Cardiovascular Research Advance Access [Accepted Manuscript] published online on January 15, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp017
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Mechanisms for increased myocardial fatty acid utilization following short-term high fat feeding
a Division of Endocrinology Metabolism and Diabetes and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah 84112
b Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Korea
c Department of Biochemistry, Boston University School of Medicine, Boston MA 02118
Address correspondence to: E. Dale Abel, Division of Endocrinology, Metabolism and Diabetes, Program Molecular Medicine, 15 N 2030 East, Bldg # 533 Rm. 3110B, Salt Lake City, Utah 84112, Phone: (801) 585-0727; Fax: (801) 585-0701; E-Mail: dale.abel{at}hmbg.utah.edu
Aim: Diet-induced obesity is associated with increased myocardial fatty acid (FA) utilization, insulin resistance and cardiac dysfunction. The study was designed to test the hypothesis that impaired glucose utilization accounts for initial changes in FA metabolism.
Methods: 10-week-old C57BL6J mice were fed a high-fat diet (HFD, 45% calories from fat) or normal chow (4% calories from fat). Cardiac function and substrate metabolism in isolated working hearts; glucose uptake in isolated cardiomyocytes; mitochondrial function; insulin stimulated protein kinase B (Akt/PKB) and Akt substrate (AS-160) phosphorylation; glucose transporter 4 (GLUT4) translocation, pyruvate dehydrogenase (PDH) activity and mRNA levels for metabolic genes were determined after 2 or 5-weeks of HFD.
Results: Two weeks of HFD reduced basal rates of glycolysis and glucose oxidation, and prevented insulin-stimulation of glycolysis in hearts and reduced insulin-stimulated glucose uptake in cardiomyocytes. Insulin-stimulated Akt/PKB and AS-160 phosphorylation were preserved, and PDH activity was unchanged. GLUT4 content was reduced by 55% and GLUT4 translocation was significantly attenuated. HFD increased FA oxidation rates and myocardial oxygen consumption (MVO2), which could not be accounted for by mitochondrial uncoupling or by increased expression of peroxisome proliferator activated receptor (PPAR)-
target genes that increased only after 5-weeks of HFD.
Conclusion: Rates of myocardial glucose utilization are altered early in the course of HFD because of reduced GLUT4 content and GLUT4 translocation despite normal insulin signaling to Akt/PKB and AS 160. The reciprocal increase in FA utilization is not due to PPAR- mediated signaling or mitochondrial uncoupling. Thus the initial increase in myocardial FA utilization in response to HFD likely results from impaired glucose transport that precedes impaired insulin signaling.
KEYWORDS Glucose Transport; Glycolysis; Fatty Acid Metabolism; Insulin Resistance; Mitochondria
Time for primary review: 22 Days
* These authors contributed equally
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