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High Dose of Dietary Nicotinamide Riboside Induces Glucose Intolerance and White Adipose Tissue Dysfunction in Mice Fed a Mildly Obesogenic Diet

Human and Animal Physiology, Wageningen University, PO Box 338, 6700 AH Wageningen, The Netherlands
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Author to whom correspondence should be addressed.
Current address: Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA.
Current address: Educational Consultancy & Professional Development, Faculty of Social and Behavioral Sciences, Utrecht University, 3508 TC Utrecht, The Netherlands.
Nutrients 2019, 11(10), 2439; https://doi.org/10.3390/nu11102439
Received: 4 September 2019 / Revised: 27 September 2019 / Accepted: 7 October 2019 / Published: 13 October 2019
Nicotinamide riboside (NR) is a nicotinamide adenine dinucleotide (NAD+) precursor vitamin. The scarce reports on the adverse effects on metabolic health of supplementation with high-dose NR warrant substantiation. Here, we aimed to examine the physiological responses to high-dose NR supplementation in the context of a mildly obesogenic diet and to substantiate this with molecular data. An 18-week dietary intervention was conducted in male C57BL/6JRccHsd mice, in which a diet with 9000 mg NR per kg diet (high NR) was compared to a diet with NR at the recommended vitamin B3 level (control NR). Both diets were mildly obesogenic (40 en% fat). Metabolic flexibility and glucose tolerance were analyzed and immunoblotting, qRT-PCR and histology of epididymal white adipose tissue (eWAT) were performed. Mice fed with high NR showed a reduced metabolic flexibility, a lower glucose clearance rate and aggravated systemic insulin resistance. This was consistent with molecular and morphological changes in eWAT, including sirtuin 1 (SIRT1)-mediated PPARγ (proliferator-activated receptor γ) repression, downregulated AKT/glucose transporter type 4 (GLUT4) signaling, an increased number of crown-like structures and macrophages, and an upregulation of pro-inflammatory gene markers. In conclusion, high-dose NR induces the onset of WAT dysfunction, which may in part explain the deterioration of metabolic health. View Full-Text
Keywords: vitamin B3; supplementation; NAD+; adipose tissue; Nnt; glucose tolerance vitamin B3; supplementation; NAD+; adipose tissue; Nnt; glucose tolerance
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Shi, W.; Hegeman, M.A.; Doncheva, A.; Bekkenkamp-Grovenstein, M.; de Boer, V.C.J.; Keijer, J. High Dose of Dietary Nicotinamide Riboside Induces Glucose Intolerance and White Adipose Tissue Dysfunction in Mice Fed a Mildly Obesogenic Diet. Nutrients 2019, 11, 2439.

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