NAMPT-dependent NAD+ biosynthesis controls circadian metabolism in a tissue-specific manner
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ABSTRACT:
PROVIDER: PRJNA914768 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22857400_1.fastq.gz | Fastqsanger.gz | |||
| SRR22857400_2.fastq.gz | Fastqsanger.gz | |||
| SRR22857401_1.fastq.gz | Fastqsanger.gz | |||
| SRR22857401_2.fastq.gz | Fastqsanger.gz | |||
| SRR22857402_1.fastq.gz | Fastqsanger.gz |
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Project description:Molecular clocks in the periphery coordinate tissue-specific daily biorhythms by integrating input from the hypothalamic master clock and intracellular metabolic signals. One such key metabolic signal is the cellular concentration of NAD+, which oscillates along with its biosynthetic enzyme, nicotinamide phosphoribosyltransferase (NAMPT). NAD+ levels feed back into the clock to influence rhythmicity of biological functions, yet whether this metabolic fine-tuning occurs ubiquitously across cell types and is a core clock feature is unknown. Here we show that NAMPT-dependent control over the molecular clock varies substantially between tissues. Brown adipose tissue (BAT) requires NAMPT to sustain the amplitude of the core clock, whereas rhythmicity in white adipose tissue (WAT) is only moderately dependent on NAD+ biosynthesis and the skeletal muscle clock is completely refractory to loss of NAMPT. In BAT and WAT, NAMPT differentially orchestrates oscillation of clock-controlled gene networks and the diurnality of metabolite levels. NAMPT coordinates the rhythmicity of TCA cycle intermediates in BAT, but not WAT, and loss of NAD+ abolishes these oscillations similarly to high fat diet (HFD)-induced circadian disruption. Adipose NAMPT depletion also improved the ability of animals to defend body temperature during cold stress but this is independent of time-of-day. Thus, our findings reveal that peripheral molecular clocks and metabolic biorhythms are shaped in a highly tissue-specific manner by NAMPT-dependent NAD+ synthesis.
2023-04-11 | GSE221550 | GEO
Project description:Vitamin B12 is emerging as a potential therapeutic agent for diabetes-associated complications, with roles in redox balance, methylation, and mitochondrial function. Recent evidence suggests that B12 may also regulate circadian rhythms, which are closely linked to metabolic health. However, the connection between B12, circadian regulation, and protection against early diabetic liver and kidney damage remains unclear. Diabetic (Elmo1H/HIns2Akita/+) and non-diabetic (Elmo1HH) mice were treated with or without Vitamin B12 (10 mg/kg/day) in drinking water for 8 weeks, starting at 8 weeks of age. At 16 weeks, blood, liver, and kidney samples were collected for biochemical, transcriptomic, and histological analysis. Vitamin B12 significantly reduced serum triglycerides, improved mesangial expansion in kidneys, and improved liver cellular structure in diabetic mice. B12 also modulated circadian gene expression, downregulating Clock, Bmal1, and Npas2 (40–50%) while upregulating Cry1/2, Per1–3, Nr1d2, and Dbp in both liver and kidney (130–180%), regardless of diabetic status. Importantly, B12 significantly increased Nampt expression in the liver (p = 0.0062) and kidney (p = 0.0013) of diabetic mice, suggesting enhancement of the NAMPT–NAD⁺–SIRT1 axis, a key pathway for mitochondrial redox control and circadian stability. Additionally, B12 upregulated several solute carrier (SLC) transporters involved in nutrient and ion homeostasis. Together, these findings indicate that Vitamin B12 offers early protective effects against diabetic complications by improving metabolic balance and enhancing Nampt expression, supporting its potential role in preventing liver and kidney damage via circadian and NAD⁺-dependent mechanisms.
2025-12-31 | GSE306999 | GEO
Project description:Type 2 diabetes (T2D) has become an epidemic in our modern lifestyle, likely due to calorie-rich diets overwhelming our adaptive metabolic pathways. One such pathway is mediated by nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in mammalian NAD+ biosynthesis, and the NAD+-dependent protein deacetylase SIRT1. Here we show that NAMPT-mediated NAD+ biosynthesis is severely compromised in metabolic organs by high-fat diet (HFD). Strikingly, nicotinamide mononucleotide (NMN), a product of the NAMPT reaction and a key NAD+ intermediate, ameliorates glucose intolerance by restoring NAD+ levels in HFD-induced T2D mice. NMN also enhances hepatic insulin sensitivity and restores gene expression related to oxidative stress, inflammatory response, and circadian rhythm, partly through SIRT1 activation. Furthermore, NAD+ and NAMPT levels show significant decreases in multiple organs during aging, and NMN improves glucose intolerance and lipid profiles in age-induced T2D mice. These findings provide critical insights into a novel intervention against diet- and age-induced T2D. 4 regular chow fed mice (RC1-4) vs 4 high-fat diet fed (HFD) (HFD1a-4a) mice were analyzed on one chip (Chip-A). 4 HFD mice (HFD1b-4b) vs 4 HFD-NMN treated mice (NMN1-4) were examined on the other chip (Chip-B).
