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

• DOI: 10.2337/db14-0667
• Publication Date: 2014-10-29T06:33:21Z
• 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...; Matthijs K.C. Hes...; Johan Auwerx; Michael Roden; Patrick Schrauwen
• Keywords: Male; 0301 basic medicine; TYPE-2 DIABETIC-PATIENTS; GLUCOSE; 03 medical and health sciences; CALORIE RESTRICTION; Humans; OXIDATIVE STRESS; Muscle, Skeletal; Hypolipidemic Agents/pharmacology; Hypolipidemic Agents; INSULIN-RESISTANCE; Cross-Over Studies; ENERGY-EXPENDITURE; FREE FATTY-ACID; Mitochondria, Muscle/drug effects/metabolism; HUMAN SKELETAL-MUSCLE; Middle Aged; Diabetes Mellitus, Type 2/metabolism; Mitochondria, Muscle; 3. Good health; NICOTINAMIDE RIBOSIDE; Metabolism; Diabetes Mellitus, Type 2; Pyrazines; Pyrazines/pharmacology; SUSTAINED REDUCTION; Female; : Genetics & genetic processes [F10] [Life sciences]; Insulin Resistance; : Génétique & processus génétiques [F10] [Sciences du vivant]; Insulin Resistance/physiology; Muscle, Skeletal/drug effects/metabolism

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/m2) 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.