Diabetes, Vol 49, Issue 5 775-781, Copyright © 2000 by American Diabetes Association

ARTICLES

Targeted upregulation of pyruvate dehydrogenase kinase (PDK)-4 in slow-twitch skeletal muscle underlies the stable modification of the regulatory characteristics of PDK induced by high-fat feeding

MJ Holness, A Kraus, RA Harris and MC Sugden
Department of Diabetes and Metabolic Medicine, St. Bartholomew's and the Royal London School of Medicine and Dentistry, Queen Mary and Westfield College, University of London, UK.

In using Western blot analysis with antibodies raised against recombinant pyruvate dehydrogenase kinase (PDK) isoforms PDK2 and PDK4, this study demonstrates selective PDK isoform switching in specific skeletal muscle types in response to high-fat feeding that is associated with altered regulation of PDK activity by pyruvate. The administration of a diet high in saturated fats led to stable (approximately 2-fold) increases in PDK activities in both a typical slow-twitch (soleus [SOL]) muscle and a typical fast-twitch (anterior tibialis [AT]) muscle. Western blot analysis revealed that high-fat feeding significantly increased (approximately 2-fold; P < 0.001) PDK4 protein expression in SOL, with a modest (1.3-fold) increase in PDK2 protein expression. The relative increase in PDK4 protein expression in SOL was associated with a 7.6-fold increase in the pyruvate concentration that was required to elicit a 50% active pyruvate dehydrogenase complex, which indicates a marked decrease in the sensitivity of PDK to inhibition by pyruvate. In AT muscle, high-fat feeding elicited comparable (1.5- to 1.7-fold) increases (P < 0.05) in PDK4 and PDK2 protein expression. Loss of sensitivity of PDK to inhibition by pyruvate was less marked. The data suggest that a positive correlation exists between increases in PDK4 expression and the propensity with which muscles use lipid-derived fuels as respiratory substrates rather than with the degree of insulin resistance induced in skeletal muscles by high-fat feeding. In conclusion, high-fat feeding leads to selective upregulation of PDK4 expression in slow-twitch muscle in response to high-fat feeding in vivo, which is associated with a pronounced loss of sensitivity of PDK activity to acute inhibition by pyruvate. Thus, increased PDK4 expression may underlie the stable modification of the regulatory characteristics of PDK observed in slow-twitch muscle in response to high-fat feeding.
CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				D. Constantin, D. Constantin-Teodosiu, R. Layfield, K. Tsintzas, A. J. Bennett, and P. L. Greenhaff PPAR{delta} agonism induces a change in fuel metabolism and activation of an atrophy programme, but does not impair mitochondrial function in rat skeletal muscle J. Physiol., August 15, 2007; 583(1): 381 - 390. [Abstract] [Full Text] [PDF]

				U. A. White, A. A. Coulter, T. K. Miles, and J. M. Stephens The STAT5A-Mediated Induction of Pyruvate Dehydrogenase Kinase 4 Expression by Prolactin or Growth Hormone in Adipocytes Diabetes, June 1, 2007; 56(6): 1623 - 1629. [Abstract] [Full Text] [PDF]

				M. J. Holness, N. D. Smith, G. K. Greenwood, and M. C. Sugden PPAR{alpha} activation reverses adverse effects induced by high-saturated-fat feeding on pancreatic beta-cell function in late pregnancy Am J Physiol Endocrinol Metab, April 1, 2007; 292(4): E1087 - E1094. [Abstract] [Full Text] [PDF]

				Y. I. Kim, F. N. Lee, W. S. Choi, S. Lee, and J. H. Youn Insulin Regulation of Skeletal Muscle PDK4 mRNA Expression Is Impaired in Acute Insulin-Resistant States. Diabetes, August 1, 2006; 55(8): 2311 - 2317. [Abstract] [Full Text] [PDF]

				M. Mourtzakis, B. Saltin, T. Graham, and H. Pilegaard Carbohydrate metabolism during prolonged exercise and recovery: interactions between pyruvate dehydrogenase, fatty acids, and amino acids J Appl Physiol, June 1, 2006; 100(6): 1822 - 1830. [Abstract] [Full Text] [PDF]

				V. Aas, M. H. Rokling-Andersen, E. T. Kase, G. H. Thoresen, and A. C. Rustan Eicosapentaenoic acid (20:5 n-3) increases fatty acid and glucose uptake in cultured human skeletal muscle cells J. Lipid Res., February 1, 2006; 47(2): 366 - 374. [Abstract] [Full Text] [PDF]

				T. Stellingwerff, L. L. Spriet, M. J. Watt, N. E. Kimber, M. Hargreaves, J. A. Hawley, and L. M. Burke Decreased PDH activation and glycogenolysis during exercise following fat adaptation with carbohydrate restoration Am J Physiol Endocrinol Metab, February 1, 2006; 290(2): E380 - E388. [Abstract] [Full Text] [PDF]

				O. Hansson, M. Donsmark, C. Ling, P. Nevsten, M. Danfelter, J. L. Andersen, H. Galbo, and C. Holm Transcriptome and proteome analysis of soleus muscle of hormone-sensitive lipase-null mice J. Lipid Res., December 1, 2005; 46(12): 2614 - 2623. [Abstract] [Full Text] [PDF]

				K. Ma, Y. Zhang, M. B. Elam, G. A. Cook, and E. A. Park Cloning of the Rat Pyruvate Dehydrogenase Kinase 4 Gene Promoter: ACTIVATION OF PYRUVATE DEHYDROGENASE KINASE 4 BY THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR {gamma} COACTIVATOR J. Biol. Chem., August 19, 2005; 280(33): 29525 - 29532. [Abstract] [Full Text] [PDF]

