Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

PNAS 104 (42): 16480-16485

Copyright © 2007 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / BIOCHEMISTRY

Continuous fat oxidation in acetyl–CoA carboxylase 2 knockout mice increases total energy expenditure, reduces fat mass, and improves insulin sensitivity

Cheol Soo Choi*, David B. Savage*, Lutfi Abu-Elheiga{dagger}, Zhen-Xiang Liu*, Sheene Kim*, Ameya Kulkarni*, Alberto Distefano*, Yu-Jin Hwang*, Richard M. Reznick*, Roberto Codella*, Dongyan Zhang*, Gary W. Cline*, Salih J. Wakil{dagger},{ddagger}, and Gerald I. Shulman*,§,||

Departments of *Internal Medicine and §Cellular and Molecular Physiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510; and {dagger}Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030

Contributed by Salih J. Wakil, July 30, 2007 (sent for review June 1, 2007)

Received for publication June 1, 2007.

Abstract: Acetyl–CoA carboxylase 2 (ACC)2 is a key regulator of mitochondrial fat oxidation. To examine the impact of ACC2 deletion on whole-body energy metabolism, we measured changes in substrate oxidation and total energy expenditure in Acc2–/– and WT control mice fed either regular or high-fat diets. To determine insulin action in vivo, we also measured whole-body insulin-stimulated liver and muscle glucose metabolism during a hyperinsulinemic–euglycemic clamp in Acc2–/– and WT control mice fed a high-fat diet. Contrary to previous studies that have suggested that increased fat oxidation might result in lower glucose oxidation, both fat and carbohydrate oxidation were simultaneously increased in Acc2–/– mice. This increase in both fat and carbohydrate oxidation resulted in an increase in total energy expenditure, reductions in fat and lean body mass and prevention from diet-induced obesity. Furthermore, Acc2–/– mice were protected from fat-induced peripheral and hepatic insulin resistance. These improvements in insulin-stimulated glucose metabolism were associated with reduced diacylglycerol content in muscle and liver, decreased PKC{theta} activity in muscle and PKC{varepsilon} activity in liver, and increased insulin-stimulated Akt2 activity in these tissues. Taken together with previous work demonstrating that Acc2–/– mice have a normal lifespan, these data suggest that Acc2 inhibition is a viable therapeutic option for the treatment of obesity and type 2 diabetes.

Key Words: diet-induced obesity prevention • intracellular diacylglycerol • increased fat oxidation • insulin resistance prevention


Author contributions: C.S.C. and D.B.S. contributed equally to this work; C.S.C., D.B.S., L.A.-E., S.J.W., and G.I.S. designed research; C.S.C., Z.-X.L., S.K., A.K., A.D., Y.-J.H., R.M.R., and D.Z. performed research; C.S.C., D.B.S., L.A.-E., Z.-X.L., S.K., A.K., A.D., Y.-J.H., R.M.R., R.C., D.Z., G.W.C., S.J.W., and G.I.S. analyzed data; and C.S.C., D.B.S., L.A.-E., Z.-X.L., S.K., A.K., A.D., Y.-J.H., R.M.R., R.C., D.Z., G.W.C., S.J.W., and G.I.S. wrote the paper.

The authors declare no conflict of interest.

{ddagger}To whom correspondence may be addressed. E-mail: swakil{at}bcm.tmc.edu

||To whom correspondence may be addressed at: Yale University School of Medicine, TAC S269, P.O. Box 9812, New Haven, CT 06536-8012. E-mail: gerald.shulman{at}yale.edu

