Evidence for a Direct Effect of the NAD+ Precursor Acipimox on Muscle Mitochondrial Function in Humans

T. van de Weijer, E. Phielix, L. Bilet, E.G. Williams, E.R. Ropelle, A. Bierwagen, R. Livingstone, P. Nowotny, L.M. Sparks, S.A. Paglialunga, J. Szendroedi, B. Havekes, N. Moullan, E. Pirinen, J.H. Hwang, V.B. Schrauwen-Hinderling, M.K. Hesselink, J. Auwerx, M. Roden, P. Schrauwen

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Abstract

Recent preclinical studies showed the potential of nicotinamide adenine dinucleotide : NAD+ : precursors to increase oxidative phosphorylation and improve metabolic health, but human data is lacking. Here, we hypothesized that the nicotinic acid derivative Acipimox, a NAD+ precursor, would directly affect mitochondrial function, independent of reductions in non-esterified fatty acid (NEFA) concentrations. In a multi-center randomized cross-over trial, 21 patients with type 2 diabetes (age 57.7+/-1.1 years, BMI, 33.4+/-0.8 kg/m2) received either placebo or 250 mg Acipimox thrice daily for 2 weeks. Acipimox treatment increased plasma NEFA (759+/-44 vs. 1135+/-97 micromol/L, p<0.01 for placebo vs. Acipimox), due to a previously described rebound effect. As a result, skeletal muscle lipid content increased and insulin sensitivity decreased. Despite the elevated plasma NEFA levels, ex vivo mitochondrial respiration in skeletal muscle increased. Subsequently, we showed that Acipimox treatment resulted in a robust elevation in expression of nuclear-encoded mitochondrial gene-sets and by presence of a mitonuclear protein imbalance, which may indicate activation of the mitochondrial unfolded protein response (UPRmt). Further studies in C2C12 myotubes confirmed a direct effect of Acipimox on NAD+ levels, mitonuclear protein imbalance and mitochondrial oxidative capacity. To the best of our knowledge, this is the first demonstration that NAD+ boosters can also directly impact skeletal muscle mitochondrial function in humans.
Original languageEnglish
Pages (from-to)1193-1201
Number of pages9
JournalDiabetes
Volume64
Issue number4
DOIs
Publication statusPublished - Apr 2015

Keywords

  • FREE FATTY-ACID
  • TYPE-2 DIABETIC-PATIENTS
  • HUMAN SKELETAL-MUSCLE
  • INSULIN-RESISTANCE
  • NICOTINAMIDE RIBOSIDE
  • SUSTAINED REDUCTION
  • CALORIE RESTRICTION
  • ENERGY-EXPENDITURE
  • OXIDATIVE STRESS
  • GLUCOSE

