Oral Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2016

Mitochondrial NAD+ Biosynthesis Regulates Hepatic Energy Metabolism (#169)

Nicholas L Bentley 1 , Corrine E Fiveash 1 , Brenna Osborne 1 , Patsie Polly 1 , Magdalene K Montgomery 1 2 , Nigel Turner 1
  1. UNSW Australia, Kensington, NSW, Australia
  2. Monash University, Melbourne, Victoria

NAD+ (nicotinamide adenine dinucleotide) is a coenzyme derived from nicotinic acid that plays a key role in the regulation of redox biology and cellular metabolism, and also serves as an essential substrate for the class of NAD+ consuming enzymes called sirtuins. Pharmacologically elevating NAD+ levels and sirtuin activity positively regulates numerous metabolic and physiological parameters in rodents, and reduces the deleterious effects of high fat feeding and age-related deterioration of health. Here, we investigated the significance of specifically elevating mitochondrial NAD production in the liver of transgenic (TG) mice overexpressing nicotinamide mononucleotide adenylyltransferase 3 (NMNAT3), a mitochondrially located enzyme that produces NAD. We found that mice overexpressing NMNAT3 displayed a 12-fold increase in the capacity for NAD production in isolated liver mitochondria when compared to WT mice (p<0.01), which resulted in a ~60% increase in intramitochondrial NAD+ (p<0.01). Hepatocytes isolated from NMNAT3 TG mice displayed ~40% reduced levels of ROS production (p<0.001) when cultured in fatty acid media, as well as significant reductions in triglyceride accumulation (p<0.05) when compared to WT mice. Expanding our studies in vivo we found that TG mice display reductions in both epididymal and inguinal adipose deposits when maintained on both a chow and high fat diet for 14 weeks, as well as having improved glucose clearance during an intraperitoneal glucose tolerance test (2g/kg, <0.05) and elevated whole body energy expenditure (~13% increase in VO2, p<0.05). These results suggest that elevating NAD biosynthesis in mitochondria is sufficient to improve metabolic health in the face of elevated lipid supply.