This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Buchanan, J. Articles by Abel, E. D. Search for Related Content PubMed PubMed Citation Articles by Buchanan, J. Articles by Abel, E. D.

Reduced Cardiac Efficiency and Altered Substrate Metabolism Precedes the Onset of Hyperglycemia and Contractile Dysfunction in Two Mouse Models of Insulin Resistance and Obesity

Program in Human Molecular Biology and Genetics (J.B., P.K.M., G.C., M.W.R., U.J.Y., E.D.A.) and Division of Endocrinology, Metabolism, and Diabetes (R.C.C., E.D.A.), The University of Utah School of Medicine, Salt Lake City, Utah 84112; and Division of Cardiology (P.H., S.E.L.), University of Utah School of Medicine, Salt Lake City, Utah 84132

Address all correspondence and requests for reprints to: E. Dale Abel, M.D., Ph.D., Program in Human Molecular Biology and Genetics, Division of Endocrinology, Metabolism, and Diabetes, University of Utah, 15 North 2030 East, Building 533, Room 3410B, Salt Lake City, Utah 84112. E-mail: dale.abel{at}hmbg.utah.edu.

Hyperglycemia is associated with altered myocardial substrate use, a condition that has been hypothesized to contribute to impaired cardiac performance. The goals of this study were to determine whether changes in cardiac metabolism, gene expression, and function precede or follow the onset of hyperglycemia in two mouse models of obesity, insulin resistance, and diabetes (ob/ob and db/db mice). Ob/ob and db/db mice were studied at 4, 8, and 15 wk of age. Four-week-old mice of both strains were normoglycemic but hyperinsulinemic. Hyperglycemia develops in db/db mice between 4 and 8 wk of age and in ob/ob mice between 8 and 15 wk. In isolated working hearts, rates of glucose oxidation were reduced by 28–37% at 4 wk and declined no further at 15 wk in both strains. Fatty acid oxidation rates and myocardial oxygen consumption were increased in 4-wk-old mice of both strains. Fatty acid oxidation rates progressively increased in db/db mice in parallel with the earlier onset and greater duration of hyperglycemia. In vivo, cardiac catheterization revealed significantly increased left ventricular contractility and relaxation (positive and negative dP/dt) in both strains at 4 wk of age. dP/dt declined over time in db/db mice but remained elevated in ob/ob mice at 15 wk of age. Increased ß-myosin heavy chain isoform expression was present in 4-wk-old mice and persisted in 15-wk-old mice. Increased expression of peroxisomal proliferator-activated receptor- regulated genes was observed only at 15 wk in both strains. These data indicate that altered myocardial substrate use and reduced myocardial efficiency are early abnormalities in the hearts of obese mice and precede the onset of hyperglycemia. Obesity per se does not cause contractile dysfunction in vivo, but loss of the hypercontractile phenotype of obesity and up-regulation of peroxisomal proliferator-activated receptor- regulated genes occur later and are most pronounced in the presence of longstanding hyperglycemia.

This article has been cited by other articles:

				I. Tabbi-Anneni, J. Buchanan, R. C. Cooksey, and E. D. Abel Captopril Normalizes Insulin Signaling and Insulin-Regulated Substrate Metabolism in Obese (ob/ob) Mouse Hearts Endocrinology, August 1, 2008; 149(8): 4043 - 4050. [Abstract] [Full Text] [PDF]

				E. D. Abel, S. E. Litwin, and G. Sweeney Cardiac Remodeling in Obesity Physiol Rev, April 1, 2008; 88(2): 389 - 419. [Abstract] [Full Text] [PDF]

				R. M. Witteles and M. B. Fowler Insulin-Resistant Cardiomyopathy: Clinical Evidence, Mechanisms, and Treatment Options J. Am. Coll. Cardiol., January 15, 2008; 51(2): 93 - 102. [Abstract] [Full Text] [PDF]

				K. R. McGaffin, C.-K. Sun, J. J. Rager, L. C. Romano, B. Zou, M. A. Mathier, R. M. O'Doherty, C. F. McTiernan, and C. P. O'Donnell Leptin signalling reduces the severity of cardiac dysfunction and remodelling after chronic ischaemic injury Cardiovasc Res, January 1, 2008; 77(1): 54 - 63. [Abstract] [Full Text] [PDF]

				S. Sena, I. R. Rasmussen, A. R. Wende, A. P. McQueen, H. A. Theobald, N. Wilde, R. O. Pereira, S. E. Litwin, J. P. Berger, and E. D. Abel Cardiac Hypertrophy Caused by Peroxisome Proliferator- Activated Receptor-{gamma} Agonist Treatment Occurs Independently of Changes in Myocardial Insulin Signaling Endocrinology, December 1, 2007; 148(12): 6047 - 6053. [Abstract] [Full Text] [PDF]

				L. S. Szczepaniak, R. G. Victor, L. Orci, and R. H. Unger Forgotten but Not Gone: The Rediscovery of Fatty Heart, the Most Common Unrecognized Disease in America Circ. Res., October 12, 2007; 101(8): 759 - 767. [Abstract] [Full Text] [PDF]

