Genetic and environmental impact on NAD⁺ levels

Abstract

The prevalence of overweight and obesity increases worldwide due to a progressively sedentary lifestyle and the intake of high-fat energy dense diets. Moreover, both syndromes are linked to the development of metabolic disorders such as diabetes type II. The NAD+-consuming family of sirtuins is able to modulate metabolic function. Hence, altering NAD+ metabolism to modulate sirtuins could be an interesting way to enhance mitochondrial function and as a consequence, to burn more energy. The goal of this thesis is to map the quantitative trait loci (QTL) and underlying quantitative trait genes (QTGs) responsible for the regulation of the NAD+ levels in the liver. The qualitative and quantitative method to measure NAD+ is validated in vitro and in vivo. NAD+ is extracted from the liver of the BXD mouse genetic reference population (GRP) on chow (CD) and high fat diet (HFD) using an acidic and alkaline extraction method. The levels of NAD+ are then analyzed on a LC-MS/MS. QTL mapping is performed with GeneNetwork and R. Since no correlation between NAD+ levels in both diets is observed, it is concluded there is no strong genetic effect on the NAD+ regulation. Thus, suggestive QTLs are located on 2 loci in BXD on CD and on 3 loci in BXD on HFD. 229 underlying QTGs are eligible for NAD+ regulation. Future network and correlation analysis would allow to identify new networks modulating NAD+ levels. Eventually this opens perspectives to develop drugs against obesity and metabolic dysfunction that target gene(s) under the QTL.