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Temple University

1. Preston, Kyle J. Macronutrient Activation of Endothelium Dependent Leukocyte Trafficking: Metabolic Implications.

Degree: PhD, 2015, Temple University

Physiology

Obesity and insulin resistance are characterized by elevated pro-inflammatory proteins in the blood and immune cell accumulation in the visceral adipose tissue. Resident leukocytes release tumor necrosis factor α (TNFα) and other inflammatory cytokines which stimulate adipocyte lipolysis, recruit leukocytes to adipose tissue, promote pro-inflammatory immune cell polarization, facilitate oxidative stress, and activate intracellular kinases which dull insulin signaling cascades in metabolic tissues. Immune cell mediated dysregulation of stromal and parenchymal cells has raised suspicion that insulin resistance is an immune disorder initiated by activated white blood cells with over-nutrition. Efforts to improve pathological metabolism by reducing inflammation have yielded mixed results in humans and animal models. The role of inflammation and immune cell accumulation in the visceral fat (VF) in the progression of insulin resistance remains presently debated. There is, however, a consensus that identifying the triggers for obesity and impaired insulin signaling is of the utmost importance. The goal of this report is to identify dietary fat absorption as a key initiator of inflammatory action and insulin desensitization which may be dampened by reducing immune cell accumulation in adipose tissue. To explore how lean, healthy organisms become obese and insulin resistant, we examined the inflammatory consequences of isocaloric but variable macronutrient loads in the VF of lean mice. Mice were administered single liquid meals composed of low-fat (10% fat) or high-fat (60% fat) diet and observed by intravital microscopy to quantify leukocyte-endothelium interactions in mesenteric postcapillary venules (MPCV) 1, 2, 3, and 4 hours after oral gavage. Leukocyte rolling and leukocyte adhesion were transiently elevated within 1 hour after feeding and returned to baseline levels 4 hours later. Endothelial cell surface expression of P-selectin (Psel), a rapidly activated cell adhesion molecule (CAM), confirmed that high-fat feeding induced Psel dependent leukocyte rolling through the VF microcirculation. Furthermore, leukocyte accumulation in the VF was modestly increased by a single high-fat meal (HFM). Repetitive high-fat diet (HFD) consumption for 24 hours prolonged elevated leukocyte-endothelium interactions and promoted neutrophil accumulation in the VF. The neutrophilic enzyme myeloperoxidase (MPO), a producer of the chlorinating agent hypochlorous acid, increased in abundance and activity in the VF of HFM fed mice. Elevated leukocyte-endothelium interactions, leukocyte infiltration, and MPO activity in VF were not observed in Psel deficient (Psel-/-) mice following lipid overload. To ascertain if MPO is required for sustained endothelial activation, leukocyte-endothelium interactions and leukocyte infiltration were monitored in high-fat fed MPO deficient (MPO-/-) mice. Similar to the Psel-/- mice, MPO-/- mice were protected from the inflammatory effects of high-fat feeding. Our data supports postprandial…

Advisors/Committee Members: Scalia, Rosario;, Autieri, Michael V., Houser, Steven R., Kilpatrick, Laurie, Shore, Scott K., Soprano, Diane R.;.

Subjects/Keywords: Physiology;

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Preston, K. J. (2015). Macronutrient Activation of Endothelium Dependent Leukocyte Trafficking: Metabolic Implications. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,361365

Chicago Manual of Style (16th Edition):

Preston, Kyle J. “Macronutrient Activation of Endothelium Dependent Leukocyte Trafficking: Metabolic Implications.” 2015. Doctoral Dissertation, Temple University. Accessed August 12, 2020. http://digital.library.temple.edu/u?/p245801coll10,361365.

MLA Handbook (7th Edition):

Preston, Kyle J. “Macronutrient Activation of Endothelium Dependent Leukocyte Trafficking: Metabolic Implications.” 2015. Web. 12 Aug 2020.

Vancouver:

Preston KJ. Macronutrient Activation of Endothelium Dependent Leukocyte Trafficking: Metabolic Implications. [Internet] [Doctoral dissertation]. Temple University; 2015. [cited 2020 Aug 12]. Available from: http://digital.library.temple.edu/u?/p245801coll10,361365.

Council of Science Editors:

Preston KJ. Macronutrient Activation of Endothelium Dependent Leukocyte Trafficking: Metabolic Implications. [Doctoral Dissertation]. Temple University; 2015. Available from: http://digital.library.temple.edu/u?/p245801coll10,361365

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