Abstract
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.
Highlights
Nicotinamide adenine dinucleotide (NAD+ ) is an essential metabolic co-factor that supports proper cell functioning
Since dietary Nicotinamide riboside (NR) was shown in multiple animal studies to improve metabolic health [3,5,11,12], and was shown to either have no effect [26] or have detrimental effects depending on the dose and animal model used [19,20,21], we analyzed the long-term (18 weeks) metabolic health effects of dietary high doses of NR in high fat (HF) diet-fed male C57BI/6JRccHsd mice
The metabolic health of C57BI/6JRccHsd mice fed a high dose NR diet (9000 mg NR/kg diet) was deteriorated in our study, since metabolic flexibility was reduced, the glucose clearance rate was lower, and insulin resistance on the whole-body level was aggravated. epididymal white adipose tissue (eWAT) depot weights were decreased by high NR feeding, whereas liver weight and liver TG were increased
Summary
Nicotinamide adenine dinucleotide (NAD+ ) is an essential metabolic co-factor that supports proper cell functioning. Long-term inadequate intake of the NAD+ precursors vitamin. NAD+ levels, leading to compromised metabolic performance, such as blunted metabolic flexibility and insulin sensitivity [2,3,4,5]. In obese individuals, reduced gene expression of the NAD+ synthesis pathway enzymes as well as NAD+ -dependent enzymes was observed, which was associated with impaired metabolic health; e.g., insulin resistance and dyslipidemia [6]. The central role of NAD+ in the link between obesity and its associated metabolic dysfunctions is not surprising, because NAD+ , NADH, nicotinamide adenine dinucleotide phosphate (NADP+ ) and NADPH serve as coenzymes in Nutrients 2019, 11, 2439; doi:10.3390/nu11102439 www.mdpi.com/journal/nutrients
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