Catabolism In The Regulation Of Glucose And Lipid Homeostasis In Rats Under Physiological And Disease Conditions, Yang Li

Doctoral Dissertations

The increased number of individuals with metabolic diseases has become a public health concern. Vitamin A (VA, retinol) is required to maintain the general health of an individual. How VA contributes to the regulation of glucose and lipid homeostasis in normal and metabolic disease states is unclear. VA’s physiological activities are mainly mediated by its metabolite, retinoic acid (RA), which activates several transcriptional factors in the nuclear receptor super family and in turn, regulates the expression of numerous genes for macronutrient metabolism. For the RA production, retinol is first oxidized into retinal and then from retinal to RA. We hypothesize …

Role Of Leucine In Modulation Of Mitochondrial Biogenesis And Sirt1-Ampk Signaling In C2c12 Myotubes, Chunzi Liang

Doctoral Dissertations

Mitochondrial dysfunction in skeletal muscle has been considered as a crucial step in the development of metabolic diseases, including insulin resistance syndrome, type 2 diabetes and cardiovascular diseases. Previous studies have demonstrated that dietary branched-chain amino acids, particularly leucine, protects against high-fat diet induced impairment of mitochondria and insulin resistance in skeletal muscle and adipose tissue through mTOR-dependent and independent pathways. In addition, previous ex vivo and in vitro approaches from this laboratory indicate that leucine and its metabolites (HMB and KIC) stimulate mitochondrial biogenesis and promote energy partitioning from adipocytes to muscle cells, partially through SIRT1 signaling. Moreover, recent …

Feeding State, Vitamin A Status And Atypical Protein Kinase C Modulate The Insulin-Regulated Gene Expression In Rat Hepatocytes, Wei Chen

Doctoral Dissertations

Hormonal and nutritional stimuli coordinately regulate the glucose and lipid metabolism in the liver. Dysregulated hormonal balance and nutrient metabolism not only disrupt the energy homeostasis, but also predispose individuals to the development of obesity and its related metabolic diseases. Research presented in this dissertation investigated the effects of a nutritional factor, vitamin A (VA), and a potential component of insulin signaling cascade, atypical protein kinase C (aPKC), on the glucose and lipid metabolic genes transcription in primary hepatocytes from Zucker lean (ZL) and fatty (ZF) rats.

To examine VA effects, we put ZL and ZF rats with different VA …

The Effects Of Leucine And Dairy Products On Adipose Tissue Inflammation: The Role Of Adipocyte Derived Microvesicles, Benjamin Jones Curry

Doctoral Dissertations

Obesity is characterized by chronic oxidative and inflammatory stress, and adipose tissue is a significant source of inflammatory cytokines. Previous studies demonstrated that dairy products (rich in calcium and leucine) can alleviate obesity-associated inflammatory stress through suppression of 1, 25-dihydroxycholecalciferol (calcitriol) with calcium and the high leucine content in dairy. We have also shown leucine treatment increases anti-inflammatory adiponectin expression and decreases pro-inflammatory cytokines TNF-a [alpha], MCP-1, and IL-6 expression in adipocytes. Therefore, we sought to determine if these alterations in inflammatory cytokine production could have a functional effect on the inflammatory process, specifically monocyte – endothelial cell adhesion as …

The Suppressive Effects Of 1,25-Dihydroxyvitamin D3 And Vitamin D Receptor On Brown Adipocyte Differentiation And Mitochondrial Respiration, Carolyn Jeanne Ricciardi

Masters Theses

The vitamin D system plays a role in metabolism regulation. It has been reported that 1,25(OH)₂D₃ [1,25-dihydroxyvitamin D] suppresses 3T3-L1 adipocyte differentiation. Vitamin D receptor (VDR) knockout mice showed increased energy expenditure whereas mice with adipose-specific VDR over expression showed decreased energy expenditure. Brown adipose tissue (BAT), which functions in non-shivering thermogenesis by uncoupling ATP synthesis from oxidation, plays important roles in energy expenditure. However, the effects of 1,25(OH)₂D₃ on brown adipocyte differentiation and mitochondrial respiration have not been studied. Reported here is the mRNA expression of VDR, UCP1, and CYP27B1 (1α[alpha]- hydroxylase) in …

