Impaired glucose metabolism in the heart of obese Zucker rats after treatment with phorbol ester.
OBJECTIVE
To investigate the influence of obesity on the regulation of myocardial glucose metabolism following protein kinase C (PKC) activation in obese (fa/fa) and lean (Fa/?) Zucker rats.


METHODS
Isolated hearts obtained from 17-week-old lean and obese Zucker rats were perfused with 200 nM phorbol 12-myristate 13-acetate (PMA) for different time periods prior to the evaluation of PKC and GLUT-4 translocation. For metabolic studies isolated hearts from 48 h starved Zucker rats were perfused with an erythrocytes-enriched buffer containing increased concentrations (10-100 nM) of PMA.


METHODS
Immunodetectable PKC isozymes and GLUT-4 were determined by Western blots. Glucose oxidation and glycolysis were evaluated by measuring the myocardial release of 14CO2 and 3H2O from [U-14C]glucose and [5-3H]glucose, respectively.


RESULTS
PMA (200 nM) induced maximal translocation of ventricular PKCalpha from the cytosol to the membranes within 10 min. This translocation was 2-fold lower in the heart from obese rats when compared to lean rats. PMA also induced a significant translocation of ventricular GLUT-4 from the microsomal to the sarcolemmal fraction within 60 min in lean but not in obese rats. Rates of basal cardiac glucose oxidation and glycolysis in obese rats were approximately 2-fold lower than those of lean rats. Perfusion with increasing concentrations of PMA (10-100 nM) led to a significant decrease of cardiac glucose oxidation in lean but not in obese rats.


CONCLUSIONS
Our results show that in the heart of the genetically obese Zucker rat, the impairment in PKCalpha activation is in line with a diminished activation of GLUT-4 as well as with the lack of PMA effect on glucose oxidation.
Morabito
D
D
Division of Endocrinology and Diabetology, Department of Internal Medicine, University Hospital of Geneva, Geneva, Switzerland.
Montessuit
C
C
Rosenblatt-Velin
N
N
Lerch
R
R
Vallotton
M B
MB
Lang
U
U
D000818:Animals; D001692:Biological Transport; D001696:Biomechanical Phenomena; D001835:Body Weight; D002250:Carbon Radioisotopes; D002462:Cell Membrane / Q000201:enzymology; D003600:Cytosol / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4; D006019:Glycolysis; D006321:Heart / Q000502:physiology; D007527:Isoenzymes / Q000378:metabolism*; D007700:Kinetics; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins; D009206:Myocardium / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D011924:Rats, Zucker; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014316:Tritium
D002250:Carbon Radioisotopes; D051275:Glucose Transporter Type 4; D007527:Isoenzymes; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C495694:Slc2a4 protein, rat; D014316:Tritium; D011493:Protein Kinase C; D005947:Glucose; D013755:Tetradecanoylphorbol Acetate