title: Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control.
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 diminution 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 beta-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.
authors: Sarah W. Stedman Nutrition and Metabolism Center, Duke University, Durham, North Carolina 27710, USA.
authors: Robert C
authors: RC
authors: Noland
authors: Timothy R
authors: TR
authors: Koves
authors: Sarah E
authors: SE
authors: Seiler
authors: Helen
authors: H
authors: Lum
authors: Robert M
authors: RM
authors: Lust
authors: Olga
authors: O
authors: Ilkayeva
authors: Robert D
authors: RD
authors: Stevens
authors: Fausto G
authors: FG
authors: Hegardt
authors: Deborah M
authors: DM
authors: Muoio
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D015153:Blotting, Western; D002331:Carnitine / Q000031:analogs & derivatives / Q000172:deficiency / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D002332:Carnitine O-Acetyltransferase / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D004041:Dietary Fats / Q000009:adverse effects; D018149:Glucose Intolerance; D005951:Glucose Tolerance Test; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000235:genetics; D044343:Overnutrition / Q000503:physiopathology*; D010085:Oxidative Phosphorylation; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014803:Vitamin B Complex / Q000494:pharmacology / Q000502:physiology*; D050563:gamma-Butyrobetaine Dioxygenase
chemical_list: D004041:Dietary Fats; C116917:acylcarnitine; D014803:Vitamin B Complex; D006899:Mixed Function Oxygenases; C025931:trimethyl-lysine hydroxylase; D050563:gamma-Butyrobetaine Dioxygenase; D002332:Carnitine O-Acetyltransferase; D002331:Carnitine