AMP-activated protein kinase is not down-regulated in human skeletal muscle of obese females.
Obesity in humans is associated with lipid accumulation in skeletal muscle, insulin and leptin resistance, and type 2 diabetes. AMP-activated protein kinase (AMPK) is an important regulator of fatty acid (FA) metabolism in skeletal muscle. To address the hypothesis that lipid accumulation in skeletal muscle of obese subjects may be due to down-regulation of AMPK, we measured mRNA and protein levels of AMPK isoforms, AMPKalpha1 and -alpha2 activity, AMPK kinase activity, acetyl-coenzyme A carboxylase (ACCbeta) expression and phosphorylation, and FA metabolism in biopsies of rectus abdominus muscle from lean and obese women. We also examined the effect of 5-aminoimidazole-4-carboxamide riboside (AICAR) on AMPK activity and the effects of AICAR and leptin on FA metabolism. Skeletal muscle of obese subjects had increased total FA uptake and triglyceride esterification, and leptin failed to stimulate FA oxidation. However, AMPK mRNA and protein expression, AMPKalpha1 and -alpha2 activities, AMPK kinase activity, ACCbeta phosphorylation, and FA oxidation were similar in lean and obese subjects. Moreover, AICAR increased AMPKalpha2 activity, ACCbeta phosphorylation, and palmitate oxidation to a similar degree in muscle from lean and obese subjects. We conclude that the abnormal lipid metabolism and leptin resistance of skeletal muscle of obese subjects is not due to down-regulation of AMPK. In addition, the similar stimulation by AICAR of AMPK in skeletal muscle of lean and obese subjects suggests that direct pharmacological activation of AMPK may be a therapeutic approach for stimulating FA oxidation in the treatment of human obesity.
Steinberg
Gregory R
GR
St. Vincent's Institute, 9 Princes Street, Fitzroy, Victoria, Australia 3065. gsteinberg@svi.edu.au
Smith
Angela C
AC
Van Denderen
Bryce J W
BJ
Chen
Zhiping
Z
Murthy
Sid
S
Campbell
Duncan J
DJ
Heigenhauser
G J F
GJ
Dyck
David J
DJ
Kemp
Bruce E
BE
D000091162:AMP-Activated Protein Kinase Kinases; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000263:Adenylate Kinase / Q000378:metabolism*; D000328:Adult; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D015536:Down-Regulation; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D006801:Humans; D020738:Leptin / Q000494:pharmacology; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000201:enzymology*; D009765:Obesity / Q000201:enzymology*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D021122:Protein Subunits; D012333:RNA, Messenger / Q000032:analysis; D012265:Ribonucleotides / Q000494:pharmacology
D005227:Fatty Acids; D020738:Leptin; D021122:Protein Subunits; D012333:RNA, Messenger; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D000263:Adenylate Kinase; D000103:Acetyl-CoA Carboxylase; C031143:AICA ribonucleotide