·       NMN supplementation increases the activity of metabolism-related genes and diminishes inflammation and scarring-related gene activity in immature mouse fat cells.
·       If translatable to people, NMN may prevent obesity-related diseases during aging by improving gene activity related to metabolism and reduction of inflammation.

As obesity becomes more prevalent globally, so too comes the rising incidence of age-related diseases including type 2 diabetes, elevated blood pressure, and cancer. These obesity-associated ailments go hand in hand with the diminished metabolic health of fat cells involved with these diseases. Understanding how to improve the metabolic health of fat cells could play a major role in preventing age-related diseases linked to obesity.

Mazloum and colleagues from Weill Cornell Medicine-Qatar published a study in Scientific Reports showing that nicotinamide mononucleotide (NMN) treatment increases gene activity linked to enhanced fat cell metabolic function. For the first time, this study shows that treating immature mouse fat cells with NMN elevates gene activity for leptin and sirtuin 1 (SIRT1), proteins that suppress appetite and maintain metabolic health, respectively. Also, NMN treatment diminishes gene activity for proteins that lead to tissue scarring called collagens. These findings from the Qatar-based research team are promising and may translate to using NMN as a therapeutic option to prevent age-related diseases in individuals with obesity.

NMN Boosts Levels of a Critical Molecule for Metabolism Called NAD+

NMN is a precursor to nicotinamide adenine dinucleotide (NAD+) — a crucial molecule for energy production and metabolic health. NAD+ is used by many enzymes to carry out their cell functions, such as the role of sirtuins — the family of proteins that includes SIRT1 — in DNA repair and metabolism maintenance.

Several studies have demonstrated a decline in cellular NAD+ levels in obesity, and strategies that replenished NAD+ by supplementation with precursors like NMN improved metabolic function. But how NAD+ is controlling metabolism and how NMN can enhance has been unclear.

NMN Increases Healthy Metabolism Gene Activity

By using NMN to boost NAD+ levels in immature fat cells, Mazloum and colleagues uncovered pieces of the puzzle for how NMN exerts its metabolism-enhancing effects. Upon confirming that NMN raises NAD+ levels in immature fat cells, which it did by 25% after 10 days of treatment, Mazloum and colleagues measured the activity of genes with known roles in metabolism. .

(Majeed et al., 2021 | Scientific Reports) Treating immature mouse fat cells with NMN substantially raises cellular NAD+ levels. The researchers treated the immature fat cells with 1 mM of NMN for 10 days and found that doing so raised NAD+ levels by about 25%.

First, they looked at the activity of genes with known roles in metabolism. The team found that, in immature fat cells, NMN treatment increased the gene activity of SIRT1 and PGC-1α, which regulates the production of mitochondria — our cells’ power-generating structures.

NMN also increased gene activity for an “appetite-suppressant” hormone molecule called leptin. But this effect was blunted with SIRT1 deletion, indicating that NMN’s leptin gene boosting effects depend on SIRT1’s activity. NMN also decreased gene activity of Col6A3, a protein component of connective tissue called collagen that plays a role in fat tissue scarring and inflammation.

“To our knowledge, stimulation of leptin transcription by ‘NAD+-boosting’ and the dependence of this effect on SIRT1 function has not been previously reported,” explained Mazloum and colleagues.

These findings provide novel evidence that NMN supplementation improves metabolism and reduces connective tissue buildup during fat cell development by enhancing the activation of specific genes related to metabolism in immature mouse fat cells.

(Majeed et al., 2021 | Scientific Reports) Treating immature fat cells (preadipocytes) with NMN increases the gene activity of the NAD+-synthesizing enzyme nicotinamide mononucleotide adenylyltransferase (NMNAT1-3). Treating immature fat cells with NMN increases the gene activity of NMNAT1-3 in a previously unrecognized way (genes colored red). As the fat cells mature to adipocytes, they display increased activity in two genes, one of which is appetite-suppressing leptin. The inflammation and scarring-associated COL6A3 gene shows reduced activity following NMN supplementation, also. By eliminating SIRT1 activity (ShSIRT1 column), NMN’s effects on these genes are blunted, suggesting that NMN’s influence on gene activity comes through boosting SIRT1 function.

NMN-Related Gene Pathways Provide Clues About the Supplement’s Effects on Cells

The new information from the study takes us a step closer to figuring out how exactly increasing NAD+ levels improve metabolism and how doing so may help prevent obesity-related diseases with age. If these results translate to fat cell metabolism in humans, it could provide insight to how NMN may help to prevent age-related diseases in people with obesity.

Also, the finding that NMN stimulates gene activity for the “appetite-suppressant” hormone leptin may give researchers clues on how to treat obesity by manipulating the leptin pathway. Other findings showing that NMN reduces gene activity for the connective tissue and inflammation-associated protein COL6A3 could give insight into obesity-related disease prevention. Future studies can confirm these pathway-related details and apply them to boost our knowledge of metabolism in obesity along with NMN’s effects in fat cells.