Mechanisms for increased myocardial fatty acid utilization following short-term high-fat feeding.
OBJECTIVE
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.


RESULTS
Ten-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. 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-alpha (PPAR-alpha) target genes, which increased only after 5 weeks of HFD.


CONCLUSIONS
Rates of myocardial glucose utilization are altered early in the course of HFD because of reduced GLUT4 content and GLUT4 translocation despite normal insulin signalling to Akt/PKB and AS-160. The reciprocal increase in FA utilization is not due to PPAR-alpha-mediated signalling 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 signalling.
Wright
Jordan J
JJ
Division of Endocrinology, Metabolism and Diabetes and Program in Molecular Medicine, University of Utah School of Medicine, 15 N 2030 East, Bldg 533, Rm 3110B, Salt Lake City, UT 84112, USA.
Kim
Jaetaek
J
Buchanan
Jonathan
J
Boudina
Sihem
S
Sena
Sandra
S
Bakirtzi
Kyriaki
K
Ilkun
Olesya
O
Theobald
Heather A
HA
Cooksey
Robert C
RC
Kandror
Kostantin V
KV
Abel
E Dale
ED
D000818:Animals; D004041:Dietary Fats / Q000494:pharmacology*; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism
D004041:Dietary Fats; D005227:Fatty Acids; D051275:Glucose Transporter Type 4; D007328:Insulin; D011768:Pyruvate Dehydrogenase Complex; C495693:Slc2a4 protein, mouse; D005947:Glucose