Malonyl coenzyme A and the regulation of functional carnitine palmitoyltransferase-1 activity and fat oxidation in human skeletal muscle

Blake Rasmussen, Ulf C. Holmbäck, Elena Volpi, Beatrice Morio-Liondore, Douglas Paddon-Jones, Robert R. Wolfe

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Abstract

Physiological hyperglycemia with hyperinsulinemia reduces fat oxidation in skeletal muscle. The mechanism responsible for this decrease in fat oxidation in human muscle is not known and may contribute to the development of insulin resistance. We hypothesized that the transfer of long-chain fatty acids (LCFAs) into the mitochondria via carnitine palmitoyltransferase-1 (CPT-1) is inhibited by increased malonyl coenzyme A (malonyl-CoA) (a known potent inhibitor of CPT-1) in human muscle during hyperglycemia with hyperinsulinemia. We studied six healthy subjects after an overnight fast and during an induced 5-hour period of hyperglycemia with hyperinsulinemia. Muscle fatty acid oxidation was calculated using stable isotope methodology combined with blood sampling from the femoral artery and vein of one leg. Muscle functional CPT-1 activity was assessed by concurrently infusing an LCFA tracer and a CPT-independent medium-chain fatty acid tracer. Muscle biopsies were obtained from the vastus lateralis after the periods of fasting and hyperglycemia with hyperinsulinemia. Hyperglycemia with hyperinsulinemia decreased LCFA oxidation, but had no effect on LCFA uptake or medium-chain fatty acid oxidation across the leg. Malonyl-CoA concentration significantly increased from 0.13 ± 0.01 to 0.35 ± 0.07 nmol/g during hyperglycemia with hyperinsulinemia. We conclude that hyperglycemia with hyper-insulinemia increases malonyl-CoA, inhibits functional CPT-1 activity, and shunts LCFA away from oxidation and toward storage in human muscle.

Original languageEnglish (US)
Pages (from-to)1687-1693
Number of pages7
JournalJournal of Clinical Investigation
Volume110
Issue number11
DOIs
StatePublished - Dec 2002

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Malonyl Coenzyme A
Carnitine O-Palmitoyltransferase
Hyperglycemia
Hyperinsulinism
Skeletal Muscle
Fatty Acids
Fats
Muscles
Leg
Femoral Vein
Quadriceps Muscle
Femoral Artery
Isotopes
Insulin Resistance
Fasting
Healthy Volunteers
Mitochondria
Biopsy

ASJC Scopus subject areas

  • Medicine(all)

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Malonyl coenzyme A and the regulation of functional carnitine palmitoyltransferase-1 activity and fat oxidation in human skeletal muscle. / Rasmussen, Blake; Holmbäck, Ulf C.; Volpi, Elena; Morio-Liondore, Beatrice; Paddon-Jones, Douglas; Wolfe, Robert R.

In: Journal of Clinical Investigation, Vol. 110, No. 11, 12.2002, p. 1687-1693.

Research output: Contribution to journalArticle

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