Activation Of Nucleotide Binding Oligomerization Domain Containing Protein 1 In 3t3-L1 Adipocytes: Effects On Adipocyte Differentiation And Lipolysis, Jaanki Shamb Purohit

Masters Theses

Obesity, defined as having excess adipose tissue, is associated with chronic inflammation. Adipose tissue is made up of many cell types, including preadipocytes and adipocytes. Both preadipocytes and adipocytes express pattern recognition receptors that play important roles in innate immunity. Two families of pattern recognition receptors that have been studied in adipose tissue are Toll-like receptors (TLRs) and NOD-like receptors (NLRs). Activation of TLR2 and TLR4 has been shown to lead to proinflammatory response in adipocytes, which is shown to suppress adipocyte differentiation and stimulate lipolysis, one of the major physiological functions of adipocytes. However, the effects of NOD activation …

Regulation Of Apolipoprotein C-Iii Gene Expression By Nuclear Receptors Hepatocyte Nuclear Factor 4 Alpha And Chicken Ovalbumin Upstream Promoter Transcription Factor Ii, But Not Retinoids In Hepatic Cells, Meredith Lee Howell

Masters Theses

Retinoic acid (RA) treatment induces hyperlipidemia in humans and animals. RA regulates the expression levels of various genes through the induction, repression, or coactivation of nuclear receptors, mediating its effects. RA-induced hyperlipidemia has been attributed to the induction of apolipoprotein CIII (gene, Apoc3), which inhibits lipoprotein lipase activity (LPL). We have shown that vitamin A (VA) status and retinoid treatment regulates hepatic lipogenic gene expression, suggesting that the induction of lipogenic genes may also contribute to hyperlipidemia. To test the hypothesis that retinoids may not affect Apoc3 expression, we analyzed the expression levels of Apoc3 mRNA in response to …

Role Of Retinoids In The Regulation Of Hepatic Glucose And Lipid Metabolism, Rui Li

Doctoral Dissertations

The liver plays an important role in controlling glucose and lipid homeostasis. Metabolic abnormalities such as obesity and type 2 diabetes are often associated with profound changes in the expression of genes involved in hepatic glucose and lipid metabolism. Dietary nutrients provide us with macronutrients for energy and micronutrients for maintenance of general health. However, the effects of individual micronutrients on the development of metabolic diseases are unknown. Sterol regulatory element binding protein-1c (SREBP-1c) is the master regulator of fatty acid synthesis, and glucokinase (GK) is the key enzyme in glucose metabolism. Based on the preliminary results from our laboratory …

The Effects Of Leucine On Mitochondrial Biogenesis And Cell Cycle In A-375 Melanoma Cells, Tia Marie Filhiol

Masters Theses

Most cancer cells undergo the Warburg effect, a shift from oxidative to glycolytic metabolism accompanied by suppression of p53. We have demonstrated leucine stimulation of mitochondrial biogenesis, fatty acid oxidation, and p53 expression in both muscle and fat cells. Accordingly, we now sought to determine if leucine stimulates mitochondrial biogenesis and exit from cell cycle in A-375 melanoma cells. Because these cells use glucose as their primary substrate, cells were grown under both standard (11.1 mM) and reduced (5.5 mM) glucose conditions. Increasing glucose reduced mitochondrial mass 50-60%, and accelerated cell proliferation by ~20%. Leucine (0.25, 0.5, 0.75, and 1.0 …

Role Of Beta-Hydroxy-Beta-Methylbutyrate (Hmb) In Leucine Stimulation Of Mitochondrial Biogenesis And Fatty Acid Oxidation, Renee Ashley Stancliffe

Masters Theses

Mitochondrial dysfunction and the resulting oxidative stress is widely recognized as a contributing factor to the development of numerous pathophysiologies including obesity, diabetes, cardiovascular disease, sarcopenia, liver disease, dementia, amongst others. Mitochondrial dysfunction results in a reduced mitochondrial number and oxidative capacity, causing an increase in free radical production and consequently oxidative stress. As such, the characterization of compounds that can upregulate mitochondrial biogenesis and function could provide the foundation for the development of therapeutic nutraceuticals that promote mitochondrial health, and consequently reduce oxidative stress. Leucine is well recognized to stimulate muscle protein synthesis, and we have recently demonstrated that …

