• ADAM17 AND AGING-RELATED VASCULAR DYSFUNCTION

      Dou, Huijuan; Department of Physiology (1/25/2018)
      A disintegrin and metalloproteinase ADAM17 (tumor necrosis factor–converting enzyme) regulates soluble TNF levels. We tested the hypothesis that aging-induced activation in adipose tissue (AT)-expressed ADAM17 contributes to the development of remote coronary microvascular dysfunction in obesity. We found that the increased activity of endothelial ADAM17 is mediated by a diminished inhibitory interaction with caveolin-1, due to age-related decline in caveolin-1 expression in obese patients and mice or to genetic deletion of caveolin-1. Coronary arterioles (CA) and AT were examined in patients who underwent heart surgery. Excess, ADAM17-shed TNF from AT arteries in older obese patients was sufficient to impair CA dilation in a bioassay in which the AT artery was serially connected to a CA. CA and AT were also studied in 6-month and 24-month lean and obese mice. We found that obesity elicited impaired endothelium-dependent CA dilations only in older patients and in aged obese mice. Transplantation of AT from aged obese, but not from young or aged, mice increased serum cytokine levels, including TNF, and impaired CA dilation in the young recipient mice. In patients and mice, obesity was accompanied by age-related activation of ADAM17, which was attributed to vascular endothelium–expressed ADAM17. Additionally, ADAM17 mediates shedding of JAM-A (junctional adhesion molecule-A). We hypothesized that ADAM17 activation, via increased JAM-A shedding impairs flow mechanosensing and induces abnormal artery remodeling in aging. We found a reduced lumen diameter and increased wall thickness in AT of aged patients. ECs using plasmid JAM-A were aligned to flow direction earlier than GFP treated control cells. Site-directed mutagenesis was employed to generate JAM-A cleavage resistant mutants, we detected soluble JAM-A in the supernatants from cells transfected with plasmid JAM-A, but not from cells expressing mutant JAM-A plasmids. Importantly, soluble JAM-A is significantly increased in the supernatant from cells with combined action of plasmid JAM-A and recombinant ADAM17, when compared to cells with plasmid JAM-A alone. Collectively, our data revealed that age-related reduction in Cav-1 expression and subsequently increased the activity of endothelial ADAM17 led to excess TNF production, which acts remotely to promote coronary arteriole dysfunction. Whereas activation of ADAM17 in vascular endothelium mediates increased JAM-A shedding and causes ECs misalignment. Our data suggest that the combined action of TNF and JAM-A lead to development of CMD and its related vascular remodeling in older obese patients.
    • EFFECTS OF CHRONIC ALOHOL AND GLUCOSE EXPOSURE ON VIABILITY OF ALVEOLAR MACROPHAGES

      Keller, Elizabeth; College of Science and Mathematics; College of Allied Health; Curry-McCoy, Tiana; Thomas, Amanda; Augusta University (2019-02-13)
      The adverse health risks associated with alcohol abuse and obesity are widely known by the general population. Although lesser known, studies have presented the lungs as secondary organs affected by such lifestyle factors. Healthy lungs are protected against infection and harmful airborne particles by macrophages, the working entities of the immune system which fight potential sources of infection. When these immune-responsive cells are compromised and unable to perform their functions, lung health may deteriorate. Therefore, a healthy pulmonary alveolar macrophage population is vital for adequate lung function. Chronic alcohol abuse and obesity have been shown to suppress alveolar macrophage function, thus lowering the lungs� first line of defense. The objective of this study is to determine the effects of exogenous ethanol and increased glucose concentration on macrophage size and viability via an�in vitro�study on NR8383 rat alveolar macrophages. The study measures macrophage viability under treatment conditions.
    • Epigenetic Regulation of Adipogenic Differentiation And Lipid Metabolism: Role of Enhancer of Zeste Homolog 2 (EZH2)

