TY - JOUR
T1 - Deleterious action of FA metabolites on ATP synthesis
T2 - Possible link between lipotoxicity, mitochondrial dysfunction, and insulin resistance
AU - Abdul-Ghani, Muhammad A.
AU - Muller, Florian L.
AU - Liu, Yuhong
AU - Chavez, Alberto O.
AU - Balas, Bogdan
AU - Zuo, Pengou
AU - Chang, Zhi
AU - Tripathy, Devjit
AU - Jani, Rucha
AU - Molina-Carrion, Marjorie
AU - Monroy, Adriana
AU - Folli, Franco
AU - Van Remmen, Holly
AU - DeFronzo, Ralph A.
PY - 2008/9
Y1 - 2008/9
N2 - Insulin resistance is a characteristic feature of type 2 diabetes and obesity. Insulin-resistant individuals manifest multiple disturbances in free fatty acid (FFA) metabolism and have excessive lipid accumulation in insulin target tissues. Although much evidence supports a causal role for altered FFA metabolism in the development of insulin resistance, i.e., " lipotoxicity", the intracellular mechanisms by which elevated plasma FFA levels cause insulin resistance have yet to be completely elucidated. Recent studies have implicated a possible role for mitochondrial dysfunction in the pathogenesis of insulin resistance in skeletal muscle. We examined the effect of FFA metabolites [palmitoyl carnitine (PC), palmitoyl-coenzyme A (CoA), and oleoyl-CoA] on ATP synthesis in mitochondria isolated from mouse and human skeletal muscle. At concentrations ranging from 0.5 to 2 μM, these FFA metabolites stimulated ATP synthesis; however, above 5 μM, there was a dose-response inhibition of ATP synthesis. Furthermore, 10 μM PC inhibits ATP synthesis from pyruvate. Elevated PC concentrations (≥10 μM) inhibit electron transport chain activity and decrease the mitochondrial inner membrane potential. These acquired mitochondrial defects, caused by a physiological increase in the concentration of FFA metabolites, provide a mechanistic link between lipotoxicity, mitochondrial dysfunction, and muscle insulin resistance.
AB - Insulin resistance is a characteristic feature of type 2 diabetes and obesity. Insulin-resistant individuals manifest multiple disturbances in free fatty acid (FFA) metabolism and have excessive lipid accumulation in insulin target tissues. Although much evidence supports a causal role for altered FFA metabolism in the development of insulin resistance, i.e., " lipotoxicity", the intracellular mechanisms by which elevated plasma FFA levels cause insulin resistance have yet to be completely elucidated. Recent studies have implicated a possible role for mitochondrial dysfunction in the pathogenesis of insulin resistance in skeletal muscle. We examined the effect of FFA metabolites [palmitoyl carnitine (PC), palmitoyl-coenzyme A (CoA), and oleoyl-CoA] on ATP synthesis in mitochondria isolated from mouse and human skeletal muscle. At concentrations ranging from 0.5 to 2 μM, these FFA metabolites stimulated ATP synthesis; however, above 5 μM, there was a dose-response inhibition of ATP synthesis. Furthermore, 10 μM PC inhibits ATP synthesis from pyruvate. Elevated PC concentrations (≥10 μM) inhibit electron transport chain activity and decrease the mitochondrial inner membrane potential. These acquired mitochondrial defects, caused by a physiological increase in the concentration of FFA metabolites, provide a mechanistic link between lipotoxicity, mitochondrial dysfunction, and muscle insulin resistance.
KW - Adenosine 5′-triphosphate synthesis
KW - Insulin resistance
KW - Mitochondria
KW - Oleoyl-coenzyme A
KW - Palmitoyl carnitine
KW - Palmitoyl-coenzyme A
KW - Type 2 diabetes
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U2 - 10.1152/ajpendo.90287.2008
DO - 10.1152/ajpendo.90287.2008
M3 - Article
C2 - 18593850
AN - SCOPUS:53149138585
SN - 0193-1849
VL - 295
SP - E678-E685
JO - American Journal of Physiology - Endocrinology and Metabolism
JF - American Journal of Physiology - Endocrinology and Metabolism
IS - 3
ER -