ABSTRACT
Pyrrolizidine alkaloids (PAs) present distinct toxicity potencies depending on their metabolites and in vivo toxicokinetics. To represent the potency differences of various PAs, the interim relative potency (REP) factors have been derived. However, little is known about the risk assessment for (herbal) teas when taking REP factors into account. In this study, a set of 68 individual 1,2-unsaturated PA in 21 types of (herbal) teas was analyzed using LC-MS/MS. The REP factors for these PAs were applied on the PA levels. The margin of exposure (MOE) approach was employed to assess the risks of the exposure to PAs due to consumption of (herbal) teas. The results show that the total PA levels ranged from 13.4 to 286,682.2 µg/kg d.m., which were decreased by REP correction in most of the teas. The MOE values for tephroseris, borage and lemon balm (melissa) tea based on REP-corrected PA levels were below 10,000, assuming daily consumption of one cup of tea during a lifetime, indicating that consuming these teas may raise a concern. Our study also indicates a priority for risk management for tephroseris tea, as having nephrosis tea for more than 11.2 weeks during a 75-year lifetime would result in an MOE of 10,000.
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.
Subject(s)
Adipose Tissue, White/metabolism , Diet, High-Fat/adverse effects , Inflammation/chemically induced , Niacinamide/analogs & derivatives , Obesity/chemically induced , Adipose Tissue, White/drug effects , Animals , Blood Glucose , Dose-Response Relationship, Drug , Energy Metabolism/drug effects , Glucose Intolerance , Glucose Tolerance Test , Male , Mice , Niacinamide/administration & dosage , Niacinamide/adverse effects , Niacinamide/pharmacology , PPAR gamma , Pyridinium CompoundsABSTRACT
SCOPE: Metabolic flexibility is the ability to switch metabolism between carbohydrate oxidation (CHO) and fatty acid oxidation (FAO) and is a biomarker for metabolic health. The effect on metabolic health of nicotinamide riboside (NR) as an exclusive source of vitamin B3 is unknown and is examined here for a wide range of NR. DESIGN AND METHODS: Nine-week-old male C57BL/6JRcc mice received a semi-purified mildly obesogenic (40 en% fat) diet containing 0.14% L-tryptophan and either 5, 15, 30, 180, or 900 mg NR per kg diet for 15 weeks. Body composition and metabolic parameters were analyzed. Metabolic flexibility was measured using indirect calorimetry. Gene expression in epididymal white adipose tissue (eWAT) was measured using qRT-PCR . RESULTS: The maximum delta respiratory exchange ratio when switching from CHO to FAO (maxΔRERCHO1âFAO ) and when switching from FAO to CHO (maxΔRERFAOâCHO2 ) were largest in 30 mg NR per kg diet (30NR). In eWAT, the gene expression of Pparγ, a master regulator of adipogenesis, and of Sod2 and Prdx3, two antioxidant genes, were significantly upregulated in 30NR compared to 5NR. CONCLUSION: 30NR is most beneficial for metabolic health, in terms of metabolic flexibility and eWAT gene expression, of mice on an obesogenic diet.