Cite this

van de Weijer, T. ; Phielix, E. ; Bilet, L. ; Williams, E.G. ; Ropelle, E.R. ; Bierwagen, A. ; Livingstone, R. ; Nowotny, P. ; Sparks, L.M. ; Paglialunga, S.A. ; Szendroedi, J. ; Havekes, B. ; Moullan, N. ; Pirinen, E. ; Hwang, J.H. ; Schrauwen-Hinderling, V.B. ; Hesselink, M.K. ; Auwerx, J. ; Roden, M. ; Schrauwen, P. / Evidence for a Direct Effect of the NAD+ Precursor Acipimox on Muscle Mitochondrial Function in Humans. In: Diabetes. 2015 ; Vol. 64, No. 4. pp. 1193-1201.
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title = "Evidence for a Direct Effect of the NAD+ Precursor Acipimox on Muscle Mitochondrial Function in Humans",
abstract = "Recent preclinical studies showed the potential of nicotinamide adenine dinucleotide : NAD+ : precursors to increase oxidative phosphorylation and improve metabolic health, but human data is lacking. Here, we hypothesized that the nicotinic acid derivative Acipimox, a NAD+ precursor, would directly affect mitochondrial function, independent of reductions in non-esterified fatty acid (NEFA) concentrations. In a multi-center randomized cross-over trial, 21 patients with type 2 diabetes (age 57.7+/-1.1 years, BMI, 33.4+/-0.8 kg/m2) received either placebo or 250 mg Acipimox thrice daily for 2 weeks. Acipimox treatment increased plasma NEFA (759+/-44 vs. 1135+/-97 micromol/L, p<0.01 for placebo vs. Acipimox), due to a previously described rebound effect. As a result, skeletal muscle lipid content increased and insulin sensitivity decreased. Despite the elevated plasma NEFA levels, ex vivo mitochondrial respiration in skeletal muscle increased. Subsequently, we showed that Acipimox treatment resulted in a robust elevation in expression of nuclear-encoded mitochondrial gene-sets and by presence of a mitonuclear protein imbalance, which may indicate activation of the mitochondrial unfolded protein response (UPRmt). Further studies in C2C12 myotubes confirmed a direct effect of Acipimox on NAD+ levels, mitonuclear protein imbalance and mitochondrial oxidative capacity. To the best of our knowledge, this is the first demonstration that NAD+ boosters can also directly impact skeletal muscle mitochondrial function in humans.",
keywords = "FREE FATTY-ACID, TYPE-2 DIABETIC-PATIENTS, HUMAN SKELETAL-MUSCLE, INSULIN-RESISTANCE, NICOTINAMIDE RIBOSIDE, SUSTAINED REDUCTION, CALORIE RESTRICTION, ENERGY-EXPENDITURE, OXIDATIVE STRESS, GLUCOSE",
author = "{van de Weijer}, T. and E. Phielix and L. Bilet and E.G. Williams and E.R. Ropelle and A. Bierwagen and R. Livingstone and P. Nowotny and L.M. Sparks and S.A. Paglialunga and J. Szendroedi and B. Havekes and N. Moullan and E. Pirinen and J.H. Hwang and V.B. Schrauwen-Hinderling and M.K. Hesselink and J. Auwerx and M. Roden and P. Schrauwen",
year = "2015",
month = "4",
doi = "10.2337/db14-0667",
language = "English",
volume = "64",
pages = "1193--1201",
journal = "Diabetes",
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number = "4",

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van de Weijer, T, Phielix, E, Bilet, L, Williams, EG, Ropelle, ER, Bierwagen, A, Livingstone, R, Nowotny, P, Sparks, LM, Paglialunga, SA, Szendroedi, J, Havekes, B, Moullan, N, Pirinen, E, Hwang, JH, Schrauwen-Hinderling, VB, Hesselink, MK, Auwerx, J, Roden, M & Schrauwen, P 2015, 'Evidence for a Direct Effect of the NAD+ Precursor Acipimox on Muscle Mitochondrial Function in Humans', Diabetes, vol. 64, no. 4, pp. 1193-1201. https://doi.org/10.2337/db14-0667

Evidence for a Direct Effect of the NAD+ Precursor Acipimox on Muscle Mitochondrial Function in Humans. / van de Weijer, T.; Phielix, E.; Bilet, L.; Williams, E.G.; Ropelle, E.R.; Bierwagen, A.; Livingstone, R.; Nowotny, P.; Sparks, L.M.; Paglialunga, S.A.; Szendroedi, J.; Havekes, B.; Moullan, N.; Pirinen, E.; Hwang, J.H.; Schrauwen-Hinderling, V.B.; Hesselink, M.K.; Auwerx, J.; Roden, M.; Schrauwen, P.

In: Diabetes, Vol. 64, No. 4, 04.2015, p. 1193-1201.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Evidence for a Direct Effect of the NAD+ Precursor Acipimox on Muscle Mitochondrial Function in Humans

AU - van de Weijer, T.

AU - Phielix, E.

AU - Bilet, L.

AU - Williams, E.G.

AU - Ropelle, E.R.

AU - Bierwagen, A.

AU - Livingstone, R.

AU - Nowotny, P.

AU - Sparks, L.M.

AU - Paglialunga, S.A.

AU - Szendroedi, J.

