What are the biochemical mechanisms responsible for enhanced fatty acid utilization by perfused hearts from type 2 diabetic db/db mice?
BACKGROUND
It is generally accepted that diabetic hearts have an altered metabolic phenotype, with enhanced fatty acid (FA) utilization. The over-utilization of FA by diabetic hearts can have deleterious functional consequences, contributing to a distinct diabetic cardiomyopathy. The objective of this review will be to examine which biochemical mechanisms are responsible for enhanced FA utilization by diabetic hearts.


RESULTS
Studies were performed with db/db mice, a monogenic model of type 2 diabetes with extreme obesity and hyperglycemia. Perfused db/db hearts exhibit enhanced FA oxidation and esterification. Hypothesis 1: Cardiac FA uptake is enhanced in db/db hearts. The plasma membrane content of two FA transporters, fatty acid translocase/CD36 (FAT/CD36) and plasma membrane fatty acid binding protein (FABPpm), was increased in db/db hearts, consistent with hypothesis 1. Hypothesis 2: Cardiac FA oxidation is enhanced in db/db hearts due to mitochondrial alterations. However, the activity of carnitine palmitoyl transferase-1 (CPT-1) and sensitivity to inhibition by malonyl CoA was unchanged in mitochondria from db/db hearts. Furthermore, total malonyl CoA content was increased, not decreased as predicted for elevated FA oxidation. Finally, the content of uncoupling protein-3 was unchanged in db/db heart mitochondria.


CONCLUSIONS
Increased plasma membrane content of FA transporters (FAT/CD36 and FABPpm) will increase FA uptake into db/db cardiomyocytes and thus increase FA utilization. On the other hand, mitochondrial mechanisms do not contribute to elevated rates of FA oxidation in db/db hearts.
Carley
Andrew N
AN
Department of Pharmacology & Therapeutics, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary AB T2N 4N1, Canada.
Severson
David L
DL
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D050612:Fatty Acid Transport Proteins / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D008929:Mitochondria, Heart / Q000378:metabolism; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism*; D010477:Perfusion
D050612:Fatty Acid Transport Proteins; D005227:Fatty Acids