Abstract
NAD+ is a crucial metabolic cofactor whose intracellular levels can influence the progression of multiple metabolic and age-related complications. There is therefore a strong interest in using NAD+ precursors (vitamin B3s) as therapeutic tools, but most current precursors exhibit either poor bioavailability or adverse effects. This study examines the metabolic impact of chronic dietary supplementation with a newly described NAD+ precursor, dihydronicotinamide riboside (NRH), in mice using a comprehensive approach including phenotyping tests, RNA sequencing in different tissues and microbiome analyses. We show that chronic NRH administration at 100 mg/(kg*day) is well tolerated, yet has minimal metabolic effects in mice on a regular diet. However, NRH mitigates high-fat diet-induced metabolic complications when used as a preventive or as a treatment strategy, including improvements in glucose tolerance, increased hepatic expression of lipid catabolism genes and fat redistribution. These results highlight the potential of NRH as a therapeutic agent, although further studies are needed to optimize its use, as higher doses reveal signs of toxicity.
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Data availability
The transcriptomic data generated in this study have been deposited on ArrayExpress under accession no. E. In addition, all 16S rRNA gene sequencing results have been deposited under accession no. E. All data supporting the findings described in this manuscript are available in the article and in the Supplementary Information (See Source Data File) and from the corresponding author upon request. Source data are provided in this paper.
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Acknowledgements
The authors thank Jessica Dessimoz at the Histology Platform from the Ecole Polytechnique Fédérale de Lausanne (EPFL) for technical and scientific support in the performance of histology analyses. We would also like to thank Roy Combe and the team at the phenotyping unit of the Centre for Phenogenomics at EPFL for technical assistance during indirect calorimetry and blood biochemistry analyses. We are also grateful to the Gene Expression Core Facility at EPFL for their support. Finally, we would like to thank Camille L.G. Lambert and Constantin Goeldel for their help and contribution in adapting the StarDist tool. This research was funded by Nestlé Research, by the EU Horizon Europe research and innovation programme MSCA-Doctoral Network NADIS (no. 101073251; to R.H.H., C.C., K.T.V., L.v.G.). We also thank NIH (NCCIH R21 grant AT009908-01) and the Mitchell Cancer Institute, F.P. Whiddon College of Medicine, University of South Alabama, for financial support to M.V.M., F.H. and M.E.M.
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M.R., S.M., M.E.M., R.H.H., B.D. and C.C. designed the different studies. F.H., M.V.M. and M.E.M. synthesised labelled and unlabelled forms of NRH. M.R., L.v.G., H.H., J.R., C.S., M.J., J.G.G., J.L.S.G. and C.C. performed the animal interventions, phenotyping and tissue collection. K.T.V., B.V.S., M.P.G., S.C., S.M. and R.H.H. performed the MS-based analyses of NAD+ metabolites. M.R. and V.G. performed gut microbiome analyses. M.R. and G.v.M. performed transcriptomic analyses. M.R., J.R. and C.C. performed all other analyses on tissue and blood samples. M.R., B.D. and C.C. wrote the manuscript, and all other authors contributed to its editing.
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M.R., M.J., J.G.G., S.M. and C.C. performed part of this research while they were employed by Nestlé Research, a part of the Société des Produits Nestlé S.A (SPN). M.P.G., S.C. and J.L.S.G. are employees of the SPN. M.E.M. is the inventor of intellectual property on the synthesis of NRH; M.E.M. and S.P.N. have filed patents related to therapeutic uses of NRH. The remaining authors declare no competing interests.
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Rumpler, M., van Mierlo, G., Vinten, K.T. et al. Therapeutic potential of dihydronicotinamide riboside (NRH) on obesity and glucose intolerance in mice. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70965-4
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DOI: https://doi.org/10.1038/s41467-026-70965-4