AU - Havekes, B.

AU - Moullan, N.

AU - Pirinen, E.

AU - Hwang, J.H.

AU - Schrauwen-Hinderling, V.B.

AU - Hesselink, M.K.

AU - Auwerx, J.

AU - Roden, M.

AU - Schrauwen, P.

PY - 2015/4

Y1 - 2015/4

N2 - Recent preclinical studies showed the potential of nicotinamide adenine dinucleotide : NAD+ : precursors to increase oxidative phosphorylation and improve metabolic health, but human data is lacking. Here, we hypothesized that the nicotinic acid derivative Acipimox, a NAD+ precursor, would directly affect mitochondrial function, independent of reductions in non-esterified fatty acid (NEFA) concentrations. In a multi-center randomized cross-over trial, 21 patients with type 2 diabetes (age 57.7+/-1.1 years, BMI, 33.4+/-0.8 kg/m2) received either placebo or 250 mg Acipimox thrice daily for 2 weeks. Acipimox treatment increased plasma NEFA (759+/-44 vs. 1135+/-97 micromol/L, p<0.01 for placebo vs. Acipimox), due to a previously described rebound effect. As a result, skeletal muscle lipid content increased and insulin sensitivity decreased. Despite the elevated plasma NEFA levels, ex vivo mitochondrial respiration in skeletal muscle increased. Subsequently, we showed that Acipimox treatment resulted in a robust elevation in expression of nuclear-encoded mitochondrial gene-sets and by presence of a mitonuclear protein imbalance, which may indicate activation of the mitochondrial unfolded protein response (UPRmt). Further studies in C2C12 myotubes confirmed a direct effect of Acipimox on NAD+ levels, mitonuclear protein imbalance and mitochondrial oxidative capacity. To the best of our knowledge, this is the first demonstration that NAD+ boosters can also directly impact skeletal muscle mitochondrial function in humans.

AB - Recent preclinical studies showed the potential of nicotinamide adenine dinucleotide : NAD+ : precursors to increase oxidative phosphorylation and improve metabolic health, but human data is lacking. Here, we hypothesized that the nicotinic acid derivative Acipimox, a NAD+ precursor, would directly affect mitochondrial function, independent of reductions in non-esterified fatty acid (NEFA) concentrations. In a multi-center randomized cross-over trial, 21 patients with type 2 diabetes (age 57.7+/-1.1 years, BMI, 33.4+/-0.8 kg/m2) received either placebo or 250 mg Acipimox thrice daily for 2 weeks. Acipimox treatment increased plasma NEFA (759+/-44 vs. 1135+/-97 micromol/L, p<0.01 for placebo vs. Acipimox), due to a previously described rebound effect. As a result, skeletal muscle lipid content increased and insulin sensitivity decreased. Despite the elevated plasma NEFA levels, ex vivo mitochondrial respiration in skeletal muscle increased. Subsequently, we showed that Acipimox treatment resulted in a robust elevation in expression of nuclear-encoded mitochondrial gene-sets and by presence of a mitonuclear protein imbalance, which may indicate activation of the mitochondrial unfolded protein response (UPRmt). Further studies in C2C12 myotubes confirmed a direct effect of Acipimox on NAD+ levels, mitonuclear protein imbalance and mitochondrial oxidative capacity. To the best of our knowledge, this is the first demonstration that NAD+ boosters can also directly impact skeletal muscle mitochondrial function in humans.

KW - FREE FATTY-ACID

KW - TYPE-2 DIABETIC-PATIENTS

KW - HUMAN SKELETAL-MUSCLE

KW - INSULIN-RESISTANCE

KW - NICOTINAMIDE RIBOSIDE

KW - SUSTAINED REDUCTION

KW - CALORIE RESTRICTION

KW - ENERGY-EXPENDITURE

KW - OXIDATIVE STRESS

KW - GLUCOSE

U2 - 10.2337/db14-0667

DO - 10.2337/db14-0667

M3 - Article

VL - 64

SP - 1193

EP - 1201

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 4

ER -