DNA Methylation Changes are Associated with the Programming of White Adipose Tissue Browning Features by Resveratrol and Nicotinamide Riboside Neonatal Supplementations in Mice.

Alba Serrano,Julien Astier,M Luisa Bonet,Madhu Asnani-Kishnani,Andreu Palou,Jean-François Landrier,Joan Ribot,Charlene Couturier

doi:10.3390/nu12020461

Abstract

Neonatal supplementation with resveratrol (RSV) or nicotinamide riboside (NR) programs in male mice brown adipocyte-like features in white adipose tissue (WAT browning) together with improved metabolism in adulthood. We tested the involvement in this programming of long-term epigenetic changes in two browning-related genes that are overexpressed in WAT of supplemented mice, Slc27a1 and Prdm16. Suckling mice received orally the vehicle, RSV or NR from postnatal days 2-to-20. After weaning (d21) onto a chow diet, male mice were habituated to a normal-fat diet (NFD) starting d75, and split on d90 into continuation on the NFD or switching to a high-fat diet (HFD) until euthanization on d164. CpG methylation by bisulfite-sequencing was analyzed on inguinal WAT. Both treatments modified methylation marks in Slc27a1 and Prdm16 and the HFD-dependent dynamics of these marks in the adult WAT, with distinct and common effects. The treatments also affected gene expression of de novo DNA methylases in WAT of young animals (euthanized at d35 in independent experiments). Studies in 3T3-L1 adipocytes indicated the direct effects of RSV and NR on the DNA methylation machinery and favoring browning features. The results support epigenetic effects being involved in WAT programming by neonatal RSV or NR supplementation in male mice.

Highlights

Epigenetic changes modifying genome activity represent a prime candidate mechanism to explain the influences of early life nutrition on later metabolic phenotypes [1], including differences in the susceptibility to obesity and the metabolic syndrome [2]
Primary adipocytes derived from the stromal vascular fraction isolated from inguinal WAT (iWAT) of young RSV-treated and nicotinamide riboside (NR)-treated male mice have Slc27a1 gene expression up-regulated relative to corresponding primary adipocytes from control littermates [8]
−1086, +448, +461, +614, +781) were found for pooled control and RSV mice. These results appear to be in good concordance with a general repressive effect of DNA methylation on gene expression, which is well established for central gene promoters [39]

Summary

Introduction

Epigenetic changes modifying genome activity represent a prime candidate mechanism to explain the influences of early life nutrition on later metabolic phenotypes [1], including differences in the susceptibility to obesity and the metabolic syndrome [2]. Changes in DNA methylation may result in altered gene expression, leading to different phenotypes with potential increased or decreased disease risk. RSV supplementation of the maternal high-fat diet promotes brown and beige adipocyte development and prevents programmed obesity in the male offspring [7]. Mechanisms behind the programming of the adipose phenotype by neonatal RSV and NR supplementations likely include changes in WAT resident progenitor cells toward a greater commitment to beige (versus white) adipogenesis, as suggested by results in primary adipocyte cultures [8]. Whether epigenetic changes affecting brown/beige adipocyte marker genes are involved in this programming has not been addressed

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Discussion

Conclusion