      YIEW, KAN HUI; Department of Pharmacology and Toxicology (2017)
      Adipose tissue expansion in obesity promotes cardiometabolic disease, for which there is an urgent need to elucidate disease mechanisms and develop novel and effective medical therapies. In obesity, adipose tissues can potentially expand through adipocyte hypertrophy and/or hyperplasia, with the latter being a healthier mechanism of fat expansion. Adipocyte hyperplasia (via adipogenic differentiation) is inexplicably restrained in diet-induced obesity (DIO), however, and hypertrophy ensues, leading to inflammation, insulin resistance, and dysregulated adipose tissue lipid metabolism, which together contribute to cardiometabolic disease. The mechanisms of impaired adipogenic differentiation and lipid metabolism during DIO are unclear, with prior studies suggesting epigenetic dysregulation of histone deacetylase 9 (HDAC9, an endogenous repressor of adipogenic differentiation). The overall goal of my dissertation project is to investigate the role of Enhancer of Zeste Homolog 2 (EZH2), a histone methyltransferase, in the aforementioned processes. In Aim 1, we hypothesized that EZH2 promotes adipogenic differentiation by repressing HDAC9. EZH2 recruitment and histone 3 lysine 27 trimethylation (H3K27me3) modification were elevated at the HDAC9 gene promoter (p<0.05) concurrent with dramatic downregulation of HDAC9 mRNA levels (p<0.05) during adipogenic differentiation of primary human preadipocytes. This suggested a role for EZH2 in silencing HDAC9 gene expression. Counterintuitively, a highly selective EZH2 pharmacological inhibitor (GSK126), at a concentration that effectively blocked H3K27me3, led to increased lipid accumulation (p<0.05) in human adipocytes, without inhibiting adipocyte marker gene expression. Consistently, mice with adipose-specific EZH2 deletion (cKO) displayed significantly elevated body weight, adipose tissue mass, and adipocyte cell size. These phenotypic alterations could not be explained by differences in feeding behavior, locomotor activity, or metabolic energy expenditure, thereby suggesting that EZH2 regulates lipid metabolism. This hypothesis was explored in Aim 2. Human adipocytes treated with either an EZH2 inhibitor or vehicle exhibited comparable rates of de novo lipogenesis (DNL), fatty acid (FA) uptake, and basal/stimulated lipolysis. Consistently, cKO and littermate control mice displayed comparable in vivo and ex vivo basal/stimulated adipose lipolysis. EZH2’s function in other important metabolic pathways such as glycolysis and β-oxidation remain to be investigated. Collectively, our findings suggest a potential role of EZH2 in regulating adipocyte lipid metabolism.
    • GIP-Overexpressing Mice Demonstrate Reduced Diet-Induced Obesity and Steatosis, and Improved Glucose Homeostasis

      Kim, Su-Jin; Nian, Cuilan; Karunakaran, Subashini; Clee, Susanne M.; Isales, Carlos M.; McIntosh, Christopher H. S.; Department of Orthopaedic Surgery; Department of Cellular Biology and Anatomy (2012-07-3)
      Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone that potentiates glucose-stimulated insulin secretion during a meal. Since GIP has also been shown to exert b-cell prosurvival and adipocyte lipogenic effects in rodents, both GIP receptor agonists and antagonists have been considered as potential therapeutics in type 2 diabetes (T2DM). In the present study, we tested the hypothesis that chronically elevating GIP levels in a transgenic (Tg) mouse model would increase adipose tissue expansion and exert beneficial effects on glucose homeostasis. In contrast, although GIP Tg mice demonstrated enhanced b-cell function, resulting in improved glucose tolerance and insulin sensitivity, they exhibited reduced diet-induced obesity. Adipose tissue macrophage infiltration and hepatic steatosis were both greatly reduced, and a number of genes involved in lipid metabolism/inflammatory signaling pathways were found to be down-regulated. Reduced adiposity in GIP Tg mice was associated with decreased energy intake, involving overexpression of hypothalamic GIP. Together, these studies suggest that, in the context of over-nutrition, transgenic GIP overexpression has the potential to improve hepatic and adipocyte function as well as glucose homeostasis.
    • Increasing Muscle Mass by Deletion of Myostatin Improves Metabolic and Vascular Function in Obese (db/db) Mice