2011-12-05 | E-GEOD-31647 | biostudies-arrayexpress
Project description:Neural stem/progenitor cell (NSPC) proliferation and self-renewal, as well as insult-induced differentiation, decrease markedly with age, but the molecular mechanisms responsible for these declines remain unclear. Here we show that levels of NAD+ and nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme in mammalian NAD+ biosynthesis, decrease with age in the hippocampus. Ablation of Nampt in adult NSPCs reduced their pool and proliferation in vivo. The decrease in the NSPC pool during aging can be rescued by enhancing hippocampal NAD+ levels. Nampt is the main source of NSPC NAD+ levels and required for G1/S progression of the NSPC cell cycle. Nampt is also critical for oligodendrocytic lineage fate decisions through a mechanism mediated redundantly by Sirt1 and Sirt2. Ablation of Nampt in the adult NSPCs in vivo reduced NSPC-mediated oligodendrogenesis upon injury. These phenotypes recapitulate defects in NSPCs during aging, implicating Nampt-mediated NAD+ biosynthesis as a mediator of these age-associated functional declines. Total RNA obtained from neurospheres derived from postnatal hippocampi subjected to 48 hours in vitro of incubation with Nampt-specific inhibitor FK866 (10 nM, 4 samples) or vehicle (DMSO, 1:1000, 4 samples).
2014-05-08 | E-GEOD-49784 | biostudies-arrayexpress
Project description:Type 2 diabetes (T2D) has become an epidemic in our modern lifestyle, likely due to calorie-rich diets overwhelming our adaptive metabolic pathways. One such pathway is mediated by nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in mammalian NAD+ biosynthesis, and the NAD+-dependent protein deacetylase SIRT1. Here we show that NAMPT-mediated NAD+ biosynthesis is severely compromised in metabolic organs by high-fat diet (HFD). Strikingly, nicotinamide mononucleotide (NMN), a product of the NAMPT reaction and a key NAD+ intermediate, ameliorates glucose intolerance by restoring NAD+ levels in HFD-induced T2D mice. NMN also enhances hepatic insulin sensitivity and restores gene expression related to oxidative stress, inflammatory response, and circadian rhythm, partly through SIRT1 activation. Furthermore, NAD+ and NAMPT levels show significant decreases in multiple organs during aging, and NMN improves glucose intolerance and lipid profiles in age-induced T2D mice. These findings provide critical insights into a novel intervention against diet- and age-induced T2D.
2011-12-05 | GSE31647 | GEO
Project description:Nicotinamide adenine dinucleotide (NAD+) is a universal coenzyme regulating cellular energy metabolism in many cell types. Recent studies have demonstrated the close relationships between defective NAD+ metabolism and aging and age-associated metabolic diseases. The major purpose of the present study was to test the hypothesis that NAD+ biosynthesis, mediated by a rate-limiting NAD+ biosynthetic enzyme, nicotinamide phosphoribosyltransferase (NAMPT), is essential for maintaining normal adipose tissue function and whole-body metabolic health during the aging process. To this end, we provided in-depth and comprehensive metabolic assessments for female adipocyte-specific Nampt knockout (ANKO) mice during aging. We first evaluated body fat mass in young (≤ 4-month-old), middle aged (10 to 14-month-old), and old (≥ 18-month-old) mice. Intriguingly, adipocyte-specific Nampt deletion protected against age-induced obesity without changing energy balance. However, data obtained from the hyperinsulinemic euglycemic clamp procedure demonstrated that, despite the lean phenotype, old ANKO mice had severe insulin resistance in skeletal muscle, heart, and white adipose tissue (WAT). Old ANKO mice also exhibited hyperinsulinemia and hypoadiponectinemia. Mechanistically, loss of Nampt caused marked decreases in WAT gene expression of lipogenic targets of peroxisome proliferator-activated receptor gamma (PPARγ) in an age-dependent manner. In addition, administration of a PPARγ agonist rosiglitazone restored fat mass and improved metabolic abnormalities in old ANKO mice. In conclusion, these findings highlight the importance of the NAMPT-NAD+-PPARγ axis in maintaining functional integrity and quantity of adipose tissue, and whole-body metabolic function in female mice during aging.
2024-05-31 | GSE152067 | GEO
Project description:Neural stem/progenitor cell (NSPC) proliferation and self-renewal, as well as insult-induced differentiation, decrease markedly with age, but the molecular mechanisms responsible for these declines remain unclear. Here we show that levels of NAD+ and nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme in mammalian NAD+ biosynthesis, decrease with age in the hippocampus. Ablation of Nampt in adult NSPCs reduced their pool and proliferation in vivo. The decrease in the NSPC pool during aging can be rescued by enhancing hippocampal NAD+ levels. Nampt is the main source of NSPC NAD+ levels and required for G1/S progression of the NSPC cell cycle. Nampt is also critical for oligodendrocytic lineage fate decisions through a mechanism mediated redundantly by Sirt1 and Sirt2. Ablation of Nampt in the adult NSPCs in vivo reduced NSPC-mediated oligodendrogenesis upon injury. These phenotypes recapitulate defects in NSPCs during aging, implicating Nampt-mediated NAD+ biosynthesis as a mediator of these age-associated functional declines.
