Nat. Rev. Endocrinol. doi:10.1038/nrendo.2015.181 Figure 7 Metabolic signalling and NAD+ homeostasis during health and disease Figure 7 | Metabolic signalling and NAD+ homeostasis during health and disease. Increased intracellular NAD+ activates sirtuins, which improves mitochondrial homeostasis, energy expenditure, antioxidant defences and lifespan. Increased energy availability lowers NAD+ levels, whereas caloric restriction, fasting and exercise can reverse this process and stimulate NAD+ accumulation. NAD+ levels are maintained by the circadian regulation of NAMPT. By administration of NAD+ precursors, such as NR or NMN, NAD+ levels can be enhanced via the NAD+ salvage pathway in mice. Inhibiting NAD+ consumers such as such as PARP and CD38 can also enhance NAD+ levels. Fasting and ketogenic diets that increase β-hydroxybutyrate also improve mitochondrial function, potentially through histone deactylase-driven sirtuin regulation. By contrast, high-fat diets increase the ratio of acetyl-CoA to CoA, releasing CoA inhibition of KAT activity and reducing mitochondrial function. An energy deficit increases MCD activity converting malonyl-CoA to acetyl-CoA, while ACC activity is heightened with energy excess increasing the reverse reaction and providing malonyl-CoA for lipid synthesis. Factors that contribute to an increased potential for oxidative phosphorylation activity are shown in pink and inhibitory factors are seen in blue. Pathways that need further validation (dashed lines). Abbreviations: β-OHB, β-hydroxybutyrate; ACC, acetyl-CoA carboxylase; CD38i, CD38 inhibitor; CoA, coenzyme A; MCD, malonyl-CoA decarboxylase; NAD+, nicotinamide adenine dinucleotide; NMN, NAM mononucleotide; NAMPT, nicontinamide phosphoribosyltransferase; NR, nicotinamide riboside; PARP, poly ADP-ribose (PAR) polymerase; PARPi, PARP inhibitor; TCA cycle, tricarboxylic acid cycle. Menzies, K. J. et al. (2015) Protein acetylation in metabolism—metabolites and cofactors Nat. Rev. Endocrinol. doi:10.1038/nrendo.2015.181