## 3 Nicotinamide Riboside as a Tool to Mitigate Metabolic Disorders  
### Nicotinamide Riboside and Obesity  
Among NAD\({}^{+}\) precursors, NR is often suggested as a dietary supplement to enhance oxidative metabolism and protect against HFD-induced obesity and deficient MT functionality for age-related diseases [25; 140]. In aging mice, NAD\({}^{+}\) supplementation via NR rejuvenated intestinal stem cells (ISCs) improved the repairing capacity of gut damages by increasing the activity of SIRT1 and mammalian target of rapamycin complex 1 (mTORC1) [141]. In experimental models of mildly obese male mice (C57 BL/6N, C57 BL/6J), NRS for eight weeks increased MT respiration. However, it had minimal impact on energy metabolism, without influencing body weight, internal organs weight, glucose metabolism, liver lipids amount, and metabolic adaptability [142]. NR- and NMN-conditioned microbiota reduced HFD-induced weight gain in C57 BL/6J male mice by increasing their energy consumption. Here, butyrate-producing _Firmicutes_ were enriched by FMT from NR-supplemented donors to HFD-fed naive mice [143; 144]. Alterations in intestinal brush border membrane functionality and bacterial populations following intra-amniotic administration (to _Gallus gallus_) were reported for 30 mg/mL doses of NR and its derivatives, water-soluble NR tributyrate chloride and oil-soluble NR trioleate chloride. _Bifidobacterium_, _Clostidium_, _Lactobacillus_, and _Escherichia coli_ populations were significantly increased by NR treatment [145]. Further, oral supplementation of NR for 12 weeks alters gut microbial composition (_Erysipelotrichaceae_, _Lactospiraceae_ and _Ruminococcaceae_ families) in HFD-fed rats and mice, but not in humans [146]. NRS exerts an anti-obesity effect and prevents inflammation and LF in white adipose tissue (WAT) of 8-week-old (young) and 16-week-old (old) female C57 BL/6J DIO mice fed an HFD/high-sucrose diet/high-cholesterol diet or HFD combined with 400 mg/kg/day NR for 20 weeks. Weight and size of gonadal WAT (gWAT) adipocytes of old mice females were decreased by NRS [147]. Similar results were seen in recent research concerning NR and CR effects on gut microbiota and liver inflammatory and morphological markers in CAF DIO in adult male Wistar rats [148]. The effect of NR on lipid metabolism and gut microflora-bile acid axis was studied in alcohol-exposed mice. NRS increased the NAD\({}^{+}\)/NADH ratio, deoxycholic acid and hyocholic acid levels, and decreased the activation of the protein phosphatase 1 (PP1) signaling pathway, phenodeoxycholic acid, TG and total bile acid levels, and lipid accumulation [149]. Oral NRS also appeared to confer metabolic benefits in obese mice. Thus, NR induces a thermogenic response in the BAT of lean mice. Over five weeks, male C57 BL/6J mice were supplemented with NR (400 mg/kg/day), giving a reduction in abdominal visceral fat depots and an increase in body temperature [150; 151]. Also, compared with CONs, NRS conferred marginal metabolic benefits, augmenting MT functionality in C57 BL/6 NJ obese mice without remodeling the skeletal muscle acetyl-proteome [152]. NRS provided daily to suckling male mice improved lipid and energy metabolism in skeletal muscle and liver in adulthood, correlated with an upregulation of SIRT1 and AMP-dependent protein kinase signaling pathways [153]. In obese rats under CR, NRS (400 mg/kg for four weeks) neutralized hypothalamic inflammation by reverting high levels of TNF-\(\alpha\) and increases weight loss without altering skeletal muscle mass [154]. Further, high doses (9 g/kg diet) of NRS for 18 weeks induced glucose intolerance and WAT dysfunction in male C57 BL/6 JRcHsd mice fed a mildly obesogenic diet (MOD) containing low but adequate tryptophan [155; 156; 157]. In an HFD mouse model, a reduction in obesity and insulin resistance was seen by dual targeting of visceral adipose tissue (VAT) and BAT using a novel combination of metabolic cofactors (NR, \(N\)-acetylcysteine, betaine, L-carnitine) orally administered for four weeks [158].