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 hyperlipemia as an inducer of transient and Psel dependent inflammatory reactions that are sustained by prolonged HFD consumption. To study whether early phase inflammatory interventions granted late phase metabolic improvements, wild-type (WT), Psel deficient (Psel-/-), and MPO deficient (MPO-/-) C57BL/6 mice were given ad libitum access to LFD (10% fat) or HFD (60% fat) for 12-16 weeks. All mouse groups given HFD became obese. Prolonged HFD consumption sustained elevated leukocyte-endothelium interactions in MPCVs and was accompanied by increased local and systemic TNFα in WT mice. High-fat fed WT mice were hyperglycemic, hyperinsulinemic, glucose intolerant, and insulin resistant compared to LFD fed controls. Psel-/- mice were protected from leukocyte-endothelium interactions as well as local and systemic TNFα accumulation despite extended HFD consumption. Surprisingly, high-fat fed Psel-/- mice were equally hyperglycemic, hyperinsulinemic, glucose intolerant, and insulin resistant as the inflamed, high-fat fed WT mice. MPO-/- mice were also protected from elevated systemic TNFα and gained slightly less weight than the other high-fat fed groups. While MPO-/- mice were hyperglycemic and glucose intolerant, they did have improved insulin stimulated glucose clearance. The data presented in this report demonstrates the pro-inflammatory nature of postprandial hyperlipemia and the insulin desensitizing nature of prolonged HFD consumption. Ablation of VF immune cell accumulation by Psel deletion is not sufficient for improving insulin signaling or glycemic control, which is consistent with prior reports. Deletion of MPO, however, did result in slightly less obesity and marginally improved insulin signaling. We conclude that while immune cell accumulation in the VF contributes to the progression of insulin resistance, it is not a prerequisite for metabolic pathology development. / Physiology
| Identifer | oai:union.ndltd.org:TEMPLE/oai:scholarshare.temple.edu:20.500.12613/3425 |
| Date | January 2015 |
| Creators | Preston, Kyle J. |
| Contributors | Scalia, Rosario, Autieri, Michael V., Houser, Steven R., Kilpatrick, Laurie, Shore, Scott K., Soprano, Dianne R. |
| Publisher | Temple University. Libraries |
| Source Sets | Temple University |
| Language | English |
| Detected Language | English |
| Type | Thesis/Dissertation, Text |
| Format | 111 pages |
| Rights | IN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available., http://rightsstatements.org/vocab/InC/1.0/ |
| Relation | http://dx.doi.org/10.34944/dspace/3407, Theses and Dissertations |
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