© 2007 by The National Academy of Sciences of the USA


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Structure-guided Development of Specific Pyruvate Dehydrogenase Kinase Inhibitors Targeting the ATP-binding Pocket.
S.-C. Tso, X. Qi, W.-J. Gui, C.-Y. Wu, J. L. Chuang, I. Wernstedt-Asterholm, L. K. Morlock, K. R. Owens, P. E. Scherer, N. S. Williams, et al. (2014)
J. Biol. Chem. 289, 4432-4443
   Abstract »    Full Text »    PDF »
Fatty acid metabolism, energy expenditure and insulin resistance in muscle.
N. Turner, G. J. Cooney, E. W. Kraegen, and C. R. Bruce (2014)
J. Endocrinol. 220, T61-T79
   Abstract »    Full Text »    PDF »
Skeletal muscle carnitine loading increases energy expenditure, modulates fuel metabolism gene networks and prevents body fat accumulation in humans.
F. B. Stephens, B. T. Wall, K. Marimuthu, C. E. Shannon, D. Constantin-Teodosiu, I. A. Macdonald, and P. L. Greenhaff (2013)
J. Physiol. 591, 4655-4666
   Abstract »    Full Text »    PDF »
Increased expression of STK25 leads to impaired glucose utilization and insulin sensitivity in mice challenged with a high-fat diet.
E. Cansby, M. Amrutkar, L. Manneras Holm, A. Nerstedt, A. Reyahi, E. Stenfeldt, J. Boren, P. Carlsson, U. Smith, J. R. Zierath, et al. (2013)
FASEB J 27, 3660-3671
   Abstract »    Full Text »    PDF »
Redox regulation of insulin sensitivity due to enhanced fatty acid utilization in the mitochondria.
P. M. Rindler, C. L. Crewe, J. Fernandes, M. Kinter, and L. I. Szweda (2013)
Am J Physiol Heart Circ Physiol 305, H634-H643
   Abstract »    Full Text »    PDF »
Early Postnatal Nutrition Determines Adult Physical Activity and Energy Expenditure in Female Mice.
G. Li, J. J. Kohorst, W. Zhang, E. Laritsky, G. Kunde-Ramamoorthy, M. S. Baker, M. L. Fiorotto, and R. A. Waterland (2013)
Diabetes 62, 2773-2783
   Abstract »    Full Text »    PDF »
Enhanced Fasting Glucose Turnover in Mice with Disrupted Action of TUG Protein in Skeletal Muscle.
M. G. Loffler, A. L. Birkenfeld, K. M. Philbrick, J. P. Belman, E. N. Habtemichael, C. J. Booth, C. M. Castorena, C. S. Choi, F. R. Jornayvaz, B. M. Gassaway, et al. (2013)
J. Biol. Chem. 288, 20135-20150
   Abstract »    Full Text »    PDF »
MYC inhibition induces metabolic changes leading to accumulation of lipid droplets in tumor cells.
H. Zirath, A. Frenzel, G. Oliynyk, L. Segerstrom, U. K. Westermark, K. Larsson, M. Munksgaard Persson, K. Hultenby, J. Lehtio, C. Einvik, et al. (2013)
PNAS 110, 10258-10263
   Abstract »    Full Text »    PDF »
Retinoic Acid Receptor {beta} Stimulates Hepatic Induction of Fibroblast Growth Factor 21 to Promote Fatty Acid Oxidation and Control Whole-body Energy Homeostasis in Mice.
Y. Li, K. Wong, K. Walsh, B. Gao, and M. Zang (2013)
J. Biol. Chem. 288, 10490-10504
   Abstract »    Full Text »    PDF »
Naringenin prevents cholesterol-induced systemic inflammation, metabolic dysregulation, and atherosclerosis in Ldlr-/- mice.
J. M. Assini, E. E. Mulvihill, B. G. Sutherland, D. E. Telford, C. G. Sawyez, S. L. Felder, S. Chhoker, J. Y. Edwards, R. Gros, and M. W. Huff (2013)
J. Lipid Res. 54, 711-724
   Abstract »    Full Text »    PDF »
AMP-activated protein kinase: an emerging drug target to regulate imbalances in lipid and carbohydrate metabolism to treat cardio-metabolic diseases: Thematic Review Series: New Lipid and Lipoprotein Targets for the Treatment of Cardiometabolic Diseases.
R. A. K. Srivastava, S. L. Pinkosky, S. Filippov, J. C. Hanselman, C. T. Cramer, and R. S. Newton (2012)
