Impaired Long-Chain Fatty Acid Oxidation and Contractile Dysfunction in the Obese Zucker Rat Heart

Impaired Long-Chain Fatty Acid Oxidation and Contractile Dysfunction in the Obese Zucker Rat Heart Martin E. Young 1 , Patrick H. Guthrie 1 , Peter Razeghi 1 , Brendan Leighton 2 , Shahrzad Abbasi 1 , Sarita Patil 1 , Keith A. Youker 3 and Heinrich Taegtmeyer 1 1 Department of Internal Medicine, Division of Cardiology, University of Texas-Houston Medical School, Houston, Texas 2 AstraZeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield, U.K 3 Department of Medicine, Section of Cardiovascular Sciences, Baylor College of Medicine, Houston, Texas Abstract We investigated whether decreased responsiveness of the heart to physiological increases in fatty acid availability results in lipid accumulation and lipotoxic heart disease. Lean and obese Zucker rats were either fed ad libitum or fasted overnight. Fasting increased plasma nonesterified fatty acid levels in both lean and obese rats, although levels were greatest in obese rats regardless of nutritional status. Despite increased fatty acid availability, the mRNA transcript levels of peroxisome proliferator-activated receptor (PPAR)-α-regulated genes were similar in fed lean and fed obese rat hearts. Fasting increased expression of all PPAR-α -regulated genes in lean Zucker rat hearts, whereas, in obese Zucker rat hearts, muscle carnitine palmitoyltransferase and medium-chain acyl-CoA dehydrogenase were unaltered with fasting. Rates of oleate oxidation were similar for hearts from fed rats. However, fasting increased rates of oleate oxidation only in hearts from lean rats. Dramatic lipid deposition occurred within cardiomyocytes of obese, but not lean, Zucker rats upon fasting. Cardiac output was significantly depressed in hearts isolated from obese rats compared with lean rats, regardless of nutritional status. Fasting increased cardiac output in hearts of lean rats only. Thus, the heart’s inability to increase fatty acid oxidation in proportion to increased fatty acid availability is associated with lipid accumulation and contractile dysfunction of the obese Zucker rat. Footnotes Address correspondence and reprint requests to Heinrich Taegtmeyer, DPhil, Department of Internal Medicine, Division of Cardiology, University of Texas-Houston Medical School, 6431 Fannin, MSB 1.246, Houston, TX 77030. E-mail: heinrich.taegtmeyer{at}uth.tmc.edu . Received for publication 4 February 2002 and accepted in revised form 26 April 2002. B.L. holds stock in AstraZeneca Pharmaceuticals. iNOS, inducible nitric oxide