Pyruvate Dehydrogenase Kinase Is a Metabolic Checkpoint for Polarization of Macrophages to the M1 Phenotype.

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.

Role of the Pyruvate Dehydrogenase Complex in Metabolic Remodeling: Differential Pyruvate Dehydrogenase Complex Functions in Metabolism.

Mitochondrial dysfunction is a hallmark of metabolic diseases such as obesity, type 2 diabetes mellitus, neurodegenerative diseases, and cancers. Dysfunction occurs in part because of altered regulation of the mitochondrial pyruvate dehydrogenase complex (PDC), which acts as a central metabolic node that mediates pyruvate oxidation after glycolysis and fuels the Krebs cycle to meet energy demands. Fine-tuning of PDC activity has been mainly attributed to post-translational modifications of its subunits, including the extensively studied phosphorylation and de-phosphorylation of the E1α subunit of pyruvate dehydrogenase (PDH), modulated by kinases (pyruvate dehydrogenase kinase [PDK] 1-4) and phosphatases (pyruvate dehydrogenase phosphatase [PDP] 1-2), respectively. In addition to phosphorylation, other covalent modifications, including acetylation and succinylation, and changes in metabolite levels via metabolic pathways linked to utilization of glucose, fatty acids, and amino acids, have been identified. In this review, we will summarize the roles of PDC in diverse tissues and how regulation of its activity is affected in various metabolic disorders.

Relationship between hepcidin and GDF15 in anemic patients with type 2 diabetes without overt renal impairment.

AIMS: Despite the absence of overt renal impairment and decreased erythropoietin (EPO) levels, patients are usually anemic. Hepcidin, which is induced by inflammatory stimuli, plays an important role in anemia in chronic disease. Growth differentiation factor 15 (GDF15) is a putative anti-inflammatory cytokine that is elevated in type 2 diabetes (T2DM). Hence, we investigated the relationship between hepcidin and GDF15 in anemic T2DM patients without overt renal impairment. METHODS: Among 1150 patients who visited Kyungpook National University Hospital for T2DM between June 2006 and June 2014, we selected 55 anemic patients without overt renal impairment (serum creatinine <1.5 mg/dL or estimated glomerular filtration rate >60 mL/min/1.73 m(2)) and other co-morbid diseases, including malignancy, thyroid disease, rheumatic arthritis, liver disease, iron-deficiency anemia and other endocrine disease. We measured anthropometric and metabolic parameters, as well as measured the serum iron, ferritin, interleukin-6 (IL-6), erythropoietin, hepcidin-25 and GDF15 levels. RESULTS: Anemic T2DM patients without overt renal impairment presented a greater inflammatory state, with increased serum hsCRP, ESR and IL-6 levels compared with non-anemic T2DM patients. Both hepcidin and GDF15 levels were increased and showed a positive correlation in anemic T2DM patients. CONCLUSION: In the absence of overt renal impairment, anemia in T2DM is associated with chronic inflammation, inducing elevation of hepcidin and GDF15 levels independently of the erythropoietin level.

Stimulation of CD107 affects LPS-induced cytokine secretion and cellular adhesion through the ERK signaling pathway in the human macrophage-like cell line, THP-1.

Lysosome-associated membrane proteins (LAMPs), a family of highly glycosylated transmembrane proteins, are well known lysosomal markers. Recent investigations revealed the cell surface expression of LAMPs, especially after activation in various cell types. Although their role in lysosome function is under intense investigation, little is known about the function of this cell surface form of LAMPs. To investigate the role of cell surface LAMPs in macrophage activities, the human macrophage-like cell line THP-1 was stimulated with monoclonal antibodies specific to CD107a (LAMP-1) or CD107b (LAMP-2). Stimulation of CD107 enhanced LPS-induced IL-8 secretion and induced adhesion of THP-1 cells to culture plates coated with extracellular matrix proteins such as collagen, fibronectin, and laminin. Utilization of specific inhibitors of signaling adapters and Western blot analysis revealed that extracellular signal-regulated kinase (ERK) mediates the regulatory action of CD107. These results suggest that stimulation of THP-1 cells through CD107 affects macrophage-associated functions such as cytokine secretion and cellular adhesion through activation of ERK.