J. Lipid Res. 53, 2490-2514
   Abstract »    Full Text »    PDF »
Germline ablation of VGF increases lipolysis in white adipose tissue.
S. Fargali, T. Scherer, A. C. Shin, M. Sadahiro, C. Buettner, and S. R. Salton (2012)
J. Endocrinol. 215, 313-322
   Abstract »    Full Text »    PDF »
miR-107: a Toll-like receptor-regulated miRNA dysregulated in obesity and type II diabetes.
N. H. Foley and L. A. O'Neill (2012)
J. Leukoc. Biol. 92, 521-527
   Abstract »    Full Text »    PDF »
Cardiac-Specific Deletion of Acetyl CoA Carboxylase 2 Prevents Metabolic Remodeling During Pressure-Overload Hypertrophy.
S. C. Kolwicz Jr, D. P. Olson, L. C. Marney, L. Garcia-Menendez, R. E. Synovec, and R. Tian (2012)
Circ. Res. 111, 728-738
   Abstract »    Full Text »    PDF »
BNip3 Regulates Mitochondrial Function and Lipid Metabolism in the Liver.
D. Glick, W. Zhang, M. Beaton, G. Marsboom, M. Gruber, M. C. Simon, J. Hart, G. W. Dorn II, M. J. Brady, and K. F. Macleod (2012)
Mol. Cell. Biol. 32, 2570-2584
   Abstract »    Full Text »    PDF »
Ventricular Assist Device Implantation Corrects Myocardial Lipotoxicity, Reverses Insulin Resistance, and Normalizes Cardiac Metabolism in Patients With Advanced Heart Failure.
A. Chokshi, K. Drosatos, F. H. Cheema, R. Ji, T. Khawaja, S. Yu, T. Kato, R. Khan, H. Takayama, R. Knoll, et al. (2012)
Circulation 125, 2844-2853
   Abstract »    Full Text »    PDF »
Lipid metabolism in skeletal muscle: generation of adaptive and maladaptive intracellular signals for cellular function.
M. J. Watt and A. J. Hoy (2012)
Am J Physiol Endocrinol Metab 302, E1315-E1328
   Abstract »    Full Text »    PDF »
Phenotypic Discrepancies in Acetyl-CoA Carboxylase 2-deficient Mice.
K. L. Hoehn, N. Turner, G. J. Cooney, and D. E. James (2012)
J. Biol. Chem. 287, 15801
   Full Text »    PDF »
Reply to Hoehn et al.: Phenotypic Discrepancies in Acetyl-CoA Carboxylase 2-deficient Mice.
L. Abu-Elheiga, H. Wu, Z. Gu, and S. J. Wakil (2012)
J. Biol. Chem. 287, 15802
   Full Text »    PDF »
Acetyl-CoA Carboxylase 2-/- Mutant Mice are Protected against Fatty Liver under High-fat, High-carbohydrate Dietary and de Novo Lipogenic Conditions.
L. Abu-Elheiga, H. Wu, Z. Gu, R. Bressler, and S. J. Wakil (2012)
J. Biol. Chem. 287, 12578-12588
   Abstract »    Full Text »    PDF »
Regulation and limitations to fatty acid oxidation during exercise.
J. Jeppesen and B. Kiens (2012)
J. Physiol. 590, 1059-1068
   Abstract »    Full Text »    PDF »
Sustained activation of PPAR{alpha} by endogenous ligands increases hepatic fatty acid oxidation and prevents obesity in ob/ob mice.
J. Huang, Y. Jia, T. Fu, N. Viswakarma, L. Bai, M. S. Rao, Y. Zhu, J. Borensztajn, and J. K. Reddy (2012)
FASEB J 26, 628-638
   Abstract »    Full Text »    PDF »
Dissociation of Inositol-requiring Enzyme (IRE1{alpha})-mediated c-Jun N-terminal Kinase Activation from Hepatic Insulin Resistance in Conditional X-box-binding Protein-1 (XBP1) Knock-out Mice.
M. J. Jurczak, A.-H. Lee, F. R. Jornayvaz, H.-Y. Lee, A. L. Birkenfeld, B. A. Guigni, M. Kahn, V. T. Samuel, L. H. Glimcher, and G. I. Shulman (2012)
J. Biol. Chem. 287, 2558-2567
   Abstract »    Full Text »    PDF »
Liver-specific Inducible Nitric-oxide Synthase Expression Is Sufficient to Cause Hepatic Insulin Resistance and Mild Hyperglycemia in Mice.
S. Shinozaki, C. S. Choi, N. Shimizu, M. Yamada, M. Kim, T. Zhang, H. H. Dong, Y.-B. Kim, and M. Kaneki (2011)
J. Biol. Chem. 286, 34959-34975
   Abstract »    Full Text »    PDF »