      Qiu, Shuiqing; Department of Biochemistry and Molecular Biology (2014)
      Obesity is the major emerging risk factor in the disease burden of western cultures. Obesity significantly reduces both metabolic and cardiovascular function, most notably inducing a state of insulin resistance in the former case and impeding endothelial control of vascular function in the latter. Mechanisms underpinning these defects are poorly understood and interventional therapies remain few. Exercise is a powerful method to limit or improve obesity-associated diseases, improving metabolic syndrome markers and endothelial function in obese patients. The salutatory effects of exercise are multi-factorial and include increases in muscle size and quality, reduction in fat mass and alterations in the components of plasma milieu. The relationships between the physiologic changes induced by exercise and improvements in metabolic and cardiovascular function are poorly defined. Myostatin, a TGF-β family member, is secreted by muscle, limits muscle growth and stimulates adipose tissue accumulation. Thus deletion of myostatin permits a method of assessing whether a component of exercise, increases in muscle mass, has positive effects on metabolic and vascular function. While myostatin deletion can improve glucose tolerance, the mechanisms are unclear. Whether myostatin deletion improves endothelial function in obesity is also not clear. The overall goal of the current study was to determine if increasing muscle mass by deletion of myostatin improves metabolic and vascular function in obese (db/db) mice.
    • Palmitoleate Induces Hepatic Steatosis but Suppresses Liver Inflammatory Response in Mice

      Guo, Xin; Li, Honggui; Xu, Hang; Halim, Vera; Zhang, Weiyu; Wang, Huan; Ong, Kuok Teong; Woo, Shih-Lung; Walzem, Rosemary L.; Mashek, Douglas G.; et al. (2012-06-29)
      The interaction between fat deposition and inflammation during obesity contributes to the development of non-alcoholic fatty liver disease (NAFLD). The present study examined the effects of palmitoleate, a monounsaturated fatty acid (16⠶1n7), on liver metabolic and inflammatory responses, and investigated the mechanisms by which palmitoleate increases hepatocyte fatty acid synthase (FAS) expression. Male wild-type C57BL/6J mice were supplemented with palmitoleate and subjected to the assays to analyze hepatic steatosis and liver inflammatory response. Additionally, mouse primary hepatocytes were treated with palmitoleate and used to analyze fat deposition, the inflammatory response, and sterol regulatory element-binding protein 1c (SREBP1c) activation. Compared with controls, palmitoleate supplementation increased the circulating levels of palmitoleate and improved systemic insulin sensitivity. Locally, hepatic fat deposition and SREBP1c and FAS expression were significantly increased in palmitoleate-supplemented mice. These pro-lipogenic events were accompanied by improvement of liver insulin signaling. In addition, palmitoleate supplementation reduced the numbers of macrophages/Kupffer cells in livers of the treated mice. Consistently, supplementation of palmitoleate decreased the phosphorylation of nuclear factor kappa B (NF-κB, p65) and the expression of proinflammatory cytokines. These results were recapitulated in primary mouse hepatocytes. In terms of regulating FAS expression, treatment of palmitoleate increased the transcription activity of SREBP1c and enhanced the binding of SREBP1c to FAS promoter. Palmitoleate also decreased the phosphorylation of NF-κB p65 and the expression of proinflammatory cytokines in cultured macrophages. Together, these results suggest that palmitoleate acts through dissociating liver inflammatory response from hepatic steatosis to play a unique role in NAFLD.
    • Pulmonary Stress in the Alcoholic and Obese Lung

