Publication: Pharmacological Blockade of Cannabinoid CB1 Receptors in Diet-Induced Obesity Regulates Mitochondrial Dihydrolipoamide Dehydrogenase in Muscle.
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Date
2015-12-15
Authors
Arrabal, Sergio
Lucena, Miguel Angel
Canduela, Miren Josune
Ramos-Uriarte, Almudena
Rivera, Patricia
Serrano, Antonia
Pavón, Francisco Javier
Decara, Juan
Vargas, Antonio
Baixeras, Elena
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Publisher
Public Library of Science
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Abstract
Cannabinoid CB1 receptors peripherally modulate energy metabolism. Here, we investigated the role of CB1 receptors in the expression of glucose/pyruvate/tricarboxylic acid (TCA) metabolism in rat abdominal muscle. Dihydrolipoamide dehydrogenase (DLD), a flavoprotein component (E3) of α-ketoacid dehydrogenase complexes with diaphorase activity in mitochondria, was specifically analyzed. After assessing the effectiveness of the CB1 receptor antagonist AM251 (3 mg kg(-1), 14 days) on food intake and body weight, we could identified seven key enzymes from either glycolytic pathway or TCA cycle--regulated by both diet and CB1 receptor activity--through comprehensive proteomic approaches involving two-dimensional electrophoresis and MALDI-TOF/LC-ESI trap mass spectrometry. These enzymes were glucose 6-phosphate isomerase (GPI), triosephosphate isomerase (TPI), enolase (Eno3), lactate dehydrogenase (LDHa), glyoxalase-1 (Glo1) and the mitochondrial DLD, whose expressions were modified by AM251 in hypercaloric diet-induced obesity. Specifically, AM251 blocked high-carbohydrate diet (HCD)-induced expression of GPI, TPI, Eno3 and LDHa, suggesting a down-regulation of glucose/pyruvate/lactate pathways under glucose availability. AM251 reversed the HCD-inhibited expression of Glo1 and DLD in the muscle, and the DLD and CB1 receptor expression in the mitochondrial fraction. Interestingly, we identified the presence of CB1 receptors at the membrane of striate muscle mitochondria. DLD over-expression was confirmed in muscle of CB1-/- mice. AM251 increased the pyruvate dehydrogenase and glutathione reductase activity in C2C12 myotubes, and the diaphorase/oxidative activity in the mitochondria fraction. These results indicated an up-regulation of methylglyoxal and TCA cycle activity. Findings suggest that CB1 receptors in muscle modulate glucose/pyruvate/lactate pathways and mitochondrial oxidative activity by targeting DLD.
Description
Journal Article; Research Support, Non-U.S. Gov't;
MeSH Terms
Medical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Oxidoreductases::Oxidoreductases Acting on Aldehyde or Oxo Group Donors::Ketone Oxidoreductases::3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)
Medical Subject Headings::Anatomy::Musculoskeletal System::Muscles::Muscle, Skeletal::Abdominal Muscles
Medical Subject Headings::Organisms::Eukaryota::Animals
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Anthropometry::Body Weights and Measures::Body Size::Body Weight
Medical Subject Headings::Chemicals and Drugs::Organic Chemicals::Hydrocarbons::Terpenes::Cannabinoids
Medical Subject Headings::Phenomena and Processes::Physiological Phenomena::Nutritional Physiological Phenomena::Diet
Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Flavoproteins::Dihydrolipoamide Dehydrogenase
Medical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Down-Regulation
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Electrochemical Techniques::Electrophoresis
Medical Subject Headings::Phenomena and Processes::Metabolic Phenomena::Metabolism::Energy Metabolism
Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Flavoproteins
Medical Subject Headings::Chemicals and Drugs::Carbohydrates::Monosaccharides::Hexoses::Glucose
Medical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Oxidoreductases::Oxidoreductases Acting on Sulfur Group Donors::Glutathione Reductase
Medical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Oxidoreductases::Alcohol Oxidoreductases::Lactate Dehydrogenases::L-Lactate Dehydrogenase
Medical Subject Headings::Chemicals and Drugs::Organic Chemicals::Carboxylic Acids::Hydroxy Acids::Lactates
Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice
Medical Subject Headings::Anatomy::Cells::Cellular Structures::Intracellular Space::Cytoplasm::Cytoplasmic Structures::Organelles::Mitochondria
Medical Subject Headings::Anatomy::Cells::Cellular Structures::Intracellular Space::Cytoplasm::Cytoplasmic Structures::Organelles::Mitochondria::Mitochondria, Muscle
Medical Subject Headings::Anatomy::Tissues::Muscles::Muscle, Striated::Muscle, Skeletal::Muscle Fibers, Skeletal
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Physical Examination::Body Constitution::Body Weights and Measures::Body Size::Body Weight::Overweight::Obesity
Medical Subject Headings::Chemicals and Drugs::Inorganic Chemicals::Phosphorus Compounds::Phosphorus Acids::Phosphoric Acids::Phosphates