Hepatitis B Virus X Protein Regulates Hepatic Glucose Homeostasis via Activation of Inducible Nitric Oxide Synthase.
H.-J. Shin, Y.-H. Park, S.-U. Kim, H.-B. Moon, D. S. Park, Y.-H. Han, C.-H. Lee, D.-S. Lee, I.-S. Song, D. H. Lee, et al. (2011)
J. Biol. Chem. 286, 29872-29881
   Abstract »    Full Text »    PDF »
CrbpI Modulates Glucose Homeostasis and Pancreas 9-cis-Retinoic Acid Concentrations.
M. A. Kane, A. E. Folias, A. Pingitore, M. Perri, C. R. Krois, J. Y. Ryu, E. Cione, and J. L. Napoli (2011)
Mol. Cell. Biol. 31, 3277-3285
   Abstract »    Full Text »    PDF »
Pigment Epithelium-Derived Factor Regulates Lipid Metabolism via Adipose Triglyceride Lipase.
M. L. Borg, Z. B. Andrews, E. J. Duh, R. Zechner, P. J. Meikle, and M. J. Watt (2011)
Diabetes 60, 1458-1466
   Abstract »    Full Text »    PDF »
SGLT2 Deletion Improves Glucose Homeostasis and Preserves Pancreatic {beta}-Cell Function.
M. J. Jurczak, H.-Y. Lee, A. L. Birkenfeld, F. R. Jornayvaz, D. W. Frederick, R. L. Pongratz, X. Zhao, G. W. Moeckel, V. T. Samuel, J. M. Whaley, et al. (2011)
Diabetes 60, 890-898
   Abstract »    Full Text »    PDF »
Coffee polyphenols suppress diet-induced body fat accumulation by downregulating SREBP-1c and related molecules in C57BL/6J mice.
T. Murase, K. Misawa, Y. Minegishi, M. Aoki, H. Ominami, Y. Suzuki, Y. Shibuya, and T. Hase (2011)
Am J Physiol Endocrinol Metab 300, E122-E133
   Abstract »    Full Text »    PDF »
Inhibition of De Novo Ceramide Synthesis Reverses Diet-Induced Insulin Resistance and Enhances Whole-Body Oxygen Consumption.
J. R. Ussher, T. R. Koves, V. J. J. Cadete, L. Zhang, J. S. Jaswal, S. J. Swyrd, D. G. Lopaschuk, S. D. Proctor, W. Keung, D. M. Muoio, et al. (2010)
Diabetes 59, 2453-2464
   Abstract »    Full Text »    PDF »
Oxidation of intramyocellular lipids is dependent on mitochondrial function and the availability of extracellular fatty acids.
E. Corpeleijn, N. P. Hessvik, S. S. Bakke, K. Levin, E. E. Blaak, G. H. Thoresen, M. Gaster, and A. C. Rustan (2010)
Am J Physiol Endocrinol Metab 299, E14-E22
   Abstract »    Full Text »    PDF »
Progressive adaptation of hepatic ketogenesis in mice fed a high-fat diet.
N. E. Sunny, S. Satapati, X. Fu, T. He, R. Mehdibeigi, C. Spring-Robinson, J. Duarte, M. J. Potthoff, J. D. Browning, and S. C. Burgess (2010)
Am J Physiol Endocrinol Metab 298, E1226-E1235
   Abstract »    Full Text »    PDF »
Recombinant yeast screen for new inhibitors of human acetyl-CoA carboxylase 2 identifies potential drugs to treat obesity.
J. Marjanovic, D. Chalupska, C. Patenode, A. Coster, E. Arnold, A. Ye, G. Anesi, Y. Lu, I. Okun, S. Tkachenko, et al. (2010)
PNAS 107, 9093-9098
   Abstract »    Full Text »    PDF »
Gene knockout of Acc2 has little effect on body weight, fat mass, or food intake.
D. P. Olson, T. Pulinilkunnil, G. W. Cline, G. I. Shulman, and B. B. Lowell (2010)
PNAS 107, 7598-7603
   Abstract »    Full Text »    PDF »
Myocardial Fatty Acid Metabolism in Health and Disease.
G. D. Lopaschuk, J. R. Ussher, C. D. L. Folmes, J. S. Jaswal, and W. C. Stanley (2010)
Physiol Rev 90, 207-258
   Abstract »    Full Text »    PDF »
PGC-1{alpha} negatively regulates hepatic FGF21 expression by modulating the heme/Rev-Erb{alpha} axis.
J. L. Estall, J. L. Ruas, C. S. Choi, D. Laznik, M. Badman, E. Maratos-Flier, G. I. Shulman, and B. M. Spiegelman (2009)
PNAS 106, 22510-22515
   Abstract »    Full Text »    PDF »
Ubiquitin C-terminal hydrolase-L3-knockout mice are resistant to diet-induced obesity and show increased activation of AMP-activated protein kinase in skeletal muscle.