				T. L. Pehleman, S. J. Peters, G. J. F. Heigenhauser, and L. L. Spriet Enzymatic regulation of glucose disposal in human skeletal muscle after a high-fat, low-carbohydrate diet J Appl Physiol, January 1, 2005; 98(1): 100 - 107. [Abstract] [Full Text] [PDF]

				E. A. Turvey, G. J. F. Heigenhauser, M. Parolin, and S. J. Peters Elevated n-3 fatty acids in a high-fat diet attenuate the increase in PDH kinase activity but not PDH activity in human skeletal muscle J Appl Physiol, January 1, 2005; 98(1): 350 - 355. [Abstract] [Full Text] [PDF]

				M. J. Watt, G. J. F. Heigenhauser, P. J. LeBlanc, J. G. Inglis, L. L. Spriet, and S. J. Peters Rapid upregulation of pyruvate dehydrogenase kinase activity in human skeletal muscle during prolonged exercise J Appl Physiol, October 1, 2004; 97(4): 1261 - 1267. [Abstract] [Full Text] [PDF]

				F. N. Lee, L. Zhang, D. Zheng, W. S. Choi, and J. H. Youn Insulin suppresses PDK-4 expression in skeletal muscle independently of plasma FFA Am J Physiol Endocrinol Metab, July 1, 2004; 287(1): E69 - E74. [Abstract] [Full Text] [PDF]

				J. Tonelli, W. Li, P. Kishore, U. B. Pajvani, E. Kwon, C. Weaver, P. E. Scherer, and M. Hawkins Mechanisms of Early Insulin-Sensitizing Effects of Thiazolidinediones in Type 2 Diabetes Diabetes, June 1, 2004; 53(6): 1621 - 1629. [Abstract] [Full Text] [PDF]

				P. J. LeBlanc, S. J. Peters, R. J. Tunstall, D. Cameron-Smith, and G. J. F. Heigenhauser Effects of aerobic training on pyruvate dehydrogenase and pyruvate dehydrogenase kinase in human skeletal muscle J. Physiol., June 1, 2004; 557(2): 559 - 570. [Abstract] [Full Text] [PDF]

				H.-S. Kwon, B. Huang, T. G. Unterman, and R. A. Harris Protein Kinase B-{alpha} Inhibits Human Pyruvate Dehydrogenase Kinase-4 Gene Induction by Dexamethasone Through Inactivation of FOXO Transcription Factors Diabetes, April 1, 2004; 53(4): 899 - 910. [Abstract] [Full Text] [PDF]

				M. J. Holness, N. D. Smith, G. K. Greenwood, and M. C. Sugden Acute {omega}-3 Fatty Acid Enrichment Selectively Reverses High-Saturated Fat Feeding-Induced Insulin Hypersecretion But Does Not Improve Peripheral Insulin Resistance Diabetes, February 1, 2004; 53(90001): S166 - 171. [Abstract] [Full Text]

				A. L. Hildebrandt, H. Pilegaard, and P. D. Neufer Differential transcriptional activation of select metabolic genes in response to variations in exercise intensity and duration Am J Physiol Endocrinol Metab, November 1, 2003; 285(5): E1021 - E1027. [Abstract] [Full Text] [PDF]

				M. J. Holness, G. K. Greenwood, N. D. Smith, and M. C. Sugden Diabetogenic Impact of Long-Chain {omega}-3 Fatty Acids on Pancreatic {beta}-Cell Function and the Regulation of Endogenous Glucose Production Endocrinology, September 1, 2003; 144(9): 3958 - 3968. [Abstract] [Full Text] [PDF]

				M. C. Sugden and M. J. Holness Recent advances in mechanisms regulating glucose oxidation at the level of the pyruvate dehydrogenase complex by PDKs Am J Physiol Endocrinol Metab, May 1, 2003; 284(5): E855 - E862. [Abstract] [Full Text] [PDF]

				H. Pilegaard, B. Saltin, and P. D. Neufer Effect of Short-Term Fasting and Refeeding on Transcriptional Regulation of Metabolic Genes in Human Skeletal Muscle Diabetes, March 1, 2003; 52(3): 657 - 662. [Abstract] [Full Text] [PDF]

				B. Huang, P. Wu, M. M. Bowker-Kinley, and R. A. Harris Regulation of Pyruvate Dehydrogenase Kinase Expression by Peroxisome Proliferator-Activated Receptor-{alpha} Ligands, Glucocorticoids, and Insulin Diabetes, February 1, 2002; 51(2): 276 - 283. [Abstract] [Full Text] [PDF]

				S. J. Peters, R. A. Harris, P. Wu, T. L. Pehleman, G. J. F. Heigenhauser, and L. L. Spriet Human skeletal muscle PDH kinase activity and isoform expression during a 3-day high-fat/low-carbohydrate diet Am J Physiol Endocrinol Metab, December 1, 2001; 281(6): E1151 - E1158. [Abstract] [Full Text] [PDF]

				M. J. Holness and M. C. Sugden Dexamethasone during Late Gestation Exacerbates Peripheral Insulin Resistance and Selectively Targets Glucose-Sensitive Functions in {beta} Cell and Liver Endocrinology, September 1, 2001; 142(9): 3742 - 3748. [Abstract] [Full Text] [PDF]

				E. A. Turvey, G. J. F. Heigenhauser, M. Parolin, and S. J. Peters Elevated n-3 fatty acids in a high-fat diet attenuate the increase in PDH kinase activity but not PDH activity in human skeletal muscle J Appl Physiol, January 1, 2005; 98(1): 350 - 355. [Abstract] [Full Text] [PDF]