      Thomas, Amanda Blair; Department Of Undergraduate Health Professions (Augusta University, 2015-05)
      In the United States today, alcoholism and obesity are increasingly becoming issues for a vast age group from young children to geriatric adults. Alcoholism and obesity have been extensively studied as separate entities that have been proven to change metabolism and cause over-lapping health issues, which prompted us to study them in conjunction with one another, especially in the lungs. One major link between these two alarmingly common problems is Krüppel-Like Factor 4 (KLF4), a cell regulatory protein crucial to cellular normality and monocyte differentiation. This particular study highlights the effects alcoholism and obesity have on the lung, specifically epithelial cells (L2) and macrophages (AM). The goal of this project is to measure the KLF4 expression in the L2 and AM cells subjected to high ethanol (EtOH) consumption, high glucose consumption, high EtOH and glucose consumption, as well as a healthy control lung in to explain the mechanism behind decreased immune function in these patients.
    • Reducing Waist Circumference among African Americans in the Fit Body and Soul Study

      Garvin, Jane; Sattin, Richard W.; Looney, Stephen W. (2014-11)
      This study aimed to determine if waist circumference decreased following the FBAS intervention when compared with the health education comparison group.
    • The Relationship of A Body Shape Index and Body Mass Index with Health-related Quality of Life among African Americans: A Study from Fit Body and Soul

      Garvin, Jane; Williams, Lovoria B.; Joshua, Thomas V. (2013-11)
      Aims: This study aimed to determine if these two measures of obesity (ABSI and BMI) were associated with health-related quality of life in this sample of overweight and obese African-American congregants seeking weight reduction.; Specifically, this study aimed to determine if health-related quality of life explained the variation in ABSI or BMI.
    • A Tailored Intervention Program for Overweight and Obese Vetrans: Who Benefits and When

      Garvin, Jane; Department of Physiological & Technological Nursing (2012-06)
      This descriptive, exploratory study examined longitudinal clinical data for variables associated with weight reduction among veterans enrolled in a weight reduction intervention, the MOVE! Program. Variables of interest included background characteristics and exposure to components of the intervention. Background, intervention, and outcome variables were organized around the Interaction Model of Client Health Behavior. In addition to the outcomes related to weight, hemoglobin A1 Thirteen percent of participants (N = 53 of 404) achieved a 5% weight reduction. Overall, the sample was primarily non-Hispanic (96%), urban (83%), Black (58.4%), married (58.4%) and male (~80%). The mean age was 56 years. Common comorbidities associated with obesity were evident including diabetes (30.2%), hypertension (60.9%), and hyperlipidemia (54.0%). The average body mass index was ~35. All available data were collected from program entry to a designated stop date; therefore, participants had unequal and irregular data points. Participants were observed repeatedly over time with 51% having 10 or more observations. A little more than half of the participants were group attendees (~56%) rather than self-managed. The majority of the intervention exposures were group rather than individual or telephone visits with providers. C, blood pressure, and serum lipid levels were examined. Achieving a 5% weight reduction was significantly associated with age in years (OR 1.04), group attendance beyond the day of orientation (OR 6.61), attendance at the holiday eating class (OR 3.67), exposure over time (measured in weeks, OR 1.02), and the interaction between time and group (OR .97). Weight reduction in pounds was significantly associated with age, baseline body mass index, total number of group classes attended, and telephone contact with the registered nurse. Using repeated measures of weight, the trajectory of weight was significantly associated with gender, baseline body mass index, and exposure to the intervention over time. Examination of additional outcomes revealed that components of the intervention were associated with beneficial changes in hemoglobin A1C, blood pressure, and serum lipid levels. Further research is needed to more fully describe successful weight reducers and the identify best practices to convert unsuccessful weight reducers to successful ones.
    • Weight Reduction Among Veterans in the MOVE! Program

      Garvin, Jane; Marion, Lucy (2013-02)
      Purpose/Aim: Determine which background and program exposure variables were associated with a 5% weight reduction
    • Weight Reduction Among Veterans in the MOVE! Program

      Garvin, Jane; Marion, Lucy; Biobehavioral Nursing (2013-03)
      Purpose: Determine which background and program exposure variables were associated with a 5% weight reduction