Nicotinamide mononucleotide (NMN) alleviates fat tissue inflammation and scarring mediated by low tissue oxygen (hypoxia) – similar to obesity conditions – in mice.
Low-grade inflammation driving metabolic conditions like type 2 diabetes and cardiovascular diseases is a key symptom of obesity. This state of inflammation triggers fat tissue fibrosis that volumetrically expands more than normally-functioning fat tissue, leading to oxygen deprivation (hypoxia) from lack of blood flow.
Hypoxia drives further inflammation and fat tissue fibrosis, creating a snowball effect where defective fat tissue perpetuates more damaged and harmful fat tissue. Finding a way to counter this spread of fat tissue damage has become paramount in researchers’ quest to mitigate the obesity epidemic.
Published in Frontiers in Endocrinology, Liu and colleagues from Central South University in China show that NMN injections counter fibrosis in mice with hypoxia-induced fat tissue fibrosis. The researchers show that NMN reduces levels of inflammatory proteins and increases the abundance of pro-insulin sensitivity and anti-inflammatory protein adiponectin. They go on to show that hypoxia increases levels of a protein that initiates fat tissue inflammation and fibrosis – HIF-1ɑ – but that NMN attenuates its abundance.
Findings from the study suggest NMN can ward off the snowball effect where fibrotic fat tissue begets more dysfunctional fat tissue in obesity.
NMN Attenuates Fat Tissue Fibrosis by Reducing HIF-1ɑ Protein Levels
To induce the dysfunctional inflammatory and fibrotic state of fat tissue, Liu and colleagues placed mice in a chamber with low oxygen – hypoxia – for four weeks. They found that hypoxia increased fibrosis about four-fold as measured by the quantity of scar tissue proteins, namely collagen.
NMN treatments more than cut in half the hypoxia-driven fibrosis in fat tissue, suggesting that NMN may provide a means to treat fat tissue fibrosis and dysfunction.
(Wu et al., 2023 | Frontiers in Endocrinology) NMN alleviates fat tissue fibrosis under hypoxic conditions. Fat tissue accumulates fibrous collagen proteins (blue coloration with arrows pointing) that makes up scar tissue and leads to fibrosis under hypoxia (hypoxia column) compared to healthy mice (Control column).
NMN reduces collagen accumulation under hypoxia (Hypoxia+NMN column). Red coloration= cytoplasm within cells.
Since inflammation is one of the factors contributing to fibrosis, the China-based research team tested whether NMN reduces hypoxia-induced fibrosis by lowering inflammatory proteins and increasing anti-inflammatory proteins. Along those lines, they measured levels of the inflammatory molecules TGF-𝛃 and IL-6, along with the pro-insulin sensitivity and anti-inflammatory protein adiponectin.
As expected hypoxia more than doubled levels of the two inflammatory proteins and more than cut in half adiponectin. However, NMN substantially reduced the hypoxia-induced inflammatory protein elevations and significantly increased adiponectin levels after hypoxia.
These results suggest that NMN attenuates hypoxia-driven fibrosis by reducing inflammatory proteins and increasing adiponectin.
(Wu et al., 2023 | Frontiers in Endocrinology) NMN attenuates inflammatory protein buildup under hypoxia in mouse fat tissue. The inflammatory proteins TGF-𝛃 and IL-6 (three bars on the left and three bars in the middle, respectively) more than double under hypoxia in fat tissue (yellow bars) compared to healthy mice (red bars), but NMN reduces their accumulation (blue bars). The anti-inflammatory and pro-insulin sensitivity protein adiponectin (APN; three bars on the right) shows reduced levels with hypoxia (yellow bar) compared to healthy mice (red bar), but NMN raises its levels toward that of healthy mice (blue bar).
Since the protein HIF-1ɑ initiates and drives hypoxia-induced fat tissue fibrosis, Liu and colleagues measured the protein’s levels with hypoxia. Hypoxia more than doubled HIF-1ɑ levels, but NMN treatments countered the elevated HIF-1ɑ proteins. These findings suggest that NMN reduces HIF-1ɑ levels under hypoxic conditions to reduce inflammation and fibrosis.
“Our study showed that NMN inhibited HIF-1ɑ activation-induced adipose tissue fibrosis and inflammation,” said Liu and colleagues.
Potential New Way to Treat Obesity
With 41.9% of the US population being obese, new treatment strategies to counter fat tissue inflammation, fibrosis, and its subsequent dysfunctional proliferation are paramount. Previous research has shown that NMN counters kidney, liver, and cardiac fibrosis, yet this is the first study to suggest that it can attenuate fat tissue fibrosis.
With recent research from Harvard showing that NMN helps with weight loss, this study illustrates one of the ways that NMN could confer its anti-obesity effects. The study suggests that by inhibiting HIF-1ɑ protein buildup, NMN can thwart fat tissue inflammation and fibrosis, thus inhibiting the perpetual accumulation of dysfunctional fat tissue.
Model and Dosage
Model: C57/B6 mice
Dosage: 500 mg/kg injected intraperitoneally every three days up to five days before hypoxia and then once after hypoxia
Adiponectin, Fat, Hypoxia, Inflammation, Nicotinamide Mononucleotide, Obesity, NMN
Wu K, Li B, Ma Y, Tu T, Lin Q, Zhu J, Zhou Y, Liu N, Liu Q. Nicotinamide mononucleotide attenuates HIF-1α activation and fibrosis in hypoxic adipose tissue via NAD+/SIRT1 axis. Front Endocrinol (Lausanne). 2023 Jan 26;14:1099134. doi: 10.3389/fendo.2023.1099134. PMID: 36777361; PMCID: PMC9909340.