title: AMPK stimulation increases LCFA but not glucose clearance in cardiac muscle in vivo.
abstract: AMP-activated protein kinase (AMPK) independently increases glucose and long-chain fatty acid (LCFA) utilization in isolated cardiac muscle preparations. Recent studies indicate this may be due to AMPK-induced phosphorylation and activation of nitric oxide synthase (NOS). Given this, the aim of the present study was to assess the effects of AMPK stimulation by 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR; 10 mg.kg(-1).min(-1)) on glucose and LCFA utilization in cardiac muscle and to determine the NOS dependence of any observed effects. Catheters were chronically implanted in a carotid artery and jugular vein of Sprague-Dawley rats. After 4 days of recovery, conscious, unrestrained rats were given either water or water containing 1 mg/ml nitro-L-arginine methyl ester (L-NAME) for 2.5 days. After an overnight fast, rats underwent one of four protocols: saline, AICAR, AICAR + L-NAME, or AICAR + Intralipid (20%, 0.02 ml.kg(-1).min(-1)). Glucose was clamped at approximately 6.5 mM in all groups, and an intravenous bolus of 2-deoxy-[(3)H]glucose and [(125)I]-15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid was administered to obtain indexes of glucose and LCFA uptake and clearance. Despite AMPK activation, as evidenced by acetyl-CoA carboxylase (Ser(221)) and AMPK phosphorylation (Thr(172)), AICAR increased cardiac LCFA but not glucose clearance. L-NAME + AICAR established that this effect was not due to NOS activation, and AICAR + Intralipid showed that increased cardiac LCFA clearance was not LCFA-concentration dependent. These results demonstrate that, in vivo, AMPK stimulation increases LCFA but not glucose clearance by a NOS-independent mechanism.
authors.affiliation: Dept. of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232-0615, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Shearer
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Fueger
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Rottman
authors.forename: Deanna P
authors.initials: DP
authors.lastname: Bracy
authors.forename: Paul H
authors.initials: PH
authors.lastname: Martin
authors.forename: David H
authors.initials: DH
authors.lastname: Wasserman
mesh_terms: D055372:AMP-Activated Protein Kinases; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005217:Fat Emulsions, Intravenous / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism* / Q000493:pharmacokinetics; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D009097:Multienzyme Complexes / Q000378:metabolism*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012265:Ribonucleotides / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D005217:Fat Emulsions, Intravenous; D005227:Fatty Acids; D007004:Hypoglycemic Agents; D009097:Multienzyme Complexes; D012265:Ribonucleotides; D009569:Nitric Oxide; D000620:Aminoimidazole Carboxamide; D019001:Nitric Oxide Synthase; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; D005947:Glucose; D019331:NG-Nitroarginine Methyl Ester