Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Metabolic effects of chronic dihydronicotinamide riboside (NRH) administration in mice - RNA-seq of murine tissues (NRH treatment)

ABSTRACT: NAD+ is a crucial cofactor for the activity of various enzymes, including sirtuins and ADP-ribosyl transferases, and its decline is associated with aging and metabolic-related diseases. Therefore, a strong interest has been raised in the therapeutic use of NAD+ precursors (Vitamin B3s), but many suffer from poor bioavailability and adverse effects. This study characterizes the metabolic impact of dihydronicotinamide riboside, a recently identified novel form of NAD+ precursor. Upon oral administration in mice, NRH reaches all tissues examined. Chronic administration in low-fat diet-fed mice showed negligible metabolic effects, while high-fat diet-fed mice were protected against body weight gain and glucose intolerance. However, our study also unveiled potential side effects at higher doses. Thus, NRH could constitute an alternative NAD+ boosting strategy to prevent diet-induced metabolic complications and conditions associated with low NAD+ levels, but the therapeutic window must be optimized to maximize benefits and minimize risks. Mice were either low-fat diet fed or high-fat diet-fet, and either in control group or supplemented with NRH groups (NRH100 and NRH400) for up to 16 weeks. Tissues were collected to extract RNA and perform RNA-seq (BRB-seq protocol)

INSTRUMENT(S): Illumina NovaSeq 6000

ORGANISM(S): Mus musculus

SUBMITTER: Marie Rumpler

PROVIDER: E-MTAB-14195 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Cockayne syndrome (CS) is an accelerated aging disorder characterized by progressive neurodegeneration caused by mutations in the genes encoding the DNA repair proteins CSA or CSB. Csbm/m mice were given a high-fat, caloric-restricted or resveratrol-supplemented diet. The high-fat diet rescued the phenotype of Csbm/m mice at the metabolic, transcriptomic and behavioral levels. Additional analysis suggests that the premature aging seen in CS mice, nematodes and human cells results from aberrant PARP activation due to deficient DNA repair leading to decreased SIRT1 activity and mitochondrial dysfunction. Notably, Î²-hydroxybutyrate levels are increased by the high-fat diet; and Î²-hydroxybutyrate, PARP inhibition, or NAD+ supplementation can activate SIRT1 and rescue CS-associated phenotypes. Mechanistically, CSB is able to displace activated PARP1 from damaged DNA to limit its activity. This study connects two emerging longevity metabolites, Î²-hydroxybutyrate and NAD+, through the deacetylase SIRT1 and suggests possible interventions for CS. 4-month-old mice, WT and Csbm/m on a C57BL/6 background, were fed a standard AIN-93G diet (SD; carbohydrate:protein:fat ratio of 64:19:17 percent of kcal) ad libitum or at 40% CR, a SD supplemented with 100 mg/kgchow resveratrol ad libitum, or a high-fat diet ad libitum consisting of AIN-93G with 60% of calories from fat, primarily hydrogenated coconut oil (HFD; carbohydrate:protein:fat ratio of 16:23:61). Each group was on the specified diet for 8 months, after which the mice were sacrificed and the cerebellum was removed. For nicotinamide treatments, 4- or 18-month-old WT and Csbm/m mice were given daily injections of nicotinamide riboside (NR) (500 mg/kg/d, ip) or saline for one week, after which the mice were sacrificed and the cerebellum was removed. RNA was extracted from the cerebellums of all mice using Trizol, and RNA quality and quantity were tested using an Agilent 2100 BioAnalyzer with RNA 6000 nano chips. RNA was labeled using the standard Illumina protocol for Illumina TotalPrep RNA Amplification Kit. Labeled RNA was hybridized to Illumina's Sentrix MouseRef-8 v2 Expression BeadChips (Illumina, San Diego, CA) overnight and washed, stained and scanned the next day.

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Metabolic effects of chronic dihydronicotinamide riboside (NRH) administration in mice - RNA-seq of murine tissues (NRH treatment)

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