Cardiac contractile dysfunction in insulin-resistant rats fed a high-fat diet is associated with elevated CD36-mediated fatty acid uptake and esterification.
OBJECTIVE
Changes in cardiac substrate utilisation leading to altered energy metabolism may underlie the development of diabetic cardiomyopathy. We studied cardiomyocyte substrate uptake and utilisation and the role of the fatty acid translocase CD36 in relation to in vivo cardiac function in rats fed a high-fat diet (HFD).


METHODS
Rats were exposed to an HFD or a low-fat diet (LFD). In vivo cardiac function was monitored by echocardiography. Substrate uptake and utilisation were determined in isolated cardiomyocytes.


RESULTS
Feeding an HFD for 8 weeks induced left ventricular dilation in the systolic phase and decreased fractional shortening and the ejection fraction. Insulin-stimulated glucose uptake and proline-rich Akt substrate 40 phosphorylation were 41% (p < 0.001) and 45% (p < 0.05) lower, respectively, in cardiomyocytes from rats on the HFD. However, long-chain fatty acid (LCFA) uptake was 1.4-fold increased (p < 0.001) and LCFA esterification into triacylglycerols and phospholipids was increased 1.4- and 1.5-fold, respectively (both p < 0.05), in cardiomyocytes from HFD compared with LFD hearts. In the presence of the CD36 inhibitor sulfo-N-succinimidyloleate, LCFA uptake and esterification were similar in LFD and HFD cardiomyocytes. In HFD hearts CD36 was relocated to the sarcolemma, and basal phosphorylation of a mediator of CD36-trafficking, i.e. protein kinase B (PKB/Akt), was increased.


CONCLUSIONS
Feeding rats an HFD induced cardiac contractile dysfunction, which was accompanied by the relocation of CD36 to the sarcolemma, and elevated basal levels of phosphorylated PKB/Akt. The permanent presence of CD36 at the sarcolemma resulted in enhanced rates of LCFA uptake and myocardial triacylglycerol accumulation, and may contribute to the development of insulin resistance and diabetic cardiomyopathy.
Ouwens
D M
DM
Department of Molecular Cell Biology, Section of Signal Transduction and Ageing, Leiden University Medical Centre, Postzone S1-P, P.O. Box 9600, NL-2300, RC Leiden, The Netherlands. d.m.ouwens@lumc.nl.
Diamant
M
M
Department of Endocrinology, Diabetes Centre, VU University Medical Centre, Amsterdam, the Netherlands.
Fodor
M
M
Department of Anatomy and Embryology/Central Animal Facility, Leiden University Medical Centre, Leiden, the Netherlands.
Habets
D D J
DDJ
Department of Molecular Genetics, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands.
Pelsers
M M A L
MMAL
Department of Molecular Genetics, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands.
El Hasnaoui
M
M
Department of Molecular Genetics, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands.
Dang
Z C
ZC
Department of Endocrinology, Diabetes Centre, VU University Medical Centre, Amsterdam, the Netherlands.|Laboratory for Physiology, VU University Medical Centre, Amsterdam, the Netherlands.
van den Brom
C E
CE
Department of Molecular Cell Biology, Section of Signal Transduction and Ageing, Leiden University Medical Centre, Postzone S1-P, P.O. Box 9600, NL-2300, RC Leiden, The Netherlands.|Department of Endocrinology, Diabetes Centre, VU University Medical Centre, Amsterdam, the Netherlands.|Laboratory for Physiology, VU University Medical Centre, Amsterdam, the Netherlands.
Vlasblom
R
R
Department of Molecular Cell Biology, Section of Signal Transduction and Ageing, Leiden University Medical Centre, Postzone S1-P, P.O. Box 9600, NL-2300, RC Leiden, The Netherlands.|Department of Endocrinology, Diabetes Centre, VU University Medical Centre, Amsterdam, the Netherlands.|Laboratory for Physiology, VU University Medical Centre, Amsterdam, the Netherlands.
Rietdijk
A
A
Department of Molecular Cell Biology, Section of Signal Transduction and Ageing, Leiden University Medical Centre, Postzone S1-P, P.O. Box 9600, NL-2300, RC Leiden, The Netherlands.
Boer
C
C
Laboratory for Physiology, VU University Medical Centre, Amsterdam, the Netherlands.
Coort
S L M
SLM
Department of Molecular Genetics, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands.
Glatz
J F C
JFC
Department of Molecular Genetics, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands.
Luiken
J J F P
JJFP
Department of Molecular Genetics, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands.|Department of Biochemical Physiology and Institute of Biomembranes, Utrecht University, Utrecht, the Netherlands.
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001835:Body Weight; D018955:CD36 Antigens / Q000502:physiology*; D009202:Cardiomyopathies / Q000453:epidemiology; D003925:Diabetic Angiopathies / Q000453:epidemiology; D004041:Dietary Fats / Q000494:pharmacology*; D004952:Esters; D005227:Fatty Acids / Q000378:metabolism*; D006321:Heart / Q000187:drug effects; D007333:Insulin Resistance; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014280:Triglycerides / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology
D001786:Blood Glucose; D018955:CD36 Antigens; D004041:Dietary Fats; D004952:Esters; D005227:Fatty Acids; D014280:Triglycerides