Abstract:
:Recent preclinical studies showed the potential of nicotinamide adenine dinucleotide (NAD(+)) precursors to increase oxidative phosphorylation and improve metabolic health, but human data are lacking. We hypothesize that the nicotinic acid derivative acipimox, an NAD(+) precursor, would directly affect mitochondrial function independent of reductions in nonesterified fatty acid (NEFA) concentrations. In a multicenter randomized crossover trial, 21 patients with type 2 diabetes (age 57.7 ± 1.1 years, BMI 33.4 ± 0.8 kg/m(2)) received either placebo or acipimox 250 mg three times daily dosage for 2 weeks. Acipimox treatment increased plasma NEFA levels (759 ± 44 vs. 1,135 ± 97 μmol/L for placebo vs. acipimox, P < 0.01) owing 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 a mitonuclear protein imbalance, which may indicate activation of the mitochondrial unfolded protein response. 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 study is the first to demonstrate that NAD(+) boosters can also directly affect skeletal muscle mitochondrial function in humans.
journal_name
Diabetesjournal_title
Diabetesauthors
van de Weijer T,Phielix E,Bilet L,Williams EG,Ropelle ER,Bierwagen A,Livingstone R,Nowotny P,Sparks LM,Paglialunga S,Szendroedi J,Havekes B,Moullan N,Pirinen E,Hwang JH,Schrauwen-Hinderling VB,Hesselink MK,Auwerx J,Rodoi
10.2337/db14-0667subject
Has Abstractpub_date
2015-04-01 00:00:00pages
1193-201issue
4eissn
0012-1797issn
1939-327Xpii
db14-0667journal_volume
64pub_type
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