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Título: | Increased β-Oxidation in Muscle Cells Enhances Insulin-stimulated Glucose Metabolism and Protects against Fatty Acid-induced Insulin Resistance Despite Intramyocellular Lipid Accumulation |
Autor: | Perdomo, Germán CSIC ORCID CVN; Commerford, S. Renee; Richard, Ann-Marie T.; Adams, Sean H.; Corkey, Barbara E.; O'Doherty, Robert M.; Brown, Nicholas F. | Fecha de publicación: | 25-jun-2004 | Citación: | The Journal of Biological Chemistry 279: 27177-27186 (2004) | Resumen: | 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 β-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 [14C]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 [14C]glucose incorporation into glycogen (60%), [3H]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 [14C]glucose into glycogen (60%) and [3H]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 [14C]glucose into glycogen and [3H]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 β-oxidation in muscle cells exerts an insulin-sensitizing effect independently of changes in intracellular lipid content. | Versión del editor: | http://dx.doi.org/10.1074/jbc.M403566200 | URI: | http://hdl.handle.net/10261/222491 | ISSN: | 0021-9258 | E-ISSN: | 1083-351X |
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