title: 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside-induced AMP-activated protein kinase phosphorylation inhibits basal and insulin-stimulated glucose uptake, lipid synthesis, and fatty acid oxidation in isolated rat adipocytes.
abstract: The objective of this study was to investigate the effects of 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR)-induced AMP-activated protein kinase (AMPK) activation on basal and insulin-stimulated glucose and fatty acid metabolism in isolated rat adipocytes. AICAR-induced AMPK activation profoundly inhibited basal and insulin-stimulated glucose uptake, lipogenesis, glucose oxidation, and lactate production in fat cells. We also describe the novel findings that AICAR-induced AMPK phosphorylation significantly reduced palmitate (32%) and oleate uptake (41%), which was followed by a 50% reduction in palmitate oxidation despite a marked increase in AMPK and acetyl-CoA carboxylase phosphorylation. Compound C, a selective inhibitor of AMPK, not only completely prevented the inhibitory effect of AICAR on palmitate oxidation but actually caused a 2.2-fold increase in this variable. Compound C also significantly increased palmitate oxidation in the presence of inhibitory concentrations of malonyl-CoA and etomoxir indicating an increase in CPT1 activity. In contrast to skeletal muscle in which AMPK stimulates fatty acid oxidation to provide ATP as a fuel, we propose that AMPK activation inhibits lipogenesis and fatty acid oxidation in adipocytes. Inhibition of lipogenesis would conserve ATP under conditions of cellular stress, although suppression of intra-adipocyte oxidation would spare fatty acids for exportation to other tissues where their utilization is crucial for energy production. Additionally, the stimulatory effect of compound C on long chain fatty acid oxidation provides a novel pharmacological approach to promote energy dissipation in adipocytes, which may be of therapeutic importance for obesity and type II diabetes.
authors.affiliation: School of Kinesiology and Health Science, York University, Toronto, Ontario M3J 1P3, Canada.
authors.forename: Mandeep Pinky
authors.initials: MP
authors.lastname: Gaidhu
authors.forename: Sergiu
authors.initials: S
authors.lastname: Fediuc
authors.forename: Rolando Bacis
authors.initials: RB
authors.lastname: Ceddia
mesh_terms: D055372:AMP-Activated Protein Kinases; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002245:Carbon Dioxide / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D004852:Epoxy Compounds / Q000378:metabolism / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism* / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D008055:Lipids / Q000096:biosynthesis*; D008297:Male; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010084:Oxidation-Reduction; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012265:Ribonucleotides / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D005227:Fatty Acids; D007004:Hypoglycemic Agents; D007328:Insulin; D008055:Lipids; D009097:Multienzyme Complexes; D021122:Protein Subunits; D012265:Ribonucleotides; D002245:Carbon Dioxide; D000620:Aminoimidazole Carboxamide; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; D005947:Glucose; C054207:etomoxir