Head to Head Comparison of Short-Term Treatment with the NAD+ Precursor Nicotinamide Mononucleotide (NMN) and 6 Weeks of Exercise in Obese Female Mice

Abstract

Obesity is well known to be a major cause of several chronic metabolic diseases, which can be partially counteracted by exercise. This is due, in part, to an upregulation of mitochondrial activity through increased nicotinamide adenine dinucleotide (NAD+). Recent studies have shown that NAD+ levels can be increased by using the NAD+ precursor, nicotinamide mononucleotide (NMN) leading to the suggestion that NMN could be a useful intervention in diet related metabolic disorders. In this study we compared the metabolic, and especially mitochondrial-associated, effects of exercise and NMN in ameliorating the consequences of high-fat diet (HFD) induced obesity in mice. Sixty female 5 week old C57BL6/J mice were allocated across five groups: Chow sedentary: CS; Chow exercise: CEX; HFD sedentary: HS; HFD NMN: HNMN; HFD exercise: HEX (12/group). After 6 weeks of diet, exercise groups underwent treadmill exercise (15 m/min for 45 min), 6 days per week for 6 weeks. NMN or vehicle (500 mg/kg body weight) was injected (i.p.) daily for the last 17 days. No significant alteration in body weight was observed in response to exercise or NMN. The HFD significantly altered adiposity, glucose tolerance, plasma insulin, NADH levels and citrate synthase activity in muscle and liver. HEX and HNMN groups both showed significantly improved glucose tolerance compared to the HS group. NAD+ levels were increased significantly both in muscle and liver by NMN whereas exercise increased NAD+ only in muscle. Both NMN and exercise ameliorated the HFD-induced reduction in liver citrate synthase activity. However, exercise, but not NMN, ameliorated citrate synthase activity in muscle. Overall these data suggest that while exercise and NMN-supplementation can induce similar reversal of the glucose intolerance induced by obesity, they are associated with tissue-specific effects and differential alterations to mitochondrial function in muscle and liver.

Nicotinamide riboside kinases display redundancy in mediating nicotinamide mononucleotide and nicotinamide riboside metabolism in skeletal muscle cells

“…Mounting evidence supports the notion that enhancing tissue NAD + availability has beneficial effects on metabolic health in the context of metabolic disease and physiological decline [22], [23], [47], [48], [49]. The leading method to accomplish NAD + augmentation is through dietary supplementation with NR and NMN.…”

NAD replenishment with nicotinamide mononucleotide protects blood–brain barrier integrity and attenuates delayed tissue plasminogen activator‐induced haemorrhagic transformation after cerebral ischaemia

“…The mice that died before the 24 h time point were included only in the experiment of post 24 h mortality rate; these mice were not included in the other analyses. In previous studies, NMN was administered to mice at doses of~1 00 mg·kg À1 (Park et al, 2016) to 500 mg·kg À1 (Long et al, 2015;Uddin et al, 2016). However, most studies applied the dose of 300 mg·kg À1 Yoshino et al, 2011;Zhang et al, 2011;Stein and Imai, 2014;Zhao et al, 2015b;de Picciotto et al, 2016;Wei et al, 2017); therefore, we used 300 mg·kg À1 in this study.…”

“…Depletion of intracellular NAD is a common pathway in many pathophysiological events, including ageing, metabolic disorders and cerebral ischaemia (Yang et al, 2002;Massudi et al, 2012;Zhang et al, 2016;Zhou et al, 2016;Wang et al, 2016a). The administration of nicotinamide mononucleotide (NMN) or nicotinamide riboside, two NAD precursors, as a supplement is able to enhance NAD levels and is used to treat high-fat-induced obesity/fatty liver (Yoshino et al, 2011;Uddin et al, 2016;Zhou et al, 2016). We and other groups have demonstrated that NMN protects against post-ischaemic NAD degradation and decreases brain damage after cerebral ischaemia Zhao et al, 2014;Park et al, 2016).…”

Influence of anaerobic and aerobic exercise on age-related pathways in skeletal muscle

“…Age-associated arterial dysfunction can be rescued and returned to young mice levels after supplementation with nicotinamide mononucleotide (NMN), a key NAD + intermediate capable to increase SIRT1 activity (de Picciotto et al, 2016). Intraperitoneal administration of NMN significantly increases NAD + levels both in liver and muscle of diet-induced obese mice, but leads to improvement in glucose tolerance and the recovery in citrate synthase activity only in the liver (Uddin et al, 2016). Interestingly, exercise allows the restoration of citrate synthase activity in muscle of obese mice on a high-fat diet indicating that NMN exerts tissue-specific effect in vivo (Uddin et al, 2016).…”

“…Intraperitoneal administration of NMN significantly increases NAD + levels both in liver and muscle of diet-induced obese mice, but leads to improvement in glucose tolerance and the recovery in citrate synthase activity only in the liver (Uddin et al, 2016). Interestingly, exercise allows the restoration of citrate synthase activity in muscle of obese mice on a high-fat diet indicating that NMN exerts tissue-specific effect in vivo (Uddin et al, 2016). …”