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Paradoxical Changes in Muscle Gene Expression in Insulin-Resistant Subjects After Sustained Reduction in Plasma Free Fatty Acid Concentration

¹ University of Texas Medical Branch, Galveston, Texas
² University of Texas Health Science Center, San Antonio, Texas
³ Center for Metabolic Biology, Arizona State University, Tempe, Arizona
⁴ Carl T. Hayden VA Medical Center, Phoenix, Arizona

Address correspondence and reprint requests to Lawrence J. Mandarino, PhD, Director, Center for Metabolic Biology, Professor and Chair, Department of Kinesiology, Professor, School of Life Sciences, Arizona State University, P.O. Box 874501, Tempe, AZ 85287-4501. E-mail: lawrence.mandarino{at}asu.edu

Abbreviations: CTGF, connective tissue growth factor; FFA, free fatty acid; OGTT, oral glucose tolerance test; TGF, transforming growth factor

Lipid oversupply plays a role in developing insulin resistance in skeletal muscle, decreasing expression of nuclear-encoded mitochondrial genes, and increasing extracellular matrix remodeling. To determine if a decrease in plasma lipid content reverses these abnormalities, insulin-resistant subjects with a family history of type 2 diabetes had euglycemic clamps and muscle biopsies before and after acipimox treatment to suppress free fatty acids. Free fatty acids fell from 0.584 ± 0.041 to 0.252 ± 0.053 mmol/l (P < 0.001) and glucose disposal increased from 5.28 ± 0.46 to 6.31 ± 0.55 mg · kg^–1 · min^–1 (P < 0.05) after acipimox; intramuscular fatty acyl CoA decreased from 10.3 ± 1.9 to 4.54 ± 0.82 pmol/mg muscle (P < 0.01). Paradoxically, expression of PGC-1–and nuclear-encoded mitochondrial genes decreased after acipimox, and expression of collagens I and III -subunits (82- and 21-fold increase, respectively, P < 0.05), connective tissue growth factor (2.5-fold increase, P < 0.001), and transforming growth factor-ß1 increased (2.95-fold increase, P < 0.05). Therefore, a reduction in lipid supply does not completely reverse the molecular changes associated with lipid oversupply in muscle. Changes in expression of nuclear-encoded mitochondrial genes do not always correlate with changes in insulin sensitivity.

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