Increased glucose uptake and oxidation in mouse hearts prevent high fatty acid oxidation but cause cardiac dysfunction in diet-induced obesity.
BACKGROUND
Shift of myocardial substrate preference has been observed in many chronic diseases such as diabetes and heart failure. This study was undertaken to elucidate the mechanisms underlying the chronic substrate switch in adult hearts and to determine the functional consequences of the switch.


RESULTS
Transgenic mice with cardiac-specific overexpression of the insulin-independent glucose transporter GLUT1 (TG) were used to increase intracellular glucose in cardiac myocytes. A high-fat diet was used to increase the fatty acid supply to the heart. High-fat diet induced a 40% increase in fatty acid oxidation in wild-type hearts, whereas glucose oxidation was decreased to 30% of the control. In contrast, glucose oxidation was >2-fold higher in TG hearts, and the high-fat diet failed to upregulate fatty acid oxidation in these hearts. Glucose induced changes in the expression of multiple metabolic genes, including peroxisome proliferator-activated receptor-alpha (decreased by 51%), 3-oxoacid CoA transferase (decreased by 67%), and acetyl-CoA carboxylase (increased by 4-fold), resulting in a remodeling of the metabolic network to favor a shift of substrate preference toward glucose. Although TG mice on a normal diet maintained normal cardiac energetics and function, the inability to upregulate myocardial fatty acid oxidation in TG mice fed a high-fat diet resulted in increased oxidative stress in the heart, activation of p38 mitogen-activated protein kinase, and contractile dysfunction.


CONCLUSIONS
We have demonstrated that chronic increases in myocardial glucose uptake and oxidation reduce the metabolic flexibility and render the heart susceptible to contractile dysfunction.
Yan
Jie
J
Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Young
Martin E
ME
Cui
Lei
L
Lopaschuk
Gary D
GD
Liao
Ronglih
R
Tian
Rong
R
D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000818:Animals; D020013:Calcium Signaling; D015256:Coenzyme A-Transferases / Q000378:metabolism; D018752:Diet, Fat-Restricted; D004041:Dietary Fats / Q000633:toxicity; D005227:Fatty Acids / Q000378:metabolism*; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D009765:Obesity / Q000209:etiology / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D047492:Peroxisome Proliferator-Activated Receptors / Q000096:biosynthesis / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013379:Substrate Specificity; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D004041:Dietary Fats; D005227:Fatty Acids; D051272:Glucose Transporter Type 1; D047492:Peroxisome Proliferator-Activated Receptors; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; C495678:Slc2a1 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases; D015256:Coenzyme A-Transferases; C021460:3-ketoacid CoA-transferase; D000103:Acetyl-CoA Carboxylase; D005947:Glucose