Adipose tissue NAD+-homeostasis, sirtuins and poly(ADP-ribose) polymerases -important players in mitochondrial metabolism and metabolic health

Abstract

Obesity, a chronic state of energy overload, is characterized by adipose tissue dysfunction that is considered to be the major driver for obesity associated metabolic complications. The reasons for adipose tissue dysfunction are incompletely understood, but one potential contributing factor is adipose tissue mitochondrial dysfunction. Derangements of adipose tissue mitochondrial biogenesis and pathways associate with obesity and metabolic diseases. Mitochondria are central organelles in energy metabolism through their role in energy derivation through catabolic oxidative reactions. The mitochondrial processes are dependent on the proper NAD⁺/NADH redox balance and NAD⁺ is essential for reactions catalyzed by the key regulators of mitochondrial metabolism, sirtuins (SIRTs) and poly(ADP-ribose) polymerases (PARPs). Notably, obesity is associated with disturbed adipose tissue NAD⁺ homeostasis and the balance of SIRT and PARP activities. In this review we aim to summarize existing literature on the maintenance of intracellular NAD⁺ pools and the function of SIRTs and PARPs in adipose tissue during normal and obese conditions, with the purpose of comprehending their potential role in mitochondrial derangements and obesity associated metabolic complications. Understanding the molecular mechanisms that are the root cause of the adipose tissue mitochondrial derangements is crucial for developing new effective strategies to reverse obesity associated metabolic complications.

Keywords: Adipose tissue; Mitochondria; NAD(+); Obesity; Poly(ADP-ribose) polymerases; Sirtuins.

Graphical abstract

Fig. 1

Adipose tissue metabolic and mitochondrial pathways in white (A) and brown (B) adipose tissue. Pyruvate and fatty-acyl-carnitines derived from glycolysis and break-down of fatty acids, respectively, enter the mitochondria where they are further catabolized to acetyl-CoA by the pyruvate dehydrogenase complex and beta-oxidation. The acetyl-CoA enters the TCA cycle and the high-energy electrons derived from the TCA cycle are used to power ATP production through oxidative phosphorylation (OXPHOS). Citrate derived from the TCA cycle is used a precursor for lipogenesis. In white adipose tissue, acetyl-CoA and succinyl-CoA derived from branched chain amino acid (BCAA) catabolism also enter the TCA cycle (A). In brown adipose tissue, the uncoupling proteins (UCPs) induce thermogenesis by uncoupling mitochondrial respiration from ATP production (B). Pathways downregulated by obesity are highlighted in blue. CS; citrate synthase, FA; fatty acid, FOXO1; forkhead box O1, GAPDH; glyceraldehyde-3-phosphate dehydrogenase, mtDNA;mitochondrial DNA, PARP; poly(ADP-ribose) polymerases, PGC-1α; peroxisome proliferator-activated receptor gamma coactivator 1-alpha, PPARγ; peroxisome proliferator-activated receptor gamma, PRDM16; PR domain containing 16, SDH; succinate dehydrogenase, SIRT; sirtuin, TCA; tricarboxylic acid, TF; transcription factor and TG; triglycerides.

Fig. 2

Cellular NAD⁺ biosynthesis and consumption processes. (A) NAD⁺ can be synthesized de novo from the amino acid tryptophan and through the salvage pathway from nicotinamide (NAM) or nicotinamide riboside (NR) or niacin (NA). (B) The competition of SIRTs and PARPs for the same intracellular NAD⁺ pool in the cell. In addition, effect of physiological stimuli on cellular NAD⁺ biosynthesis via nicotinamide phosphoribosyltransferase (NAMPT) and the activities of sirtuins (SIRTs) and poly(ADP-ribose) polymerases (PARPs). AMPK; AMP-activated protein kinase, NRK; nicotinamide riboside kinase, NMNAT; nicotinamide mononucleotide adenylyltransferase, NAPRT; niacin phosphoribosyltransferase and ROS; reactive oxygen species.

Fig. 3

Adipose tissue pathways regulated by sirtuins (SIRTs) and poly(ADP-ribose) polymerases (PARPs) based on current literature in mouse models, adipocyte cell lines and human studies. The effect of obesity on white and brown adipose tissue NAD⁺ levels and expression levels of SIRTs, PARPs and NAD⁺ biosynthesis gene nicotinamide phosphoribosyltransferase (NAMPT) are also shown in separate boxes next to both tissues. Arrows indicate increased (↑), decreased (↓) or unchanged (−) pathway activity/gene expression level. OXPHOS; oxidative phosphorylation.

Fig. S1

Supplementary Fig 1. Relative gene expression level poly(ADP-ribose) polymerases in human subcutaneous WAT. Gene expression values are presented as means with standard deviation from normalized and log2 transformed values from Affymetrix U133 Plus 2.0 chips (arbitrary units) from the lean twins of BMI discordant monozygotic twins (, see original publication for technical details). Expression of PARP4, PARP10, PARP11 or PARP15 was not detected in this study material.