Head to head comparison of short term Treatment with the NAD+ Precursor Nicotinamide Mononucleotide(NMN) and 6 weeks of exercise in obese female mice
This study compared the changes associated with NMN or exercise interventions in mice. The 60 mice were separated into 5 groups: chow sedentary, chow exercise, high-fat diet (HFD) sedentary, HFT with NMN, and HFT with exercise. After 6 weeks of diet, the animals in the exercise intervention began 6 weeks of 6 day / week exercise regimen. Mice in the NMN group received 500 mg/kg NMN intra-peritoneally for the last 17 days of the study. Following 6 weeks of their respective diets, the mice in the HFD group were 23% heavier than the chow-fed mice. In the HFD mice, the authors found that both NMN and exercise improved insulin sensitivity, as evidenced by the area under the curve of a glucose vs. time graph following feeding (p < 0.05 for both compared to HFD sedentary). Additionally, the authors found that HFD was associated with lower NAD+ in liver and skeletal muscle tissues and that NMN treatment increased NAD+ levels in both tissues, whereas exercise only significantly increased NAD+ in muscle tissue. In addition, citrate synthase, an enzyme which is associated with mitochondrial activity, was reduced in muscle and liver in mice on the HFD. Exercise resulted in significant increases in citrate synthase activity in skeletal muscle while NMN supplementation did not, and NMN supplementation and exercise both resulted in increased activity in liver tissue[1].
Contents
Article 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.
Implications
This article highlighted not only the pathology associated with high-fat diet (HFD), but also the potential utility of NMN in addressing this pathology. Specifically, this research showed that both exercise and NMN supplementation were effective in addressing some of the changes that resulted from HFD; however, there appeared to be tissue-specific differences in these effects. This is important, because NMN tended to exert more change in the liver, whereas the benefits from exercise were seen primarily in the muscle tissue. This could mean that NMN may be effective in reversing some of the more systemic negative effects of HFD such as fatty liver.
Additional Research to be Conducted
Future work will likely continue to build upon the findings made in this report – that NMN and exercise exert different effects on different tissues. The authors of this study note that their future work may focus on identifying exactly why NMN supplementation seems to affect liver mitochondrial function whereas exercise’s effects on mitochondria seem specific to skeletal muscle.
Institution
Dr. Morris’ lab is located at the University of New South Wales. Her group has published several other papers investigating the potential applications of NMN to improve obesity-related disease as well as male and female reproductive health[2][3][4].
Funding
This research was funded by the National Health and Medical Research Council (NHMRC).
Authors/Researchers
Golam Uddin – Department of Pharmacology, University of New South Wales
Neil Youngson - Department of Pharmacology, University of New South Wales David Sinclair – Department of Genetics, Harvard Medical School Margaret Morris - Department of Pharmacology, University of New South Wales
References
- ↑ Uddin GM, Youngson NA, Sinclair DA, Morris MJ. Head to head comparison of short-term treatment with the NAD+ precursor nicotinamide mononucleotide (NMN) and 6 weeks of exercise in obese female mice. Front Pharmacol. 2016;7(AUG)
- ↑ Uddin GM, Youngson NA, Doyle BM, Sinclair DA, Morris MJ. Nicotinamide mononucleotide (NMN) supplementation ameliorates the impact of maternal obesity in mice: Comparison with exercise. Sci Rep. 2017;7(1)
- ↑ Uddin GM, Youngson NA, Chowdhury SS, Hagan C, Sinclair DA, Morris MJ. Administration of Nicotinamide Mononucleotide (NMN) Reduces Metabolic Impairment in Male Mouse Offspring from Obese Mothers. Cells. 2020;9(4):791.
- ↑ Youngson NA, Mezbah Uddin G, Das A, et al. Impacts of obesity, maternal obesity and nicotinamide mononucleotide supplementation on sperm quality in mice. Reproduction. 2019;158(2):169-179.
