Increased beta-oxidation in muscle cells enhances insulin-stimulated glucose metabolism and protects against fatty acid-induced insulin resistance despite intramyocellular lipid accumulation.
Skeletal muscle insulin resistance may be aggravated by intramyocellular accumulation of fatty acid-derived metabolites that inhibit insulin signaling. We tested the hypothesis that enhanced fatty acid oxidation in myocytes should protect against fatty acid-induced insulin resistance by limiting lipid accumulation. L6 myotubes were transduced with adenoviruses encoding carnitine palmitoyltransferase I (CPT I) isoforms or beta-galactosidase (control). Two to 3-fold overexpression of L-CPT I, the endogenous isoform in L6 cells, proportionally increased oxidation of the long-chain fatty acids palmitate and oleate and increased insulin stimulation of [(14)C]glucose incorporation into glycogen by 60% while enhancing insulin-stimulated phosphorylation of p38MAPK. Incubation of control cells with 0.2 mm palmitate for 18 h caused accumulation of triacylglycerol, diacylglycerol, and ceramide (but not long-chain acyl-CoA) and decreased insulin-stimulated [(14)C]glucose incorporation into glycogen (60%), [(3)H]deoxyglucose uptake (60%), and protein kinase B phosphorylation (20%). In the context of L-CPT I overexpression, palmitate preincubation produced a relative decrease in insulin-stimulated incorporation of [(14)C]glucose into glycogen (60%) and [(3)H]deoxyglucose uptake (40%) but did not inhibit phosphorylation of protein kinase B. Due to the enhancement of insulin-stimulated glucose metabolism induced by L-CPT I overexpression itself, net insulin-stimulated incorporation of [(14)C]glucose into glycogen and [(3)H]deoxyglucose uptake in L-CPT I-transduced, palmitate-treated cells were significantly greater than in palmitate-treated control cells (71 and 75% greater, respectively). However, L-CPT I overexpression failed to decrease intracellular triacylglycerol, diacylglycerol, ceramide, or long-chain acyl-CoA. We propose that accelerated beta-oxidation in muscle cells exerts an insulin-sensitizing effect independently of changes in intracellular lipid content.
Perdomo
German
G
Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Commerford
S Renee
SR
Richard
Ann-Marie T
AM
Adams
Sean H
SH
Corkey
Barbara E
BE
O'Doherty
Robert M
RM
Brown
Nicholas F
NF
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003847:Deoxyglucose / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology*; D007527:Isoenzymes; D050356:Lipid Metabolism; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000378:metabolism*; D010084:Oxidation-Reduction; D010168:Palmitates / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D015398:Signal Transduction; D014161:Transduction, Genetic
D005227:Fatty Acids; D007328:Insulin; D007527:Isoenzymes; D010168:Palmitates; D012333:RNA, Messenger; D006003:Glycogen; D003847:Deoxyglucose; D002334:Carnitine O-Palmitoyltransferase; D005947:Glucose