title: ANT1-mediated fatty acid-induced uncoupling as a target for improving myocellular insulin sensitivity.
abstract: OBJECTIVE
  Dissipating energy via mitochondrial uncoupling has been suggested to contribute to enhanced insulin sensitivity. We hypothesised that skeletal muscle mitochondria of endurance-trained athletes have increased sensitivity for fatty acid (FA)-induced uncoupling, which is driven by the mitochondrial protein adenine nucleotide translocase 1 (ANT1).
  
  
  METHODS
  Capacity for FA-induced uncoupling was measured in endurance-trained male athletes (T) and sedentary young men (UT) in an observational study and also in isolated skeletal muscle mitochondria from Zucker diabetic fatty (ZDF) rats and C2C12 myotubes following small interfering RNA (siRNA)-mediated gene silencing of ANT1. Thus, fuelled by glutamate/succinate (fibres) or pyruvate (mitochondria and myotubes) and in the presence of oligomycin to block ATP synthesis, increasing levels of oleate (fibres) or palmitate (mitochondria and myotubes) were automatically titrated while respiration was monitored. Insulin sensitivity was measured by hyperinsulinaemic-euglycaemic clamp in humans and via insulin-stimulated glucose uptake in myotubes.
  
  
  RESULTS
  Skeletal muscle from the T group displayed increased sensitivity to FA-induced uncoupling (p = 0.011) compared with muscle from the UT group, and this was associated with elevated insulin sensitivity (p = 0.034). ANT1 expression was increased in T (p = 0.013). Mitochondria from ZDF rats displayed decreased sensitivity for FA-induced uncoupling (p = 0.008). This difference disappeared in the presence of the adenine nucleotide translocator inhibitor carboxyatractyloside. Partial knockdown of ANT1 in C2C12 myotubes decreased sensitivity to the FA-induced uncoupling (p = 0.008) and insulin-stimulated glucose uptake (p = 0.025) compared with controls.
  
  
  CONCLUSIONS
  Increased sensitivity to FA-induced uncoupling is associated with enhanced insulin sensitivity and is affected by ANT1 activity in skeletal muscle. FA-induced mitochondrial uncoupling may help to preserve insulin sensitivity in the face of a high supply of FAs.
  
  
  BACKGROUND
  www.trialregister.nl NTR2002.
authors.affiliation: Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, P. O. Box 616, 6200MD, Maastricht, the Netherlands.|Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Orlando, FL, USA.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Sparks
authors.affiliation: Department of Human Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands.
authors.forename: Anne
authors.initials: A
authors.lastname: Gemmink
authors.affiliation: Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, P. O. Box 616, 6200MD, Maastricht, the Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: Phielix
authors.affiliation: Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, P. O. Box 616, 6200MD, Maastricht, the Netherlands.|Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Madeleen
authors.initials: M
authors.lastname: Bosma
authors.affiliation: Department of Human Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands.
authors.forename: Gert
authors.initials: G
authors.lastname: Schaart
authors.affiliation: Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, P. O. Box 616, 6200MD, Maastricht, the Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: Moonen-Kornips
authors.affiliation: Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, P. O. Box 616, 6200MD, Maastricht, the Netherlands.
authors.forename: Johanna A
authors.initials: JA
authors.lastname: Jörgensen
authors.affiliation: Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, P. O. Box 616, 6200MD, Maastricht, the Netherlands.
authors.forename: Emmani B M
authors.initials: EB
authors.lastname: Nascimento
authors.affiliation: Department of Human Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands.
authors.forename: Matthijs K C
authors.initials: MK
authors.lastname: Hesselink
authors.affiliation: Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, P. O. Box 616, 6200MD, Maastricht, the Netherlands.
authors.forename: Patrick
authors.initials: P
authors.lastname: Schrauwen
authors.affiliation: Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, P. O. Box 616, 6200MD, Maastricht, the Netherlands. j.hoeks@maastrichtuniversity.nl.
authors.forename: Joris
authors.initials: J
authors.lastname: Hoeks
mesh_terms: D033741:Adenine Nucleotide Translocator 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D005227:Fatty Acids / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D008297:Male; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism; D000226:Mitochondrial ADP, ATP Translocases / Q000235:genetics / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D019301:Oleic Acid / Q000494:pharmacology; D019308:Palmitic Acid / Q000494:pharmacology; D051381:Rats; D011924:Rats, Zucker
chemical_list: D033741:Adenine Nucleotide Translocator 1; D005227:Fatty Acids; D007328:Insulin; D019301:Oleic Acid; D019308:Palmitic Acid; D000226:Mitochondrial ADP, ATP Translocases
keywords: ANT1; Fatty acid-induced uncoupling; Skeletal muscle insulin sensitivity