Function of NAD metabolism in white adipose tissue: lessons from mouse models

Figures & data

Figure 1. Main pathways of NAD+ synthesis and consumption in mammals. NAD+ is either synthesized from tryptophan (de novo biosynthesis) or from NMN by NMNAT. NMN can be provided by NR and NAM. The synthesized NAD+ is broken down by NAD+-dependent enzymes such as SIRT1, PARP1, and CD38, and therefore the recycled NAM can be re-synthesized to NAD+ via the NAD+ salvage pathway. NAD±consuming enzymes have several functions. For example, SIRT1 controls circadian rhythm, whereas PARP1 and CD38 regulate DNA repair and mitochondrial function, respectively. Trp, tryptophan; NAD+, a reduced form of nicotinamide adenine dinucleotide; NMNAT, nicotinamide mononucleotide adenylyltransferase; NMN, nicotinamide mononucleotide; NR, nicotinamide riboside; NRK, nicotinamide riboside kinase; NAMPT, nicotinamide phosphoribosyltransferase; NAM, nicotinamide; SIRT1, sirtuin 1; PARP1, poly (ADP-ribose) polymerase 1; CD38, cluster of differentiation 38.

Figure 2. Effects of boosting NAD+ through the NAD+ salvage pathway by SIRT1 in the liver, skeletal muscle, and white adipose tissue. NMN is synthesized from NAM and NR by NAMPT and NRK, respectively. The synthesized NAD+ from NMN is used as a SIRT1 substrate, which leads to the recycling of NAD+ via the salvage pathway. In this process, NAD+ can exert different effects depending on the tissue. NAMPT, nicotinamide phosphoribosyltransferase; NAM, nicotinamide; NMN, nicotinamide mononucleotide; NR, nicotinamide riboside; NRK, nicotinamide riboside kinase; NMNAT, nicotinamide mononucleotide adenylyltransferase; NAD+, reduced form of nicotinamide adenine dinucleotide; SIRT1, sirtuin 1.

Table 1. Effects of NAD+ precursors in white adipose tissue¹.

Supplementation	Sex	Age	Systemic results	Results in WAT	Ref
12 months NMN (300 mg/kg) fed normal diet	♂	5-month-old	• Suppressed age-associated weight gain • Maintained food and water consumption level • Improved insulin sensitivity	• Decreased tendency of fat mass • Down-regulated biological pathways associated with immune function and inflammation in WAT	[15]
3 weeks NAM (37.5 mg/g) fed high fat diet (60 kcal% fat)		4-week-old	• Reduced body weight	• Reduced fat accumulation • Enhanced mitochondrial biogenesis and functions in WAT • Increased glucose-derived glutathione biosynthesis	[48]
20 weeks NR (400 mg/kg) Fed high fat/sucrose/cholesterol diet (34 kcal% fat)	♀	8 or 16-week-old	8-week-old (young mice) • Unaltered body weight • Unaltered insulin sensitivity 16-week-old (old mice) • Reduced body weight • Increased metabolic rate, energy expenditure, and physical activity	8-week-old (young mice) No result 16-week-old (old mice) • Reduced fat mass • Improved insulin sensitivity and glucose tolerance • Reduced fibrosis and inflammation in WAT	[47]

¹C57BL/6N wild type mice were used as models in all references.

Table 2. Evidence of NAMPT function based on NAMPT genetically modified mouse models.

Model	Target tissue	Target location	Sex	Age (months)	Systemic results	Results in tissues	Ref
Nampt floxed & Ubc-Cre mice	Ubiquitous	Exon 2	-	-	• Reduced body weight (20% loss) • Abnormal serum lipid profile • Delayed metabolic and biosynthetic processes in the liver	• Depleted fat tissue	[49]
Nampt^tm1Oleo/ImaiJ & Adiponectin-Cre mice	Fat	Exon 5–6	♀	2–6	• Unchanged body weight • Decreased plasma eNAMPT levels in both fed and fasted condition • Decreased NAD+ levels in the hypothalamus • Decreased physical activity during dark periods	• Unchanged fat mass	[51]
				2–9	• Unchanged body weight • Multiple organ insulin resistance	• Unchanged fat mass • Increased inflammation and dysfunction in WAT but not systemic inflammation • Decreased expression of obesity-linked target genes in WAT	[20]
			-	-	• Decreased rectal temperature during cold exposure • Decreased oxygen consumption	• Impaired adrenergic-mediated lipolytic activity in WAT	[21]
			-	3~	• Insulin resistance • Unaltered energy expenditure and food intake • Impaired whole-body metabolic flexibility such as RQ value and glucose/fat oxidation	• Upregulation of genes associated with inflammation and oxidative stress in WAT • Downregulation of genes associated with lipolysis and mitochondrial oxidative metabolism in WAT	[22]
Nampt^tm1Oleo/ImaiJ & Myosin light-chain 1f (Mlc1f)-Cre mice	Muscle		♂/♀	3–7	• Increased body weight	• Decreased muscle mass • Myonecrosis and progressive loss of muscle function • Stimulation of pathways related to muscle injury, inflammation, and immune response	[38]
Nampt^tm1Jtree & Adiponectin-Cre mice	Fat	Exon 3	♂	5–9	• Resistant to HFD-induced obesity • Decreased food intake • Improved glucose tolerance	• Reduced fat mass • Decreased adipocyte marker gene expression in WAT • Massive fibrosis in WAT	[23]
			♂	-	• Unchanged food intake • Unchanged physical activity	• Disrupted circadian transcriptome in WAT and BAT • Abolished biorhythms of energy metabolism in BAT • Increased cold tolerance without rhythmicity changes in BAT	[52]
Nampt floxed & Albumin-Cre mice	Liver		♀	2–6	• Unchanged body weight • Unchanged insulin sensitivity and glucose tolerance	• Unchanged liver weight • Unaltered mitochondrial respiratory function in liver	[50]

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Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article [and/or] its supplementary materials.