# Advances in the Synthesis and Physiological Metabolic Regulation of Nicotinamide Mononucleotide
## 4 NMN Regulates Physiological Metabolism
### Treatment of Metabolic Diseases  
Obesity is increasing worldwide due to changes in diet and lifestyle [100]. Obese individuals are more likely to develop metabolic diseases, including cardiovascular disease [101], type 2 diabetes [102], non-alcoholic fatty liver disease [103], and arteriosclerosis [104]. In addition, studies found that obesity can exacerbate aging and shorten the healthy lifespan of the elderly [105]. There is a growing body of evidence that appropriate supplementation of NMN targeting the regulation of NAD\({}^{+}\) metabolic balance has a significant therapeutic effect on obesity-related metabolic diseases and aging [106; 5; 18].  
Initially, NAD\({}^{+}\) was found to be involved in regulating the metabolic rate of yeast extracts, so the link between NAD\({}^{+}\) and metabolism has been extensively studied [107; 108]. NMN regulates metabolism by increasing NAD\({}^{+}\) flux [7; 19]. It is necessary to maintain the normal function of organs such as fat, muscle, intestines, kidneys, and liver. However, obesity, diabetes, and cardiovascular diseases caused by a high-fat diet will disrupt the metabolic balance, leading to a decrease in the level of NAD\({}^{+}\) in tissues, reducing the activity of sirtuins, destroying mitochondrial function, and disrupting other NAD\({}^{+}\)-dependent cellular processes [7; 8]. Numerous studies have shown that increasing intracellular NAD\({}^{+}\) levels can drive the metabolic response of organisms towards equilibrium [109]. High levels of NAD\({}^{+}\) were found to promote the deacetylase activity of nuclear SIRT1 and protect against metabolic diseases induced by a high-fat diet [81; 91]. NMN can also regulate the NAD\({}^{+}\) content of endothelial cells, inhibit endothelial inflammation, and improve NO-dependent functions. In this pathway, CD73 located on the luminal surface  
\begin{table}
\begin{tabular}{c c c c} \hline \multicolumn{4}{c}{**Human Clinical Trials Focusing on Ageing**} \\ \hline
**Compound** & **Study Design** & **Dose and Duration** & **NcT/uMiN No.** \\ \hline \multicolumn{4}{c}{Mouse models focusing on metabolism} \\ \hline Compound & Model & Results & References \\ \hline Tg (SIRT2) and Bubr1H/\({}^{+}\) mice & Increased NAD\({}^{+}\) contents and restored & [94] \\ \hline \multicolumn{4}{c}{Inhibited age-induced weight gain, increased} \\ \multicolumn{4}{c}{Male C57 BL/6N mice} \\ \multicolumn{4}{c}{Male C57 BL/6N mice} \\ \multicolumn{4}{c}{} &
\begin{tabular}{c} Insubitted age-induced weight gain, increased \\ insulin sensitivity, plasma lipid levels, physical \\ activity, and energy expenditure, while also \\ improving mitochondrial function in muscles \\ \end{tabular} & [1; 9] \\  
of endothelial cells converts NMN into extracellular nicotinamide riboside, which is an important protective mechanism for maintaining intracellular NAD\({}^{+}\)[110].  
NMN is the most effective and efficient precursor for improving the levels of NAD\({}^{+}\)[7]. Mice treated with oral NMN exhibited a significant increase in NAD\({}^{+}\) levels after only 15 min [5]. Multiple studies have demonstrated the potential of NMN supplements to restore diminished NAD\({}^{+}\) levels associated with aging and mitigate obesity in rodent models [18; 88]. This implies their potential therapeutic utility in reinstating metabolic health among obese individuals. While most relevant research focused on determining safe and efficacious NMN doses for elevating NAD\({}^{+}\) levels in healthy subjects [111], recent clinical trials started exploring the efficacy of NAD\({}^{+}\) precursors for enhancing metabolic health and glucose metabolism in obese patients.