Medical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Lyases::Carbon-Oxygen Lyases::Hydro-Lyases::Phosphopyruvate Hydratase
Medical Subject Headings::Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 1-Ring::Piperidines
Medical Subject Headings::Disciplines and Occupations::Natural Science Disciplines::Chemistry::Biochemistry::Proteomics
Medical Subject Headings::Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 1-Ring::Azoles::Pyrazoles
Medical Subject Headings::Chemicals and Drugs::Organic Chemicals::Aldehydes::Glyoxal::Pyruvaldehyde
Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, G-Protein-Coupled::Receptors, Cannabinoid::Receptor, Cannabinoid, CB1
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Chemistry Techniques, Analytical::Mass Spectrometry::Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Medical Subject Headings::Chemicals and Drugs::Organic Chemicals::Carboxylic Acids::Acids, Acyclic::Tricarboxylic Acids
Medical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Isomerases::Intramolecular Oxidoreductases::Aldose-Ketose Isomerases::Triose-Phosphate Isomerase
Medical Subject Headings::Phenomena and Processes::Chemical Phenomena::Chemical Processes::Biochemical Processes::Up-Regulation
Medical Subject Headings::Anatomy::Musculoskeletal System::Muscles::Muscle, Skeletal::Abdominal Muscles
Medical Subject Headings::Organisms::Eukaryota::Animals
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Anthropometry::Body Weights and Measures::Body Size::Body Weight
Medical Subject Headings::Chemicals and Drugs::Organic Chemicals::Hydrocarbons::Terpenes::Cannabinoids
Medical Subject Headings::Phenomena and Processes::Physiological Phenomena::Nutritional Physiological Phenomena::Diet
Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Flavoproteins::Dihydrolipoamide Dehydrogenase
Medical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Down-Regulation
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Electrochemical Techniques::Electrophoresis
Medical Subject Headings::Phenomena and Processes::Metabolic Phenomena::Metabolism::Energy Metabolism
Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Flavoproteins
Medical Subject Headings::Chemicals and Drugs::Carbohydrates::Monosaccharides::Hexoses::Glucose
Medical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Oxidoreductases::Oxidoreductases Acting on Sulfur Group Donors::Glutathione Reductase
Medical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Oxidoreductases::Alcohol Oxidoreductases::Lactate Dehydrogenases::L-Lactate Dehydrogenase
Medical Subject Headings::Chemicals and Drugs::Organic Chemicals::Carboxylic Acids::Hydroxy Acids::Lactates
Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice
Medical Subject Headings::Anatomy::Cells::Cellular Structures::Intracellular Space::Cytoplasm::Cytoplasmic Structures::Organelles::Mitochondria
Medical Subject Headings::Anatomy::Cells::Cellular Structures::Intracellular Space::Cytoplasm::Cytoplasmic Structures::Organelles::Mitochondria::Mitochondria, Muscle
Medical Subject Headings::Anatomy::Tissues::Muscles::Muscle, Striated::Muscle, Skeletal::Muscle Fibers, Skeletal
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Physical Examination::Body Constitution::Body Weights and Measures::Body Size::Body Weight::Overweight::Obesity
Medical Subject Headings::Chemicals and Drugs::Inorganic Chemicals::Phosphorus Compounds::Phosphorus Acids::Phosphoric Acids::Phosphates
Medical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Lyases::Carbon-Oxygen Lyases::Hydro-Lyases::Phosphopyruvate Hydratase
Medical Subject Headings::Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 1-Ring::Piperidines
Medical Subject Headings::Disciplines and Occupations::Natural Science Disciplines::Chemistry::Biochemistry::Proteomics
Medical Subject Headings::Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 1-Ring::Azoles::Pyrazoles
Medical Subject Headings::Chemicals and Drugs::Organic Chemicals::Aldehydes::Glyoxal::Pyruvaldehyde
Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, G-Protein-Coupled::Receptors, Cannabinoid::Receptor, Cannabinoid, CB1
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Chemistry Techniques, Analytical::Mass Spectrometry::Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Medical Subject Headings::Chemicals and Drugs::Organic Chemicals::Carboxylic Acids::Acids, Acyclic::Tricarboxylic Acids
Medical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Isomerases::Intramolecular Oxidoreductases::Aldose-Ketose Isomerases::Triose-Phosphate Isomerase
Medical Subject Headings::Phenomena and Processes::Chemical Phenomena::Chemical Processes::Biochemical Processes::Up-Regulation
DeCS Terms
CIE Terms
Keywords
Músculos abdominales, Peso corporal, Cannabinoides, Metabolismo energético, Glucosa, Ratas, Obesidad
Citation
Arrabal S, Lucena MA, Canduela MJ, Ramos-Uriarte A, Rivera P, Serrano A, et al. Pharmacological Blockade of Cannabinoid CB1 Receptors in Diet-Induced Obesity Regulates Mitochondrial Dihydrolipoamide Dehydrogenase in Muscle. PLoS ONE. 2015; 10(12):e0145244