After every hearty meal, there's often a sense of guilt. So people try various methods like dieting and taking enzymes, hoping to boost their metabolism and make accumulated fat "leave on its own". Can weight loss and delicious food really not coexist?
Recently, a latest study by a Japanese research team found that with the anti-aging drug NMN for just 8 weeks, weight can be easily reduced even with a high-fat diet[1]. How does this magical substance enable "losing weight while eating"?
PART 1 Gained weight? NMN treatment reduces weight in 8 weeks
Researchers induced obesity in mice with a high-fat diet, then added NMN to the high-fat diet for treatment, while setting up normal diet (ND) and 单纯 high-fat diet (HFD) groups as controls.
After 8 weeks of treatment, obese mice taking NMN showed a significant decrease in weight even though they continued on the high-fat diet. Their subcutaneous white adipose tissue (sWAT) was significantly reduced, but the amount of epididymal white adipose tissue (eWAT) showed no obvious change.
Figure note: Mice with obesity induced by a high-fat diet showed significant weight loss and reduced fat mass after 8 weeks of the experiment.
Epididymal fat belongs to visceral fat, which is different from subcutaneous fat. In the early stage of obesity, visceral fat expands rapidly by increasing the volume of fat cells and promoting lipid neogenesis, while the increase in subcutaneous fat is mainly due to the enlargement of fat cell volume[2].
Researchers measured changes in the size of mouse fat cells and found that the volume of mouse fat cells was also significantly reduced after NMN treatment.
Figure note: After taking NMN, the volume of mouse fat cells was significantly smaller than that in the high-fat diet group.
Weight decreased, fat mass reduced, and fat cell volume shrank—how does NMN achieve this?
PART 2 Fat "disappearing trick": NMN upregulates lipolytic enzymes to accelerate fat breakdown
Fat mass is mainly determined by the size of fat cells, which is regulated by both the rate of fat synthesis and fat breakdown.
The mouse experiment also found that NMN treatment improved adipocyte hypertrophy and significantly reduced the volume of mouse fat cells.
The next experiment was to explore whether NMN reduces weight by accelerating fat breakdown, slowing down fat synthesis, or both?
Researchers used NMN to treat 3T3-L1 adipocytes, the most commonly used in vitro model in adipocyte biology research.
Results showed that treating with 0.5mM NMN for 4 days significantly reduced fat accumulation in mouse adipocytes without affecting cell viability.
Figure note: After 4 days of treatment with 0.5mM NMN, mouse fat accumulation decreased without affecting cell viability.
Glycerol is one of the products of fat catabolism. Researchers measured the glycerol concentration in the culture medium of 3T3-L1 adipocytes after NMN treatment and found that its content increased, indicating that fat breakdown was accelerated after NMN treatment.
Figure note: Glycerol content increased after NMN treatment.
To further determine whether fat synthesis is affected during NMN treatment, researchers also examined the expression of four genes related to fat breakdown and synthesis.
After treating differentiated 3T3-L1 adipocytes with NMN for 24 hours, researchers found that the expression level of the fat breakdown-related protein Atgl in adipocytes increased, while the expression of genes related to fat synthesis (Srebf1c and Pparγ) did not change.
Figure note: After NMN treatment, the expression of Atgl in adipocytes was upregulated.
Atgl (adipose triglyceride lipase) is considered the main lipolytic enzyme, catalyzing the first step of fat breakdown. It can convert intracellular triglycerides into diacylglycerols and free fatty acids, inducing fat breakdown.
Previous studies have also found that fat mass is negatively correlated with Atgl expression levels. The expression of Atgl in white adipose tissue of obese animals and humans is reduced, while systemic or adipose tissue-specific Atgl deficiency in mice leads to increased fat mass.
The results of this study also confirm this: NMN induces fat breakdown by increasing the expression of the lipolytic enzyme Atgl in adipocytes.
PART 3 NMN upregulates Atgl expression in adipocytes through the SIRT1-AMPK axis
Although studies have shown that upregulating Atgl expression can reduce fat mass, the mechanism by which NMN regulates Atgl expression is not fully clear.
Further exploration found that NMN treatment significantly increased the expression of the longevity protein Sirt1 in 3T3-L1 adipocytes and also enhanced AMPK phosphorylation. AMPK is a key molecule regulating energy metabolism, and studies have shown that Sirt1-mediated enhancement of the activity of LKB1, an upstream kinase of AMPK, is achieved through the deacetylation of LKB1.
Figure note: NMN significantly increased the expression of Sirt1 in adipocytes.
To determine whether NMN regulates fat breakdown through the SIRT1-AMPK axis, an AMPK inhibitor was used in the experiment. It was clearly observed that compared with the group using NMN alone, after inhibiting AMPK expression, the expression level of Atgl did not increase significantly as in the normal NMN group, and there was no significant change in mouse fat.
Figure note: When NMN was used in combination with an AMPK inhibitor, the expression of the lipolytic enzyme Atgl decreased.
This indicates that after inhibiting the AMPK pathway, NMN cannot upregulate the expression of the lipolytic enzyme Atgl, suggesting that NMN is involved in regulating Atgl expression through the SIRT1-AMPK axis. The secret of NMN's final fat reduction lies in the AMPK pathway.