Overexpression of carnitine palmitoyltransferase-1 in skeletal muscle is sufficient to enhance fatty acid oxidation and improve high-fat diet-induced insulin resistance

Clinton R Bruce, Andrew James Hoy, Nigel Turner, Matthew James Watt, Tamara L Allen, Kevin Carpenter, Gregory J Cooney, Mark A Febbraio, Edward W Kraegen

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216 Citations (Scopus)

Abstract

Objective: Skeletal muscle insulin resistance is associated with lipid accumulation, but whether insulin resistance is due to reduced or enhanced flux of long-chain fatty acids into the mitochondria is both controversial and unclear. We hypothesized that skeletal muscle specific overexpression of the muscle isoform of carnitine palmitoyltransferase 1 (CPT1), the enzyme that controls the entry of long-chain fatty acyl CoA into mitochondria, would enhance rates of fatty acid (FA) oxidation and improve insulin action in muscle in high fat diet insulin resistant rats. Research Design and Methods: Rats were fed a standard (Chow) or high fat diet (HFD) for 4 wk. After 3 weeks, in vivo electrotransfer was used to overexpress the muscle isoform of CPT1 in the distal hindlimb muscles [tibialis anterior (TA) and extensor digitorum longus (EDL)]. Skeletal muscle insulin action was examined in vivo during a hyperinsulinemic-euglycemic clamp. Results: In vivo electrotransfer produced a physiologically relevant increase of approximately 20 in enzyme activity and although the HFD produced insulin resistance in the sham-treated muscle, insulin action was improved in the CPT1 overexpressing muscle. This improvement was associated with a reduction in triacylglycerol content, the membrane-to-cytosolic ratio of diacylglycerol and PKC activity. Importantly, overexpression of CPT1 did not affect markers of mitochondrial capacity or function nor did it alter skeletal muscle acylcarnitine profiles irrespective of diet. Conclusions: Our data provide clear evidence that a physiologic increase in the capacity of long-chain fatty acyl CoA entry into mitochondria is sufficient to ameliorate lipid-induced insulin resistance in muscle.
Original languageEnglish
Pages (from-to)550 - 558
Number of pages9
JournalDiabetes
Volume58
Issue number3
DOIs
Publication statusPublished - 2009

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