ABSTRACT
Dyslipidemia-induced atherosclerosis, which has a risk of high morbidity and mortality, can be alleviated by metabolic activation associated with mitochondrial function. The effect of dichloroacetate (DCA), a general pyruvate dehydrogenase kinase (PDK) inhibitor, on in vivo energy expenditure in ApoE-/- mice fed a western diet (WD) has not yet been investigated. WD-fed ApoE-/- mice developed atherosclerotic plaques and hyperlipidemia along with obesity, which were significantly ameliorated by DCA administration. Increased oxygen consumption was associated with heat production in the DCA-treated group, with no change in food intake or physical activity compared with those of the control. These processes were correlated with the increased gene expression of Dio2 and Ucp-1, which represents brown adipose tissue (BAT) activation, in both WD-induced atherosclerosis and high-fat-induced obesity models. In addition, we found that DCA stimulated hepatic fibroblast growth factor 21 (Fgf21) mRNA expression, which might be important for lowering lipid levels and insulin sensitization via BAT activation, in a dose- and time-dependent manner associated with serum FGF21 levels. Interestingly, Fgf21 mRNA expression was mediated in an AMP-activated protein kinase (AMPK)-dependent manner within several minutes after DCA treatment independent of peroxisome proliferator-activated receptor alpha (PPARα). Taken together, the results suggest that enhanced glucose oxidation by DCA protects against atherosclerosis by inducing hepatic FGF21 expression and BAT activation, resulting in augmented energy expenditure for heat generation.
Subject(s)
AMP-Activated Protein Kinases/genetics , Atherosclerosis/drug therapy , Cardiovascular Agents/pharmacology , Dichloroacetic Acid/pharmacology , Enzyme Inhibitors/pharmacology , Fibroblast Growth Factors/genetics , Plaque, Atherosclerotic/drug therapy , AMP-Activated Protein Kinases/metabolism , Adipose Tissue, Brown/drug effects , Adipose Tissue, Brown/metabolism , Adipose Tissue, Brown/pathology , Animals , Apolipoproteins E/deficiency , Apolipoproteins E/genetics , Atherosclerosis/etiology , Atherosclerosis/genetics , Atherosclerosis/pathology , Diet, Western/adverse effects , Dyslipidemias/drug therapy , Dyslipidemias/etiology , Dyslipidemias/genetics , Dyslipidemias/pathology , Energy Metabolism/drug effects , Fibroblast Growth Factors/agonists , Fibroblast Growth Factors/metabolism , Gene Expression Regulation , Iodide Peroxidase/genetics , Iodide Peroxidase/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout, ApoE , Mitochondria/drug effects , Mitochondria/metabolism , Obesity/drug therapy , Obesity/etiology , Obesity/genetics , Obesity/pathology , Oxygen Consumption/drug effects , PPAR alpha/genetics , PPAR alpha/metabolism , Plaque, Atherosclerotic/etiology , Plaque, Atherosclerotic/genetics , Plaque, Atherosclerotic/pathology , Pyruvate Dehydrogenase Acetyl-Transferring Kinase/antagonists & inhibitors , Pyruvate Dehydrogenase Acetyl-Transferring Kinase/genetics , Pyruvate Dehydrogenase Acetyl-Transferring Kinase/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Signal Transduction , Uncoupling Protein 1/genetics , Uncoupling Protein 1/metabolism , Iodothyronine Deiodinase Type IIABSTRACT
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.
