Dataset Information

Triple-Isotope Tracing for Pathway Discernment of NMN-Induced NAD⁺ Biosynthesis in Whole Mice.

ABSTRACT: Numerous efforts in basic and clinical studies have explored the potential anti-aging and health-promoting effects of NAD⁺-boosting compounds such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). Despite these extensive efforts, our understanding and characterization of their whole-body pharmacodynamics, impact on NAD⁺ tissue distribution, and mechanism of action in various tissues remain incomplete. In this study, we administered NMN via intraperitoneal injection or oral gavage and conducted a rigorous evaluation of NMN's pharmacodynamic effects on whole-body NAD⁺ homeostasis in mice. To provide more confident insights into NMN metabolism and NAD⁺ biosynthesis across different tissues and organs, we employed a novel approach using triple-isotopically labeled [¹⁸O-phosphoryl-¹⁸O-carbonyl-¹³C-1-ribosyl] NMN. Our results provide a more comprehensive characterization of the NMN impact on NAD⁺ concentrations and absolute amounts in various tissues and the whole body. We also demonstrate that mice primarily rely on the nicotinamide and NR salvage pathways to generate NAD⁺ from NMN, while the uptake of intact NMN plays a minimal role. Overall, the tissue-specific pharmacodynamic effects of NMN administration through different routes offer novel insights into whole-body NAD⁺ homeostasis, laying a crucial foundation for the development of NMN as a therapeutic supplement in humans.

SUBMITTER: Sauve AA

PROVIDER: S-EPMC10342116 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Triple-Isotope Tracing for Pathway Discernment of NMN-Induced NAD+ Biosynthesis in Whole Mice.

Sauve Anthony A AA Wang Qinghui Q Zhang Ning N Kang Seolhee S Rathmann Abigail A Yang Yue Y

International journal of molecular sciences 20230705 13

Numerous efforts in basic and clinical studies have explored the potential anti-aging and health-promoting effects of NAD+-boosting compounds such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). Despite these extensive efforts, our understanding and characterization of their whole-body pharmacodynamics, impact on NAD+ tissue distribution, and mechanism of action in various tissues remain incomplete. In this study, we administered NMN via intraperitoneal ...[more]

PMID: 37446292

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Project description:As the sole producers of insulin under physiological conditions, the normal functioning of pancreatic β cells is crucial for maintaining glucose homeostasis in the body. Due to the high oxygen and energy demands required for insulin secretion, hypoxia has been shown to play a critical role in pancreatic β-cell dysfunction. Lipid metabolism abnormalities, a common metabolic feature in type 2 diabetic patients, are often accompanied by tissue hypoxia caused by metabolic overload and lead to increased free fatty acid (FFA) levels. However, the specific mechanisms underlying FFA-induced β-cell dysfunction remain unclear. Nicotinamide mononucleotide (NMN), a naturally occurring bioactive nucleotide, has garnered significant attention in recent years for its effectiveness in replenishing NAD+ and alleviating various diseases. Nevertheless, studies exploring the mechanisms through which NMN influences β-cell dysfunction remain scarce. In this study, we established an in vitro β-cell dysfunction model by treating INS-1 cells with palmitate (PA), including control, PA-treated, and PA combined with NMN or activator/inhibitor groups. Compared to the control group, cells treated with PA alone showed significantly reduced insulin secretion capacity and decreased expression of proteins related to the NAD+/AMPK/SIRT1/HIF-1α pathway. In contrast, NMN supplementation significantly restored the expression of pathway-related proteins by activating NAD+ and effectively improved insulin secretion. Results obtained using HIF-1α and AMPK inhibitors/activators further supported these findings. In conclusion, our study demonstrates that NMN reversed the PA-induced downregulation of the NAD+/AMPK/SIRT1/HIF-1α pathway, thereby alleviating β-cell dysfunction. Our study investigated the mechanisms underlying PA-induced β-cell dysfunction, examined how NMN mitigates this dysfunction and offered new insights into the therapeutic potential of NMN for treating β-cell dysfunction and T2DM.

Dataset Information

Triple-Isotope Tracing for Pathway Discernment of NMN-Induced NAD⁺ Biosynthesis in Whole Mice.

Publications

Triple-Isotope Tracing for Pathway Discernment of NMN-Induced NAD<sup>+</sup> Biosynthesis in Whole Mice.

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