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This version published online on September 1, 2005
Endocrinology, doi:10.1210/en.2005-0938
A more recent version of this article appeared on December 1, 2005
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*Nutrition
*Obesity

Submitted on July 25, 2005
Accepted on August 26, 2005

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

Jonathan Buchanan, Pradip K. Mazumder, Ping Hu, Gopa Chakrabarti, Matthew W. Roberts, Ui Jeong Yun, Robert C. Cooksey, Sheldon E. Litwin, and E. Dale Abel*

Program in Human Molecular Biology and Genetics, and Division of Endocrinology, Metabolism and Diabetes, The University of Utah School of Medicine, Salt Lake City, UT 84112.; Division of Cardiology, University of Utah School of Medicine, Salt Lake City, UT 84132

* To whom correspondence should be addressed. E-mail: dale.abel{at}hmbg.utah.edu.

Hyperglycemia is associated with altered myocardial substrate utilization, a condition that has been hypothesized to contribute to impaired cardiac performance. The goals of this study were to determine if 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 weeks of age. 4-week old mice of both strains were normoglycemic, but hyperinsulinemic. Hyperglycemia develops in db/db mice between 4 and 8 weeks of age and in ob/ob mice between 8 and 15 weeks. In isolated working hearts, rates of glucose oxidation were reduced by 28-37% at 4-weeks and declined no further at 15-weeks in both strains. Fatty acid oxidation rates (FAOX) and myocardial oxygen consumption were increased in 4-week -old mice of both strains. FAOX progressively increased in db/db mice in parallel with the earlier onset and greater duration of hyperglycemia. In vivo, cardiac catheterization revealed significantly increased LV contractility and relaxation (positive and negative dP/dt) in both strains at 4-weeks of age. dP/dt declined over time in db/db mice, but remained elevated in ob/ob mice at 15-weeks of age. Increased {beta} myosin heavy chain isoform expression was present in 4-week-old mice and persisted in 15-week old mice. Increased expression of PPAR-{alpha} regulated genes was observed only at 15-weeks in both strains. These data indicate that altered myocardial substrate utilization 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 PPAR-{alpha} regulated genes occur later and are most pronounced in the presence of longstanding hyperglycemia.
Key words: Diabetes • Obesity • Metabolism • Heart • Gene Expression




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