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Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility.

Publication ,  Journal Article
Muoio, DM; Noland, RC; Kovalik, J-P; Seiler, SE; Davies, MN; DeBalsi, KL; Ilkayeva, OR; Stevens, RD; Kheterpal, I; Zhang, J; Covington, JD ...
Published in: Cell Metab
May 2, 2012

The concept of "metabolic inflexibility" was first introduced to describe the failure of insulin-resistant human subjects to appropriately adjust mitochondrial fuel selection in response to nutritional cues. This phenomenon has since gained increasing recognition as a core component of the metabolic syndrome, but the underlying mechanisms have remained elusive. Here, we identify an essential role for the mitochondrial matrix enzyme, carnitine acetyltransferase (CrAT), in regulating substrate switching and glucose tolerance. By converting acetyl-CoA to its membrane permeant acetylcarnitine ester, CrAT regulates mitochondrial and intracellular carbon trafficking. Studies in muscle-specific Crat knockout mice, primary human skeletal myocytes, and human subjects undergoing L-carnitine supplementation support a model wherein CrAT combats nutrient stress, promotes metabolic flexibility, and enhances insulin action by permitting mitochondrial efflux of excess acetyl moieties that otherwise inhibit key regulatory enzymes such as pyruvate dehydrogenase. These findings offer therapeutically relevant insights into the molecular basis of metabolic inflexibility.

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Published In

Cell Metab

DOI

EISSN

1932-7420

Publication Date

May 2, 2012

Volume

15

Issue

5

Start / End Page

764 / 777

Location

United States

Related Subject Headings

  • Muscle Fibers, Skeletal
  • Mitochondria
  • Mice, Knockout
  • Mice
  • Insulin Resistance
  • Insulin
  • Humans
  • Glucose Tolerance Test
  • Glucose
  • Fatty Acids
 

Citation

APA
Chicago
ICMJE
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Muoio, D. M., Noland, R. C., Kovalik, J.-P., Seiler, S. E., Davies, M. N., DeBalsi, K. L., … Mynatt, R. L. (2012). Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility. Cell Metab, 15(5), 764–777. https://doi.org/10.1016/j.cmet.2012.04.005
Muoio, Deborah M., Robert C. Noland, Jean-Paul Kovalik, Sarah E. Seiler, Michael N. Davies, Karen L. DeBalsi, Olga R. Ilkayeva, et al. “Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility.Cell Metab 15, no. 5 (May 2, 2012): 764–77. https://doi.org/10.1016/j.cmet.2012.04.005.
Muoio DM, Noland RC, Kovalik J-P, Seiler SE, Davies MN, DeBalsi KL, et al. Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility. Cell Metab. 2012 May 2;15(5):764–77.
Muoio, Deborah M., et al. “Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility.Cell Metab, vol. 15, no. 5, May 2012, pp. 764–77. Pubmed, doi:10.1016/j.cmet.2012.04.005.
Muoio DM, Noland RC, Kovalik J-P, Seiler SE, Davies MN, DeBalsi KL, Ilkayeva OR, Stevens RD, Kheterpal I, Zhang J, Covington JD, Bajpeyi S, Ravussin E, Kraus W, Koves TR, Mynatt RL. Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility. Cell Metab. 2012 May 2;15(5):764–777.
Journal cover image

Published In

Cell Metab

DOI

EISSN

1932-7420

Publication Date

May 2, 2012

Volume

15

Issue

5

Start / End Page

764 / 777

Location

United States

Related Subject Headings

  • Muscle Fibers, Skeletal
  • Mitochondria
  • Mice, Knockout
  • Mice
  • Insulin Resistance
  • Insulin
  • Humans
  • Glucose Tolerance Test
  • Glucose
  • Fatty Acids