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 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.

• Authors: Tineke van de Weijer, Esther Phielix, Lena Bilet, Evan G Williams, Eduardo R Ropelle, Alessandra Bierwagen, Roshan Livingstone, Peter Nowotny, Lauren M Sparks, Sabina Paglialunga, Julia Szendroedi, Bas Havekes, Norman Moullan, Eija Pirinen, Jong-Hee Hwang, Vera B Schrauwen-Hinderling, Matthijs K C Hesselink, Johan Auwerx, Michael Roden, Patrick Schrauwen
• Journal: Diabetes (Diabetes) Vol. 64 Issue 4 Pg. 1193-201 (Apr 2015) ISSN: 1939-327X [Electronic] United States
• PMID: 25352640 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Chemical References

• Hypolipidemic Agents
• Pyrazines
• acipimox

Topics

• Cross-Over Studies
• Diabetes Mellitus, Type 2 (metabolism)
• Female
• Humans
• Hypolipidemic Agents (pharmacology)
• Insulin Resistance (physiology)
• Male
• Middle Aged
• Mitochondria, Muscle (drug effects, metabolism)
• Muscle, Skeletal (drug effects, metabolism)
• Pyrazines (pharmacology)