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Pyruvate dehydrogenase kinase is a metabolic checkpoint for polarization of macrophages to the M1 phenotype

ABSTRACT: Metabolic reprogramming during macrophage polarization supports the effector functions of these cells in health and disease. Although the importance of glycolytic and oxidative metabolism in M1 and M2 macrophages, respectively, is well established, our knowledge of metabolic checkpoints controlling these effector states is limited. Here we demonstrate that pyruvate dehydrogenase kinase (PDK), which inhibits the conversion of cytosolic pyruvate to mitochondrial acetyl-CoA by pyruvate dehydrogenase, functions as a metabolic checkpoint in M1 macrophages. 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). The therapeutic potential of attenuation of pro-inflammatory responses by PDK inhibition was tested, both genetically and pharmacologically, in obesity-induced insulin resistance, a disease process in which M1 macrophages contribute to adipose tissue inflammation and insulin resistance. Taken together, these studies identify PDK2/4 as a metabolic checkpoint for M1 phenotype polarization of macrophages.

ORGANISM(S): Mus musculus

PROVIDER: GSE112595 | GEO | 2019/05/11

REPOSITORIES: GEO

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Pyruvate dehydrogenase kinase is a metabolic checkpoint for polarization of macrophages to the M1 phenotype

Project description:Pyruvate dehydrogenase kinase is a metabolic checkpoint for polarization of macrophages to the M1 phenotype

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