Date on Master's Thesis/Doctoral Dissertation
8-2024
Document Type
Doctoral Dissertation
Degree Name
Ph. D.
Department
Physiology and Biophysics
Degree Program
Physiology and Biophysics, PhD
Committee Chair
Hellmann, Jason
Committee Co-Chair (if applicable)
Hill, Bradford G.
Committee Member
LeBlanc, Amanda
Committee Member
Schuschke, Dale
Committee Member
Maldonado, Claudio
Author's Keywords
Inflammation resolution; specialized proresolving lipid mediators; high fat diet; obesity; exercise; macrophage metabolism
Abstract
Diet-induced obesity and adipose tissue (AT) inflammation that ensues sets the stage for systemic metabolic inflammation, disrupted insulin signaling, and eventual type 2 diabetes (T2D) development. At the center of this pathology lies a disruption in endogenous inflammation resolution pathways characterized by an imbalance in lipid mediator production (greater abundance of pro-inflammatory to pro-resolving lipids). Additionally, obese states are characterized by adrenergic deficiency, especially in response to physical activity. Inflammatory processes have been experimentally mitigated by either the pharmacological inhibition of pro-inflammatory signals (i.e., Leukotriene B4 (LTB4) and its receptor BLT1, which establishes a potent chemotactic stimulus for infiltrating neutrophils) or by the exogenous restoration of pro-resolving lipid mediators. Systemically and within the AT, physical activity elicits potent anti-inflammatory and immunomodulatory effects that protect against obesity-induced metabolic inflammation and cardiovascular disease (CVD), in part via adrenergic-dependent signaling on key innate immune cells such as monocyte-macrophages. However, if and how physical activity promotes resolution of inflammation and endogenous pro-resolving pathways in macrophages remains largely unexplored. Moreover, if and how dietary habits modify this immune-modulating effect of exercise also remains largely unexplored. Therefore, in this thesis work, we tested the general hypothesis that exercise-induced adrenergic stimulation enhances the production of specialized proresolving lipid mediators (SPM) – molecular agonists of inflammation resolution – and macrophage phagocytosis to promote the resolution of inflammation. Additionally, we challenge the current dogma that exercise is anti-inflammatory and provide evidence to support that it can additionally promote the active resolution of inflammation. First, in Chapter II we examined the contribution of proresolving lipid mediators in exercise-induced inflammation resolution and found that exercise promotes catecholamine secretion and SPM biosynthesis and enhances macrophage phagocytosis (and thus resolution kinetics) in an α1-adrenergic receptor (α1-AR) dependent manner during acute inflammatory challenges. Secondly, in Chapter III, we explored potential mechanisms by which exercise-stimulated SPM biosynthesis enhances macrophage pro-resolving phenotypes. To this end, we found that various SPMs, each acting on separate cognate cell surface receptors in multiple human and mouse macrophage subtypes, elicited an AMP-activated protein kinase (AMPK)-dependent increase in mitochondrial respiration, consistent with an M2 pro-resolving macrophage phenotype. Interestingly, we also report that the expression of the M2 macrophage marker CD301 is directly coupled with fatty acid β oxidation, which is stimulated by 12/15‑lipoxygenase (12/15-LO)-derived SPMs. Lastly, in Chapter IV, focusing on the early stages of high fat diet induced AT alterations, we explored the dietary dependence of exercise-stimulated adrenergic signaling in inflammation resolution programs without overt diet-induced AT inflammation. In this study we found that exercise-induced epinephrine release and adipose tissue SPM biosynthesis increases M2 adipose tissue macrophage abundance, an effect abrogated by high fat diet feeding. Collectively, these findings provide novel mechanistic insights regarding the role that diet and exercise play in modifying the endogenous elicitation of inflammation resolution programs, both in the healthy state as well as during acute inflammatory challenges.
Recommended Citation
Pena Calderin, Ernesto H., "Molecular mechanisms of exercise-stimulated resolution of inflammation and its dietary dependence." (2024). Electronic Theses and Dissertations. Paper 4440.
Retrieved from https://ir.library.louisville.edu/etd/4440
Included in
Endocrinology Commons, Exercise Physiology Commons, Immunopathology Commons, Lipids Commons, Molecular, Genetic, and Biochemical Nutrition Commons, Systems and Integrative Physiology Commons