Effects Of Folate Availability On Expression Of Adipocyte Metabolic Genes Via Modulation Of Dna Methylation, Julia Stair Gouffon

Doctoral Dissertations

Epigenetic modifications serve as a means of intermediate gene expression control and nutritional inputs may modify methylation patterns in regulatory regions of genes. Therefore, we proposed that specific nutrient availability of folate affects adipocyte development and metabolism through impacting the one-carbon cycle and subsequent DNA methylation patterns. Accordingly, we sought to determine if the methylation level of CpG islands could be influenced in adipocytes and if so, how this might affect gene signaling in mature adipocytes. We treated adipocytes with 0 to 0.9 millimolar [mM] folate, the methyl donor S-adenosylmethionine (SAMe) and the methylation inhibitor, 5-aza-2-deoxycitidine (2-DC) both during adipocyte …

Angiotensinogen Gene Silencing Reduces Lipid Accumulation And Inflammation In Cultured 3t3-L1 Adipocytes, Wenting Xin Carroll

Masters Theses

Obesity is characterized by metabolic complications which are related to several life-threatening diseases. Dysregulated inflammatory adipokines secretion from adipose tissue is believed as the major contributor to obesity-associated local and systemic inflammation, insulin resistance, and other metabolic dysfunctions.

Numerous studies in our lab and others pointed to the role of local adipose tissue renin-angiotensin system (RAS) in the pathogenesis of obesity, inflammation and insulin resistance. We hypothesized that adipocytes-derived angiotensinogen (Agt) played a critical role in adipogenesis and/or lipogenesis as well as adipose inflammation. To test, we established 3T3-L1 preadipocytes stably transfected with Agt-shRNA or scrambled sequence (Sc-shRNA). Transfected preadipocytes …

Genetic And Nutritional Studies To Elucidate The Role Of Adipose Tissue In The Pathogenesis Of Metabolic Syndrome, Nishan Sudheera Kalupahana

Doctoral Dissertations

Obesity is a major health problem in the United States and worldwide. It increases the risk for type-2 diabetes and cardiovascular diseases. A chronic low-grade inflammation occurring in white adipose tissue (WAT) is causally linked to the development of insulin resistance (IR), metabolic syndrome and obesity-associated chronic diseases. The aim of this dissertation research was to elucidate the WAT function in metabolic syndrome using genetic (overexpression of an adipose pro-inflammatory hormone, angiotensinogen) and nutritional manipulations/approaches (caloric restriction and omega-3 fatty acids), with specific emphasis on the role of inflammation.

Previous research indicates that WAT renin-angiotensin system (RAS) is overactivated in …

Angiotensin Iv And The Molecular Mechanisms Involved In The Development Of Insulin Resistance In 3t3-L1 Adipocytes, Julie Anne Jungwirth

Masters Theses

This study explored angiotensin IV’s (Ang IV) affects on the signaling pathways involved in the development of insulin resistance in 3T3-L1 adipocytes. Ang IV, working through the AT₄ receptor, interferes with insulin signaling through the blockade of the phosphatidylinositol 3-kinases (PI3K)/Akt pathway and through activating mitogen activated protein kinases (MAPK): extracellular signal regulated kinase (ERK) and c-Jun-N-terminal kinase (JNK) which are known to impair insulin receptor substrate-1 (IRS-1) signaling. The expression of AT₄ receptors was confirmed by reverse transcription polymerase chain reaction. Ang IV’s effects were found by treating adipocytes with combinations of Ang IV, AT …

Allometric Scaling Of Dietary Linoleic Acid On Changes In Tissue Arachidonic Acid Using Human Equivalent Diets In Mice, Kylie A Weldon

Masters Theses

The ability to extrapolate nutritional intervention data from experimental rodent models to humans requires standardization of dietary design. The inability to translate the level of nutrients from animal models to humans has contributed to contradictory findings between species. It is hypothesized that dietary linoleic acid (LA) promotes chronic and acute diseases by enriching tissues with arachidonic acid (AA), its downstream metabolite. However, levels of LA in rodent diets are notoriously erratic making interspecies comparisons unreliable. Therefore, the ability to extrapolate the biological effects of dietary LA from experimental rodents to humans necessitates an allometric scaling model that is rooted within …