Deleterious action of FA metabolites on ATP synthesis: Possible link between lipotoxicity, mitochondrial dysfunction, and insulin resistance

Muhammad A. Abdul-Ghani, Florian L. Muller, Yuhong Liu, Alberto O. Chavez, Bogdan Balas, Pengou Zuo, Zhi Chang, Devjit Tripathy, Rucha Jani, Marjorie Molina-Carrion, Adriana Monroy, Franco Folli, Holly Van Remmen, Ralph A. DeFronzo

Research output: Contribution to journalArticlepeer-review

102 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)E678-E685
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume295
Issue number3
DOIs
StatePublished - Sep 1 2008

Keywords

  • Adenosine 5′-triphosphate synthesis
  • Insulin resistance
  • Mitochondria
  • Oleoyl-coenzyme A
  • Palmitoyl carnitine
  • Palmitoyl-coenzyme A
  • Type 2 diabetes

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

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