• Acute NMN treatment improved impaired glucose tolerance due to maternal and post-weaning high-fat diet.
  • Short-term NMN treatment reduced liver lipid accumulation in regular and high-fat diet-fed offspring of obese mothers.

Extensive evidence links increased maternal obesity to adverse offspring metabolic and cardiovascular outcomes, with increased risk for obesity and metabolic disease like non-alcoholic fatty liver disease. To treat such metabolic impairments, there has been recent interest in using boosting agents like nicotinamide mononucleotide (NMN) for the vital molecule nicotinamide adenine dinucleotide (NAD+). Previous research shows that, in female offspring of obese mouse mothers, NMN injection improved metabolism and reduced fat accumulation. However, no studies to date have specifically examined the effects of NMN on metabolism in male offspring from obese mouse mothers.

Uddin and colleagues published an article in the journal Cells showing that only three weeks of NMN administration was able to reduce fat mass, liver and plasma levels of a type of fat called triglyceride, and to improve glucose tolerance in mice with severe metabolic impacts due to the combination of maternal obesity and chronic high fat diet consumption. The research team based out of The University of New South Wales in Sydney, Australia, showed that the benefits of NMN appear to have been partly mediated by the modulation of genes with roles in fat transport and metabolism in the liver. “These data support the use of NMN as a potential method to combat the intergenerational consequences of the obesity epidemic,” said the authors.

(Uddin et al. 2020 | Cells) Administration of NMN reduces metabolic impairment in male mouse offspring from obese mothers. Offspring exposed to both maternal obesity pre- and post-gestation and then 30 weeks post-weaning high-fat diet had marked changes in liver metabolic profile. Three weeks of NMN injections significantly reduced these metabolic impairments in extremely obese mice.

Obesity can be passed onto offspring

Parental obesity is considered a key contributor to the risk of being overweight or obese in early life. Also, it has been reported that early life developmental issues strongly associate with the prevalence of obesity and related metabolic disorders later in life. Furthermore, these impacts are known to be exacerbated by post-weaning high-fat diet consumption. While these long-term impacts of maternal obesity and chronic post-weaning high-fat diets for offspring underline the crucial need for intervention, the appropriate intervention for an individual will likely depend on many variables such as gender, age, and severity of disease features.

Treating metabolic disease with NAD+ precursors

Recently, it was shown that long term administration of NMN in drinking water successfully reversed age-associated body weight gain and improved energy metabolism, and insulin sensitivity. Also, research has shown that only 18 days of NMN injection improved glucose tolerance, reduced fat accumulation, and increased gene activity levels responsible for the metabolism of fat in female offspring of obese mothers.

However, no studies to date have examined the effects of NMN in obese male offspring. Investigating both male and female offspring is important due to the differences that have been reported in both human and rodent studies on the scale of changes in growth and adiposity of offspring. After observing improvements in metabolic performance in female offspring, Uddin and colleagues were interested in investigating whether short term NMN administration has any effect on male offspring even after long-term post-weaning exposure to a high-fat diet that caused extreme obesity.

NMN cancels out maternal and post-weaning diet effects

So, the Australian research team examined whether, under these more chronic conditions, short-term NMN (500 mg/kg body weight) administration could exert beneficial effects in male offspring consuming a high-fat diet. In this study, mice exposed to both maternal obesity and chronic post-weaning high fat diet were twice as heavy as mice fed normal diets. The male offspring of obese mothers were significantly heavier than those from lean mothers regardless of their post-weaning diet, indicating their having an obese mother facilitated weight increase.

Also, significant maternal diet effects were observed in the liver, quadriceps muscle, and retroperitoneal fat. Uddin and colleagues found that three weeks of NMN administration was able to reduce fat mass. Also, NMN mitigated high liver and plasma levels of fat compounds called triglycerides that lead to cardiovascular complications in mice with severe metabolic impacts due to the combination of maternal obesity and chronic high fat diet consumption. 

(Uddin et al. 2020 | Cells) Maternal and post-weaning diet effects on triglyceride levels of male offspring are mitigated by NMN. The first letter represents the maternal diet and the second letter post-weaning diet; chow (C) or high-fat diet (H); the third letter represents treatment; control (V) or NMN (N).

The researchers also examined the effects of short term NMN treatment (eight days). The effect of NMN on glucose intolerance, an indicator of prediabetes where the body doesn’t dispose of blood sugars, appeared to vary with the maternal dietary status. In the offspring of obese mothers, the increased glucose intolerance in mice consuming a high-fat diet post-weaning was significantly improved in the group receiving NMN injection. On the other hand, in offspring of obese mothers who consumed chow post-weaning, there was a significant increase in blood glucose concentrations, albeit briefly, in the mice receiving NMN, indicative of glucose intolerance. Overall, it appears that NMN was beneficial in those that were most metabolically compromised.

(Uddin et al. 2020 | Cells) Eight days of NMN treatment ameliorates glucose tolerance defects in male offspring obese mothers at 32 weeks of age. The first letter represents the maternal diet; chow (C, dotted lines) or high-fat diet (H, solid lines). The second letter represents a post-weaning diet; chow (C, open circle) or high-fat diet (H, closed circle). The third letter represents control (V) or NMN (N, squares). Effects of NMN treatment on the glucose tolerance test in offspring from lean (A, B) and obese (C, D) mothers were analyzed at 32 weeks of age.

“Overall, our data clearly highlight the negative effects of maternal and long term post-weaning high-fat diet on male offspring, and point to beneficial metabolic outcomes induced by a short period of NMN administration,” said the authors. “Our data invite further work on the potential for mitochondrial activators as later-life interventions in conditions of maternal obesity and related complications such as diabetes and fatty liver disease.”