Abstract
Metabolic reprogramming during macrophage polarization supports the effector functions of these cells in health and disease. Here, we demonstrate that pyruvate dehydrogenase kinase (PDK), which inhibits the pyruvate dehydrogenase-mediated conversion of cytosolic pyruvate to mitochondrial acetyl-CoA, functions as a metabolic checkpoint in M1 macrophages. Polarization was not prevented by PDK2 or PDK4 deletion but was fully prevented by the combined deletion of PDK2 and PDK4; this lack of polarization was correlated with improved mitochondrial respiration and rewiring of metabolic breaks that are characterized by increased glycolytic intermediates and reduced metabolites in the TCA cycle. Genetic deletion or pharmacological inhibition of PDK2/4 prevents polarization of macrophages to the M1 phenotype in response to inflammatory stimuli (lipopolysaccharide plus IFN-γ). Transplantation of PDK2/4-deficient bone marrow into irradiated wild-type mice to produce mice with PDK2/4-deficient myeloid cells prevented M1 polarization, reduced obesity-associated insulin resistance, and ameliorated adipose tissue inflammation. A novel, pharmacological PDK inhibitor, KPLH1130, improved high-fat diet-induced insulin resistance; this was correlated with a reduction in the levels of pro-inflammatory markers and improved mitochondrial function. These studies identify PDK2/4 as a metabolic checkpoint for M1 phenotype polarization of macrophages, which could potentially be exploited as a novel therapeutic target for obesity-associated metabolic disorders and other inflammatory conditions.
Highlights
Macrophage polarization (M1/M2) requires metabolic reprogramming that enhances glycolysis and repurposes mitochondrial function [1,2,3]
The evidence for this includes a) dramatically induced PDK4 expression by LPS + INF-γ; b) reduced HIF-1α levels and suppression of the Warburg effect in response to PDK2/4 deficiency; c) PDK2/4 deficiency-mediated check on the pool size of glycolytic intermediates that would, otherwise, feed into anabolic pathways required for proliferation of macrophages; and d) significantly reduced levels of NO and proinflammatory cytokines including TNFα, IL-6, and IL-1β in response to PDK2/4 deficiency
Markers of adipose tissue (AT) inflammation including the number of infiltrated AT macrophages in response to over-nutrition, M1 macrophage population, presence of crown-like structures, and the levels of proinflammatory markers were found to be significantly reduced in the global PDK2/4 DKO mice compared to that in WT mice
Summary
Macrophage polarization (M1/M2) requires metabolic reprogramming that enhances glycolysis and repurposes mitochondrial function [1,2,3]. The importance of these metabolic pathway differences between M1 and M2 macrophages is well-established, our knowledge of the checkpoints in affected metabolic pathways is limited primarily to HIF-1α and pyruvate kinase M2 (PKM2) [4]. Obesity-induced insulin resistance is a disease process in which M1 macrophages contribute to adipose tissue (AT) inflammation and insulin resistance. Recruitment of M1 macrophages, IFN-γ-secreting Th1 cells, CD8+ T cells, and B cells in the adipose tissue drives the inflammatory response, locally promoting systemic inflammation and impaired insulin action as a result of over-nutrition [6, 7]. The phenotypic changes in macrophages that occur in response to over consumption of energy are considered potential therapeutic targets for managing chronic metabolic diseases
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