title: Palmitate-induced changes in energy demand cause reallocation of ATP supply in rat and human skeletal muscle cells.
abstract: Mitochondrial dysfunction has been associated with obesity-related muscle insulin resistance, but the causality of this association is controversial. The notion that mitochondrial oxidative capacity may be insufficient to deal appropriately with excessive nutrient loads is for example disputed. Effective mitochondrial capacity is indirectly, but largely determined by ATP-consuming processes because skeletal muscle energy metabolism is mostly controlled by ATP demand. Probing the bioenergetics of rat and human myoblasts in real time we show here that the saturated fatty acid palmitate lowers the rate and coupling efficiency of oxidative phosphorylation under conditions it causes insulin resistance. Stearate affects the bioenergetic parameters similarly, whereas oleate and linoleate tend to decrease the rate but not the efficiency of ATP synthesis. Importantly, we reveal that palmitate influences how oxidative ATP supply is used to fuel ATP-consuming processes. Direct measurement of newly made protein demonstrates that palmitate lowers the rate of de novo protein synthesis by more than 30%. The anticipated decrease of energy demand linked to protein synthesis is confirmed by attenuated cycloheximide-sensitivity of mitochondrial respiratory activity used to make ATP. This indirect measure of ATP turnover indicates that palmitate lowers ATP supply reserved for protein synthesis by at least 40%. This decrease is also provoked by stearate, oleate and linoleate, albeit to a lesser extent. Moreover, palmitate lowers ATP supply for sodium pump activity by 60-70% and, in human cells, decreases ATP supply for DNA/RNA synthesis by almost three-quarters. These novel fatty acid effects on energy expenditure inform the 'mitochondrial insufficiency' debate.
authors.affiliation: School of Biomedical and Healthcare Sciences, Plymouth University, Drake Circus, PL4 8AA, Plymouth, UK.
authors.forename: Raid B
authors.initials: RB
authors.lastname: Nisr
authors.affiliation: School of Biomedical and Healthcare Sciences, Plymouth University, Drake Circus, PL4 8AA, Plymouth, UK. Electronic address: charles.affourtit@plymouth.ac.uk.
authors.forename: Charles
authors.initials: C
authors.lastname: Affourtit
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004734:Energy Metabolism / Q000187:drug effects*; D006801:Humans; D018482:Muscle, Skeletal / Q000378:metabolism*; D019308:Palmitic Acid / Q000494:pharmacology*; D014176:Protein Biosynthesis / Q000187:drug effects; D051381:Rats
chemical_list: D019308:Palmitic Acid; D000255:Adenosine Triphosphate
keywords: ATP turnover; Mitochondrial dysfunction; Obesity; Palmitate-induced insulin resistance; Skeletal muscle; Type 2 diabetes