TY - JOUR
T1 - Palmitate-induced insulin resistance in rat and human skeletal muscle cells associates with inhibited ATP turnover
AU - Nisr, Raid B.
AU - Affourtit, Charles
N1 - Copyright:
© 2015 Published by Elsevier B.V.
PY - 2016/8
Y1 - 2016/8
N2 - Mitochondrial dysfunction correlates with the loss of skeletal muscle insulin sensitivity in obesity, but the causal relation between these pathologies remains subject of debate. At present, there is for example disagreement as to what extent the oxidative capacity of muscle cells may be insufficient to manage the elevated nutrient supply in obesity. Analogously with a market economy, the energy metabolism of muscle is largely controlled by ATP demand, which means that the effective capacity of mitochondrial oxidative phosphorylation is set indirectly by ATP turnover. The experiments reported here aimed to establish if ATP-consuming processes in rat and human myoblasts are altered when cells are exposed to palmitate, an abundant saturated fatty acid whose concentration increases in obesity. Measuring myocellular bioenergetics in real time we show that palmitate lowers the rate and efficiency of oxidative phosphorylation under the same conditions where it causes insulin resistance. Our data suggest that the decrease of ATP synthesis rate, at least partly, results from changed ATP demand. Direct measurement of de novo protein synthesis reveals that palmitate lowers this ATP-consuming process by 30%. This inhibition is reflected by a significantly decreased proportion of ATP supply allocated to protein synthesis: cycloheximide-sensitivity of oligomycin-sensitive respiration is decreased by 40%. Moreover, in both rat and human cells, palmitate lowers ATP supply used to drive the sodium pump by 60-70% and, in human cells only, decreases ATP supply reserved for DNA/RNA synthesis by almost 75%. These palmitate effects on ATP turnover shed new light on the ‘mitochondrial insufficiency’ debate and highlight that mitochondrial involvement in fatty-acid-induced insulin resistance is best evaluated in context of bioenergetics control.
AB - Mitochondrial dysfunction correlates with the loss of skeletal muscle insulin sensitivity in obesity, but the causal relation between these pathologies remains subject of debate. At present, there is for example disagreement as to what extent the oxidative capacity of muscle cells may be insufficient to manage the elevated nutrient supply in obesity. Analogously with a market economy, the energy metabolism of muscle is largely controlled by ATP demand, which means that the effective capacity of mitochondrial oxidative phosphorylation is set indirectly by ATP turnover. The experiments reported here aimed to establish if ATP-consuming processes in rat and human myoblasts are altered when cells are exposed to palmitate, an abundant saturated fatty acid whose concentration increases in obesity. Measuring myocellular bioenergetics in real time we show that palmitate lowers the rate and efficiency of oxidative phosphorylation under the same conditions where it causes insulin resistance. Our data suggest that the decrease of ATP synthesis rate, at least partly, results from changed ATP demand. Direct measurement of de novo protein synthesis reveals that palmitate lowers this ATP-consuming process by 30%. This inhibition is reflected by a significantly decreased proportion of ATP supply allocated to protein synthesis: cycloheximide-sensitivity of oligomycin-sensitive respiration is decreased by 40%. Moreover, in both rat and human cells, palmitate lowers ATP supply used to drive the sodium pump by 60-70% and, in human cells only, decreases ATP supply reserved for DNA/RNA synthesis by almost 75%. These palmitate effects on ATP turnover shed new light on the ‘mitochondrial insufficiency’ debate and highlight that mitochondrial involvement in fatty-acid-induced insulin resistance is best evaluated in context of bioenergetics control.
U2 - 10.1016/j.bbabio.2016.04.195
DO - 10.1016/j.bbabio.2016.04.195
M3 - Conference article
SN - 0005-2728
VL - 1857
SP - e98
JO - Biochimica et Biophysica Acta - Bioenergetics
JF - Biochimica et Biophysica Acta - Bioenergetics
IS - Supplement
ER -