				M. Sebastiani, C. Giordano, C. Nediani, C. Travaglini, E. Borchi, M. Zani, M. Feccia, M. Mancini, V. Petrozza, A. Cossarizza, et al. Induction of Mitochondrial Biogenesis Is a Maladaptive Mechanism in Mitochondrial Cardiomyopathies J. Am. Coll. Cardiol., October 2, 2007; 50(14): 1362 - 1369. [Abstract] [Full Text] [PDF]

				S. Boudina, S. Sena, H. Theobald, X. Sheng, J. J. Wright, X. X. Hu, S. Aziz, J. I. Johnson, H. Bugger, V. G. Zaha, et al. Mitochondrial Energetics in the Heart in Obesity-Related Diabetes: Direct Evidence for Increased Uncoupled Respiration and Activation of Uncoupling Proteins Diabetes, October 1, 2007; 56(10): 2457 - 2466. [Abstract] [Full Text] [PDF]

				G. D. Lopaschuk, C. D.L. Folmes, and W. C. Stanley Cardiac Energy Metabolism in Obesity Circ. Res., August 17, 2007; 101(4): 335 - 347. [Abstract] [Full Text] [PDF]

				S. Boudina and E. D. Abel Diabetic Cardiomyopathy Revisited Circulation, June 26, 2007; 115(25): 3213 - 3223. [Abstract] [Full Text] [PDF]

				J. Giger, A. X. Qin, P. W. Bodell, K. M. Baldwin, and F. Haddad Activity of the beta-myosin heavy chain antisense promoter responds to diabetes and hypothyroidism Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H3065 - H3071. [Abstract] [Full Text] [PDF]

				W. Hsueh, E. D. Abel, J. L. Breslow, N. Maeda, R. C. Davis, E. A. Fisher, H. Dansky, D. A. McClain, R. McIndoe, M. K. Wassef, et al. Recipes for Creating Animal Models of Diabetic Cardiovascular Disease Circ. Res., May 25, 2007; 100(10): 1415 - 1427. [Abstract] [Full Text] [PDF]

				E. Arikawa, R. C.W. Ma, K. Isshiki, I. Luptak, Z. He, Y. Yasuda, Y. Maeno, M. E. Patti, G. C. Weir, R. A. Harris, et al. Effects of Insulin Replacements, Inhibitors of Angiotensin, and PKC{beta}'s Actions to Normalize Cardiac Gene Expression and Fuel Metabolism in Diabetic Rats Diabetes, May 1, 2007; 56(5): 1410 - 1420. [Abstract] [Full Text] [PDF]

				P. Yue, T. Arai, M. Terashima, A. Y. Sheikh, F. Cao, D. Charo, G. Hoyt, R. C. Robbins, E. A. Ashley, J. Wu, et al. Magnetic resonance imaging of progressive cardiomyopathic changes in the db/db mouse Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2106 - H2118. [Abstract] [Full Text] [PDF]

				J. Fauconnier, D. C. Andersson, S.-J. Zhang, J. T. Lanner, R. Wibom, A. Katz, J. D. Bruton, and H. Westerblad Effects of Palmitate on Ca2+ Handling in Adult Control and ob/ob Cardiomyocytes: Impact of Mitochondrial Reactive Oxygen Species Diabetes, April 1, 2007; 56(4): 1136 - 1142. [Abstract] [Full Text] [PDF]

				D. Qi and B. Rodrigues Glucocorticoids produce whole body insulin resistance with changes in cardiac metabolism Am J Physiol Endocrinol Metab, March 1, 2007; 292(3): E654 - E667. [Abstract] [Full Text] [PDF]

				J. G. Duncan, J. L. Fong, D. M. Medeiros, B. N. Finck, and D. P. Kelly Insulin-Resistant Heart Exhibits a Mitochondrial Biogenic Response Driven by the Peroxisome Proliferator-Activated Receptor-{alpha}/PGC-1{alpha} Gene Regulatory Pathway Circulation, February 20, 2007; 115(7): 909 - 917. [Abstract] [Full Text] [PDF]

				D. An and B. Rodrigues Role of changes in cardiac metabolism in development of diabetic cardiomyopathy Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H1489 - H1506. [Abstract] [Full Text] [PDF]

				S. Boudina and E. D. Abel Mitochondrial uncoupling: a key contributor to reduced cardiac efficiency in diabetes. Physiology, August 1, 2006; 21: 250 - 258. [Abstract] [Full Text] [PDF]

				N. D. Oakes, P. Thalen, E. Aasum, A. Edgley, T. Larsen, S. M. Furler, B. Ljung, and D. Severson Cardiac metabolism in mice: tracer method developments and in vivo application revealing profound metabolic inflexibility in diabetes Am J Physiol Endocrinol Metab, May 1, 2006; 290(5): E870 - E881. [Abstract] [Full Text] [PDF]