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Science 30 March 2001:
Vol. 291. no. 5513, pp. 2613 - 2616
DOI: 10.1126/science.1056843
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Reports

Continuous Fatty Acid Oxidation and Reduced Fat Storage in Mice Lacking Acetyl-CoA Carboxylase 2 

Lutfi Abu-Elheiga,1 Martin M. Matzuk,2 Khaled A. H. Abo-Hashema,1 Salih J. Wakil1*

Malonyl-coenzyme A (malonyl-CoA), generated by acetyl-CoA carboxylases ACC1 and ACC2, is a key metabolite in the regulation of energy homeostasis. Here, we show that Acc2-/- mutant mice have a normal life span, a higher fatty acid oxidation rate, and lower amounts of fat. In comparison to the wild type, Acc2-deficient mice had 10- and 30-fold lower levels of malonyl-CoA in heart and muscle, respectively. The fatty acid oxidation rate in the soleus muscle of the Acc2-/- mice was 30% higher than that of wild-type mice and was not affected by addition of insulin; however, addition of insulin to the wild-type muscle reduced fatty acid oxidation by 45%. The mutant mice accumulated 50% less fat in their adipose tissue than did wild-type mice. These results raise the possibility that pharmacological manipulation of ACC2 may lead to loss of body fat in the context of normal caloric intake.

1 Verna and Marrs McLean Department of Biochemistry and Molecular Biology and
2 Departments of Pathology, Molecular and Cellular Biology, and Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
*   To whom correspondence should be addressed. E-mail: swakil{at}bcm.tmc.edu

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Physiological role of AMP-activated protein kinase in the heart: graded activation during exercise.
D. L. Coven, X. Hu, L. Cong, R. Bergeron, G. I. Shulman, D. G. Hardie, and L. H. Young (2003)
Am J Physiol Endocrinol Metab 285, E629-E636
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Acetyl-CoA Carboxylase {beta} Gene Is Regulated by Sterol Regulatory Element-binding Protein-1 in Liver.
S.-Y. Oh, S.-K. Park, J.-W. Kim, Y.-H. Ahn, S.-W. Park, and K.-S. Kim (2003)
J. Biol. Chem. 278, 28410-28417
   Abstract »    Full Text »    PDF »
Crystal Structure of the Carboxyltransferase Domain of Acetyl-Coenzyme A Carboxylase.
H. Zhang, Z. Yang, Y. Shen, and L. Tong (2003)
Science 299, 2064-2067
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SREBP-1 integrates the actions of thyroid hormone, insulin, cAMP, and medium-chain fatty acids on ACC{alpha} transcription in hepatocytes.
Y. Zhang, L. Yin, and F. B. Hillgartner (2003)
J. Lipid Res. 44, 356-368
   Abstract »    Full Text »    PDF »
Role for Stearoyl-CoA Desaturase-1 in Leptin-Mediated Weight Loss.
P. Cohen, M. Miyazaki, N. D. Socci, A. Hagge-Greenberg, W. Liedtke, A. A. Soukas, R. Sharma, L. C. Hudgins, J. M. Ntambi, and J. M. Friedman (2002)
Science 297, 240-243
   Abstract »    Full Text »    PDF »
Metformin Increases AMP-Activated Protein Kinase Activity in Skeletal Muscle of Subjects With Type 2 Diabetes.
N. Musi, M. F. Hirshman, J. Nygren, M. Svanfeldt, P. Bavenholm, O. Rooyackers, G. Zhou, J. M. Williamson, O. Ljunqvist, S. Efendic, et al. (2002)
Diabetes 51, 2074-2081
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The Effect of a 3-Month Low-Intensity Endurance Training Program on Fat Oxidation and Acetyl-CoA Carboxylase-2 Expression.
P. Schrauwen, D. P.C. van Aggel-Leijssen, G. Hul, A. J.M. Wagenmakers, H. Vidal, W. H.M. Saris, and M. A. van Baak (2002)
Diabetes 51, 2220-2226
   Abstract »    Full Text »    PDF »
Understanding adipose tissue development from transgenic animal models.
P. Valet, G. Tavernier, I. Castan-Laurell, J. S. Saulnier-Blache, and D. Langin (2002)
J. Lipid Res. 43, 835-860
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A Biotin Analog Inhibits Acetyl-CoA Carboxylase Activity and Adipogenesis.
K. L. Levert, G. L. Waldrop, and J. M. Stephens (2002)
J. Biol. Chem. 277, 16347-16350
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Transgenic Mice Expressing Human Fibroblast Growth Factor-19 Display Increased Metabolic Rate and Decreased Adiposity.
E. Tomlinson, L. Fu, L. John, B. Hultgren, X. Huang, M. Renz, J. P. Stephan, S. P. Tsai, L. Powell-Braxton, D. French, et al. (2002)
Endocrinology 143, 1741-1747
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Cold elicits the simultaneous induction of fatty acid synthesis and {beta}-oxidation in murine brown adipose tissue: prediction from differential gene expression and confirmation in vivo.
X. X. YU, D. A. LEWIN, W. FORREST, and S. H. ADAMS (2002)
FASEB J 16, 155-168
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Banting Lecture 2001: Dysregulation of Fatty Acid Metabolism in the Etiology of Type 2 Diabetes.
J. D. McGarry (2002)
Diabetes 51, 7-18
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Quaternary structure of human fatty acid synthase by electron cryomicroscopy.
J. Brink, S. J. Ludtke, C.-Y. Yang, Z.-W. Gu, S. J. Wakil, and W. Chiu (2001)
PNAS
   Abstract »    Full Text »    PDF »
Peripheral Signals Conveying Metabolic Information to the Brain: Short-Term and Long-Term Regulation of Food Intake and Energy Homeostasis.
P. J. Havel (2001)
Experimental Biology and Medicine 226, 963-977
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Nonalcoholic Steatosis and Steatohepatitis: III. Peroxisomal beta -oxidation, PPARalpha , and steatohepatitis.
J. K. Reddy (2001)
Am J Physiol Gastrointest Liver Physiol 281, G1333-G1339
   Abstract »    Full Text »    PDF »
Energy-sensing and signaling by AMP-activated protein kinase in skeletal muscle.
W. W. Winder (2001)
J Appl Physiol 91, 1017-1028
   Abstract »    Full Text »    PDF »
Quaternary structure of human fatty acid synthase by electron cryomicroscopy.
J. Brink, S. J. Ludtke, C.-Y. Yang, Z.-W. Gu, S. J. Wakil, and W. Chiu (2002)
PNAS 99, 138-143
   Abstract »    Full Text »    PDF »


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