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AMPK stimulation increases LCFA but not glucose clearance in cardiac muscle in vivo

Departments of ¹Molecular Physiology and Biophysics, ²Cardiology, ³Diabetes Research and Training Center, and ⁴Environmental and Civil Engineering, Vanderbilt University, Nashville, Tennessee 37232-0615

Submitted 15 March 2004 ; accepted in final form 2 July 2004

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--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 6.5 mM in all groups, and an intravenous bolus of 2-deoxy-[³H]glucose and [¹²⁵I]-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 (Ser²²¹) and AMPK phosphorylation (Thr¹⁷²), 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.

substrate; lipid; carbohydrate; heart; interaction; AMP-activated protein kinase; long-chain fatty acid

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