Nicotinamide mononucleotide attenuates hepatic endoplasmic reticulum stress and modulates circadian rhythms in young mice with diet-induced obesity

Apr 13, 2026Nutrition research and practice

Nicotinamide mononucleotide reduces liver stress and affects daily body rhythms in young mice with diet-induced obesity

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Abstract

Short-term administration of nicotinamide mononucleotide (NMN) at 500 mg/kg/day significantly decreased body weight and fat mass in young mice.

Nicotinamide adenine dinucleotide (NAD) levels may be linked to obesity and dyslipidemia.
Potential pathways identified include those related to circadian regulation and hepatic endoplasmic reticulum stress.
NMN administration reduced hepatic ER stress response in young mice.
Diet-induced metabolic stress and NAMPT deficiency were associated with phase shifts in the hepatic circadian clock.
Time-restricted feeding influenced the circadian phase in the opposite direction compared to metabolic stress.

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BACKGROUND/OBJECTIVES: Supplementation of nicotinamide adenine dinucleotide (NAD) precursors has been investigated for its potential to counteract age-related physiological decline. While decreased NADlevel is associated with conditions such as obesity and dyslipidemia, few studies have explored its metabolic impact in relatively young animals. Here, we hypothesized that nicotinamide mononucleotide (NMN) could alleviate high-fat diet-induced metabolic stress in young mice and sought to elucidate the underlying mechanisms. +

MATERIALS/METHODS: We first conducted a secondary analysis of hepatic transcriptome datasets from multiple NMN intervention studies to identify target pathways. Next, 11-week-old lean and obese C57BL/6N mice administrated NMN (500 mg/kg/day) for 1 mon were analyzed for metabolic parameters and gene expression for the target pathways.study using AML12 cell line was then conducted to confirm the effects of NMN. Additionally, transcriptomic data from liver-specific nicotinamide phosphoribosyltransferase (NAMPT)-deficient mice were analyzed to examine the relationship between NADmetabolism, endoplasmic reticulum (ER) stress, and circadian rhythm. In vitro +

RESULTS: The secondary analysis of hepatic transcriptome datasets revealed potential target pathways related to circadian regulation and hepatic ER stress. In mouse study, short-term NMN administration significantly decreased body weight and fat mass. NMN also alleviated hepatic ER stress responseand. Additional analysis revealed that the mice with diet-induced metabolic stress or NAMPT deficiency led to phase shifts of the hepatic circadian core clock oscillation by advancing the peak time, while time-restricted feeding shifted the opposite, indicating the metabolic regulation of the circadian phase. in vivo in vitro

CONCLUSION: Short-term NMN administration effectively attenuated obese condition in young mice and mitigated hepatic ER stress. The altered ER stress was regulated by NAMPT, potentially through the phase shift of the hepatic circadian rhythm.

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Nicotinamide mononucleotide attenuates hepatic endoplasmic reticulum stress and modulates circadian rhythms in young mice with diet-induced obesity

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