title: Mitochondrial dysfunction caused by saturated fatty acid loading induces myocardial insulin-resistance in differentiated H9c2 myocytes: a novel ex vivo myocardial insulin-resistance model.
abstract: Heart failure (HF) is often accompanied with metabolic disorders and insufficient energy production. Some previous studies have suggested an elevated serum free fatty acid (FA) due to chronic adrenergic stimulation induces myocardial insulin-resistance, which further impairs myocardial energy production. Because little is known about the pathogenesis of FA-induced cardiac insulin-resistance, we established an ex vivo cardiac insulin-resistant model and investigated the relationship between insulin-resistance and mitochondrial dysfunction. The ex vivo insulin-resistant myocytes, which was produced by treating differentiated H9c2 myocytes with palmitate (saturated FA; 0.2mM) for 24h, exhibited insulin-signaling deficiency and attenuated 2-deoxy-d-glucose (2-DG) uptake. When myocytes were pretreated with Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (TMPyP, a ROS scavenger; 200 μM), the insulin-signaling deficiency by palmitate was restored, whereas the attenuated 2-DG uptake was remained. In contrast to TMPyP, the pretreatment with perhexiline (a mitochondrial FA uptake inhibitor; 2 μM) restored the insulin-signaling deficiency and the attenuated 2-DG uptake by palmitate. Perhexiline restored the depolarized mitochondrial membrane potential (ΔΨm) and the reduced intracellular ATP by palmitate, and thereby improved the impaired GLUT4 recruitment to plasma membrane after insulin, whereas TMPyP failed to do so. These results suggested that the mitochondrial dysfunction by saturated FA loading and consequent intracellular energy shortage induced myocardial insulin-resistance in our ex vivo insulin-resistant model.
authors: Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan.
authors: Mamoru
authors: M
authors: Nobuhara
authors: Masao
authors: M
authors: Saotome
authors: Tomoyuki
authors: T
authors: Watanabe
authors: Tsuyoshi
authors: T
authors: Urushida
authors: Hideki
authors: H
authors: Katoh
authors: Hiroshi
authors: H
authors: Satoh
authors: Makoto
authors: M
authors: Funaki
authors: Hideharu
authors: H
authors: Hayashi
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D004734:Energy Metabolism / Q000502:physiology; D005227:Fatty Acids / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D006321:Heart / Q000187:drug effects*; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000502:physiology
chemical_list: D005227:Fatty Acids; D007328:Insulin; D005947:Glucose