ANT1-mediated fatty acid-induced uncoupling as a target for improving myocellular insulin sensitivity

Lauren Sparks; A. Gemmink; E. Phielix; M. Bosma; G. Schaart; E. Moonen-Kornips; J.A. Jorgensen; E.B.M. Nascimento; M.K.C. Hesselink; P. Schrauwen; J. Hoeks

doi:10.1007/s00125-016-3885-8

ANT1-mediated fatty acid-induced uncoupling as a target for improving myocellular insulin sensitivity

Lauren Sparks, A. Gemmink, E. Phielix, M. Bosma, G. Schaart, E. Moonen-Kornips, J.A. Jorgensen, E.B.M. Nascimento, M.K.C. Hesselink, P. Schrauwen, J. Hoeks^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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).

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.

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.

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.

www.trialregister.nl NTR2002.

Original language	English
Pages (from-to)	1030-1039
Number of pages	10
Journal	Diabetologia
Volume	59
Issue number	5
DOIs	https://doi.org/10.1007/s00125-016-3885-8
Publication status	Published - May 2016

Keywords

ANT1
Fatty acid-induced uncoupling
Skeletal muscle insulin sensitivity
HUMAN SKELETAL-MUSCLE
ADENINE-NUCLEOTIDE TRANSLOCASE
OXYGEN SPECIES PRODUCTION
OXIDATIVE-PHOSPHORYLATION
MITOCHONDRIAL-FUNCTION
ROS PRODUCTION
IN-VIVO
RESISTANCE
MICE
DYSFUNCTION

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title = "ANT1-mediated fatty acid-induced uncoupling as a target for improving myocellular insulin sensitivity",

abstract = "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).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.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.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.www.trialregister.nl NTR2002.",

keywords = "ANT1, Fatty acid-induced uncoupling, Skeletal muscle insulin sensitivity, HUMAN SKELETAL-MUSCLE, ADENINE-NUCLEOTIDE TRANSLOCASE, OXYGEN SPECIES PRODUCTION, OXIDATIVE-PHOSPHORYLATION, MITOCHONDRIAL-FUNCTION, ROS PRODUCTION, IN-VIVO, RESISTANCE, MICE, DYSFUNCTION",

author = "Lauren Sparks and A. Gemmink and E. Phielix and M. Bosma and G. Schaart and E. Moonen-Kornips and J.A. Jorgensen and E.B.M. Nascimento and M.K.C. Hesselink and P. Schrauwen and J. Hoeks",

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TY - JOUR

T1 - ANT1-mediated fatty acid-induced uncoupling as a target for improving myocellular insulin sensitivity

AU - Sparks, Lauren

AU - Gemmink, A.

AU - Phielix, E.

AU - Bosma, M.

AU - Schaart, G.

AU - Moonen-Kornips, E.

AU - Jorgensen, J.A.

AU - Nascimento, E.B.M.

AU - Hesselink, M.K.C.

AU - Schrauwen, P.

AU - Hoeks, J.

PY - 2016/5

Y1 - 2016/5

N2 - 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).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.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.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.www.trialregister.nl NTR2002.

AB - 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).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.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.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.www.trialregister.nl NTR2002.

KW - ANT1

KW - Fatty acid-induced uncoupling

KW - Skeletal muscle insulin sensitivity

KW - HUMAN SKELETAL-MUSCLE

KW - ADENINE-NUCLEOTIDE TRANSLOCASE

KW - OXYGEN SPECIES PRODUCTION

KW - OXIDATIVE-PHOSPHORYLATION

KW - MITOCHONDRIAL-FUNCTION

KW - ROS PRODUCTION

KW - IN-VIVO

KW - RESISTANCE

KW - MICE

KW - DYSFUNCTION

U2 - 10.1007/s00125-016-3885-8

DO - 10.1007/s00125-016-3885-8

M3 - Article

C2 - 26886198

SN - 0012-186X

VL - 59

SP - 1030

EP - 1039

JO - Diabetologia

JF - Diabetologia

IS - 5

ER -