R. Setsuie, M. Suzuki, T. Kabuta, H. Fujita, S. Miura, N. Ichihara, D. Yamada, Y.-L. Wang, O. Ezaki, Y. Suzuki, et al. (2009)
FASEB J 23, 4148-4157
   Abstract »    Full Text »    PDF »
Insulin Resistance and Altered Systemic Glucose Metabolism in Mice Lacking Nur77.
L. C. Chao, K. Wroblewski, Z. Zhang, L. Pei, L. Vergnes, O. R. Ilkayeva, S. Y. Ding, K. Reue, M. J. Watt, C. B. Newgard, et al. (2009)
Diabetes 58, 2788-2796
   Abstract »    Full Text »    PDF »
The Randle cycle revisited: a new head for an old hat.
L. Hue and H. Taegtmeyer (2009)
Am J Physiol Endocrinol Metab 297, E578-E591
   Abstract »    Full Text »    PDF »
Insulin-Stimulated Cardiac Glucose Oxidation Is Increased in High-Fat Diet-Induced Obese Mice Lacking Malonyl CoA Decarboxylase.
J. R. Ussher, T. R. Koves, J. S. Jaswal, L. Zhang, O. Ilkayeva, J. R.B. Dyck, D. M. Muoio, and G. D. Lopaschuk (2009)
Diabetes 58, 1766-1775
   Abstract »    Full Text »    PDF »
Fibroblast Growth Factor-19, a Novel Factor That Inhibits Hepatic Fatty Acid Synthesis.
S. Bhatnagar, H. A. Damron, and F. B. Hillgartner (2009)
J. Biol. Chem. 284, 10023-10033
   Abstract »    Full Text »    PDF »
Fatty acid metabolism: target for metabolic syndrome.
S. J. Wakil and L. A. Abu-Elheiga (2009)
J. Lipid Res. 50, S138-S143
   Abstract »    Full Text »    PDF »
Overexpression of Carnitine Palmitoyltransferase-1 in Skeletal Muscle Is Sufficient to Enhance Fatty Acid Oxidation and Improve High-Fat Diet-Induced Insulin Resistance.
C. R. Bruce, A. J. Hoy, N. Turner, M. J. Watt, T. L. Allen, K. Carpenter, G. J. Cooney, M. A. Febbraio, and E. W. Kraegen (2009)
Diabetes 58, 550-558
   Abstract »    Full Text »    PDF »
Skeletal Muscle-Specific Deletion of Lipoprotein Lipase Enhances Insulin Signaling in Skeletal Muscle but Causes Insulin Resistance in Liver and Other Tissues.
H. Wang, L. A. Knaub, D. R. Jensen, D. Young Jung, E.-G. Hong, H.-J. Ko, A. M. Coates, I. J. Goldberg, B. A. de la Houssaye, R. C. Janssen, et al. (2009)
Diabetes 58, 116-124
   Abstract »    Full Text »    PDF »
Paradoxical effects of increased expression of PGC-1{alpha} on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism.
C. S. Choi, D. E. Befroy, R. Codella, S. Kim, R. M. Reznick, Y.-J. Hwang, Z.-X. Liu, H.-Y. Lee, A. Distefano, V. T. Samuel, et al. (2008)
PNAS 105, 19926-19931
   Abstract »    Full Text »    PDF »
AMP Activated Protein Kinase-{alpha}2 Deficiency Exacerbates Pressure-Overload-Induced Left Ventricular Hypertrophy and Dysfunction in Mice.
P. Zhang, X. Hu, X. Xu, J. Fassett, G. Zhu, B. Viollet, W. Xu, B. Wiczer, D. A. Bernlohr, R. J. Bache, et al. (2008)
Hypertension 52, 918-924
   Abstract »    Full Text »    PDF »
The malonyl CoA axis as a potential target for treating ischaemic heart disease.
J. R. Ussher and G. D. Lopaschuk (2008)
Cardiovasc Res 79, 259-268
   Abstract »    Full Text »    PDF »
Reduced heart size and increased myocardial fuel substrate oxidation in ACC2 mutant mice.
M. F. Essop, H. S. Camp, C. S. Choi, S. Sharma, R. M. Fryer, G. A. Reinhart, P. H. Guthrie, A. Bentebibel, Z. Gu, G. I. Shulman, et al. (2008)
Am J Physiol Heart Circ Physiol 295, H256-H265
   Abstract »    Full Text »    PDF »
Setting the stage: possible mechanisms by which acute contraction restores insulin sensitivity in muscle.
J. P. Thyfault (2008)
Am J Physiol Regulatory Integrative Comp Physiol 294, R1103-R1110
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882