2014-05-08 | GSE49784 | GEO
Project description:Maintenance of NAD+ levels by mitochondrial complex I, the NAD+ salvage pathway, and other routes is an important factor in of neurodegenerative disease and cancer. Both the production of NAD+ and the metabolic enzymes that require it as a redox cofactor or substrate differ widely in abundance across cell types and conditions. Disruption in the NAD+ supply thus exerts different effects depending on the cellular NAD+ requirements existing in the cell. Pharmacological depletion of NAD+ is actively being pursued in cancer and other diseases but these effects are not fully understood. Here, we combine quantitative proteomics and metabolomics to understand the consequences of disrupting cellular NAD+ levels and find that inhibiting the NAD+ salvage pathway depletes serine biosynthesis from glucose by impeding the NAD+-dependent protein 3-phosphoglycerate dehydrogenase (PHGDH). Importantly, breast cancers that depend on PHGDH are exquisitely sensitive to blocking the NAD+ salvage pathway. PHGDH, and the rate-limiting enzyme of NAD+ salvage are also correlated in public tumor proteome and transcript datasets. These findings are immediately translatable to the pharmacological inhibition of NAMPT in PHGDH-dependent cancers.
2018-08-14 | PXD007790 | Pride
Project description:Molecular clocks in the periphery coordinate tissue-specific daily biorhythms by integrating input from the hypothalamic master clock and intracellular metabolic signals. One such key metabolic signal is the cellular concentration of NAD+, which oscillates along with its biosynthetic enzyme, nicotinamide phosphoribosyltransferase (NAMPT). NAD+ levels feed back into the clock to influence rhythmicity of biological functions, yet whether this metabolic fine-tuning occurs ubiquitously across cell types and is a core clock feature is unknown. Here, we show that NAMPT-dependent control over the molecular clock varies substantially between tissues. Brown adipose tissue (BAT) requires NAMPT to sustain the amplitude of the core clock, whereas rhythmicity in white adipose tissue (WAT) is only moderately dependent on NAD+ biosynthesis, and the skeletal muscle clock is completely refractory to loss of NAMPT. In BAT and WAT, NAMPT differentially orchestrates oscillation of clock-controlled gene networks and the diurnality of metabolite levels. NAMPT coordinates the rhythmicity of TCA cycle intermediates in BAT, but not in WAT, and loss of NAD+ abolishes these oscillations similarly to high-fat diet-induced circadian disruption. Moreover, adipose NAMPT depletion improved the ability of animals to defend body temperature during cold stress but in a time-of-day-independent manner. Thus, our findings reveal that peripheral molecular clocks and metabolic biorhythms are shaped in a highly tissue-specific manner by NAMPT-dependent NAD+ synthesis.
| S-EPMC10083581 | biostudies-literature
Project description:Nicotinamide phosphoribosyltransferase (NAMPT) is a key enzyme in NAD biosynthesis and is frequently upregulated in tumors, including melanoma, where it drives disease progression and resistance to targeted therapies. Beyond its metabolic role, NAMPT also exerts immune-modulatory functions, acting as a cytokine-like mediator that shapes tumor–host interactions and influences the efficacy of immunotherapy. Building on recent evidence indicating a connection between the pro-inflammatory cytokine interferon-gamma (IFN-γ) signaling and NAD metabolism, we sought to explore this poorly understood relationship in melanoma context. Analysis of the TCGA melanoma cohort revealed a significant correlation between NAMPT expression and IFN-γ signaling, including specific genes belonging to this pathway, such as IRF1, STAT1, and CD274/PD-L1. The correlation between NAMPT and PD-L1 was also confirmed at the protein level in more than 100 cases included in a melanoma tissue microarray (TMA). Functionally, IFN-γ treatment (100ng/ml for 24h) of three MM cell lines led to increased NAMPT transcription and intracellular expression, as well as increased release. Molecularly, as previously demonstrated for IFN-γ-inducible PD-L1, also NAMPT expression upon IFN-γ signaling activation is regulated at epigenetic/transcriptional level via bromodomain protein BRD4/IRF1 complex, as revealed using BRD4 inhibitors and chromatin immunoprecipitation (ChIP)-RT-PCR experiments. In the second part of our results, we showed a bidirectional regulation between NAD/NAMPT axis and IFN-γ signaling. NAMPT inhibition, as well as genetic silencing, reduced IFN-γ signaling activation, as highlighted by RNAseq data and confirmed by biochemical validation. This reciprocal regulation involved the modulation of mitochondrial respiration, specifically mitochondrial Complex I. Analysis of the melanoma TCGA cohort revealed a significant correlation between NAMPT expression, IFN signaling and several mitochondrial Complex I subunit genes. Consistently, activation of IFN-γ signaling in melanoma cell lines induced an increase in oxygen consumption rate, which was completely abrogated by NAD/NAMPT-dependent inhibition of complex I activity, indicating a direct metabolic crosstalk.
2025-11-18 | GSE310354 | GEO