Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control

Robert C. Noland, Timothy R. Koves, Sarah E. Seiler, Helen Lum, Robert M. Lust, Olga Ilkayeva, Robert D. Stevens, Fausto G. Hegardt, Deborah M. Muoio

Research output: Contribution to journalArticle

192 Citations (Scopus)

Abstract

In addition to its essential role in permitting mitochondrial import and oxidation of long chain fatty acids, carnitine also functions as an acyl group acceptor that facilitates mitochondrial export of excess carbons in the form of acylcarnitines. Recent evidence suggests carnitine requirements increase under conditions of sustained metabolic stress. Accordingly, we hypothesized that carnitine insufficiency might contribute to mitochondrial dysfunction and obesity-related impairments in glucose tolerance. Consistent with this prediction whole body carnitine dimunition was identified as a common feature of insulin-resistant states such as advanced age, genetic diabetes, and diet-induced obesity. In rodents fed a lifelong (12 month) high fat diet, compromised carnitine status corresponded with increased skeletal muscle accumulation of acylcarnitine esters and diminished hepatic expression of carnitine biosynthetic genes. Diminished carnitine reserves in muscle of obese rats was accompanied by marked perturbations in mitochondrial fuel metabolism, including low rates of complete fatty acid oxidation, elevated incomplete β-oxidation, and impaired substrate switching from fatty acid to pyruvate. These mitochondrial abnormalities were reversed by 8 weeks of oral carnitine supplementation, in concert with increased tissue efflux and urinary excretion of acetylcarnitine and improvement of whole body glucose tolerance. Acetylcarnitine is produced by the mitochondrial matrix enzyme, carnitine acetyltransferase (CrAT). A role for this enzyme in combating glucose intolerance was further supported by the finding that CrAT overexpression in primary human skeletal myocytes increased glucose uptake and attenuated lipid-induced suppression of glucose oxidation. These results implicate carnitine insufficiency and reduced CrAT activity as reversible components of the metabolic syndrome.

Original languageEnglish (US)
Pages (from-to)22840-22852
Number of pages13
JournalJournal of Biological Chemistry
Volume284
Issue number34
DOIs
StatePublished - Aug 21 2009
Externally publishedYes

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Overnutrition
Carnitine
Aging of materials
Carnitine O-Acetyltransferase
Glucose
Acetylcarnitine
Oxidation
Fatty Acids
Nutrition
Muscle
Obesity
Physiological Stress
Glucose Intolerance
Skeletal Muscle Fibers
High Fat Diet
Enzymes
Medical problems
Pyruvic Acid
Metabolism
Rats

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Noland, R. C., Koves, T. R., Seiler, S. E., Lum, H., Lust, R. M., Ilkayeva, O., ... Muoio, D. M. (2009). Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control. Journal of Biological Chemistry, 284(34), 22840-22852. https://doi.org/10.1074/jbc.M109.032888

Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control. / Noland, Robert C.; Koves, Timothy R.; Seiler, Sarah E.; Lum, Helen; Lust, Robert M.; Ilkayeva, Olga; Stevens, Robert D.; Hegardt, Fausto G.; Muoio, Deborah M.

In: Journal of Biological Chemistry, Vol. 284, No. 34, 21.08.2009, p. 22840-22852.

Research output: Contribution to journalArticle

Noland, RC, Koves, TR, Seiler, SE, Lum, H, Lust, RM, Ilkayeva, O, Stevens, RD, Hegardt, FG & Muoio, DM 2009, 'Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control', Journal of Biological Chemistry, vol. 284, no. 34, pp. 22840-22852. https://doi.org/10.1074/jbc.M109.032888
Noland, Robert C. ; Koves, Timothy R. ; Seiler, Sarah E. ; Lum, Helen ; Lust, Robert M. ; Ilkayeva, Olga ; Stevens, Robert D. ; Hegardt, Fausto G. ; Muoio, Deborah M. / Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 34. pp. 22840-22852.
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