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Cited by 437Cardiovascular Function and Risk FactorsDiabetes, Cardiovascular Risks, and LipoproteinsCardiac Ischemia and Reperfusion

Impaired Cardiac Efficiency and Increased Fatty Acid Oxidation in Insulin-Resistant ob/ob Mouse Hearts

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Mazumder, Pradip K., O’Neill, Brian T., Roberts, Matthew W., Buchanan, Jonathan, Yun, Ui Jeong, Cooksey, Robert C., Boudina, Sihem, Abel, E. Dale·2004·Diabetes
DOI 10.2337/diabetes.53.9.2366
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Abstract

Diabetes alters cardiac substrate metabolism. The cardiac phenotype in insulin-resistant states has not been comprehensively characterized. The goal of these studies was to determine whether the hearts of leptin-deficient 8-week-old ob/ob mice were able to modulate cardiac substrate utilization in response to insulin or to changes in fatty acid delivery. Ob/ob mice were insulin resistant and glucose intolerant. Insulin signal transduction and insulin-stimulated glucose uptake were markedly impaired in ob/ob cardiomyocytes. Insulin-stimulated rates of glycolysis and glucose oxidation were 1.5- and 1.8-fold higher in wild-type hearts, respectively, versus ob/ob, and glucose metabolism in ob/ob hearts was unresponsive to insulin. Increasing concentrations of palmitate from 0.4 mmol/l (low) to 1.2 mmol/l (high) led to a decline in glucose oxidation in wild-type hearts, whereas glucose oxidation remained depressed and did not change in ob/ob mouse hearts. In contrast, fatty acid utilization in ob/ob hearts was 1.5- to 2-fold greater in the absence or presence of 1 nmol/l insulin and rose with increasing palmitate concentrations. Moreover, the ability of insulin to reduce palmitate oxidation rates was blunted in the hearts of ob/ob mice. Under low-palmitate and insulin-free conditions, cardiac performance was significantly greater in wild-type hearts. However, in the presence of high palmitate and 1 nmol/l insulin, cardiac performance in ob/ob mouse hearts was relatively preserved, whereas function in wild-type mouse hearts declined substantially. Under all perfusion conditions, myocardial oxygen consumption was higher in ob/ob hearts, ranging from 30% higher in low-palmitate conditions to greater than twofold higher under high-palmitate conditions. These data indicate that although the hearts of glucose-intolerant ob/ob mice are capable of maintaining their function under conditions of increased fatty acid supply and hyperinsulinemia, they are insulin-resistant, metabolically inefficient, and unable to modulate substrate utilization in response to changes in insulin and fatty acid supply.

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  • Ob/ob mice on the C57BL6/J background develop obesity, hyperinsulinemia, and impaired glucose tolerance shortly after weaning and develop overt diabetes between 10 and 15 wk of age.

    “Ob/ob mice on the C57BL6/J background develop obesity, hyperinsulinemia, and impaired glucose tolerance shortly after weaning and develop overt diabetes between 10 and 15 wk of age (227).”

    From Cardiac remodeling in obesity (2008) · cites this paper as [227]

  • Some groups have reported cardiac hypertrophy in hearts of young ob/ob mice, while others have only observed this phenotype in older animals.

    “For example, while some groups have reported cardiac hypertrophy in hearts of young ob/ob mice (30, 34, 227), others have only observed this phenotype in older animals (23, 24).”

    From Cardiac remodeling in obesity (2008) · cites this paper as [227]

  • When perfused with 5 mM glucose and 0.4 or 1.0 mM palmitate, significant reductions in cardiac performance were observed in ob/ob mouse hearts.

    “Similarly, when perfused with 5 mM glucose and 0.4 or 1.0 mM palmitate, significant reductions in cardiac performance were also observed in ob/ob mouse hearts (227).”

    From Cardiac remodeling in obesity (2008) · cites this paper as [227]

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Authors
Mazumder, P. K., O’Neill, B. T., Roberts, M. W., Buchanan, J., Yun, U. J., Cooksey, R. C., Boudina, S., & Abel, E. D.
Affiliations
  • University of Utah (US)
  • From the Program in Human Molecular Biology and Genetics, Division of Endocrinology, Metabolism and Diabetes, The University of Utah School of Medicine, Salt Lake City, Utah
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2004-09-01
Volume
53
Issue
9
Pages
2366-2374
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/diabetes.53.9.2366
OpenAlex
W2144766505
Cited by
437
References
26
Citations by year
2026: 7 · 2025: 10 · 2024: 13 · 2023: 14 · 2022: 17 · 2021: 19 · 2020: 18 · 2019: 19 · 2018: 27 · 2017: 28 · 2016: 34 · 2015: 26 · 2014: 27 · 2013: 26 · 2012: 20
FWCI
12.31
Type
journal article
Language
en
Open access
Locations
  • Diabetes (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • American Diabetes Association
  • American Heart Association
  • National Institutes of Health
  • U.S. Public Health Service (U01-70525)
  • National Heart, Lung, and Blood Institute (HL 73167, R01HL073167)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
Keywords
insulin resistance, ob/ob mice, leptin deficiency, cardiac substrate metabolism, fatty acid oxidation, glucose oxidation, insulin signaling, palmitate, myocardial oxygen consumption, cardiac efficiency, impaired glucose tolerance, hyperinsulinemia
MeSH terms
Animals, Glucose, Insulin, Insulin Resistance, Male, Mice, Inbred C57BL, Mice, Obese, Myocardial Contraction, Myocardium, Oxidation-Reduction, Oxygen Consumption, Palmitates, Signal Transduction, Myocytes, Cardiac, Mice

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