Neonatal Resveratrol and Nicotinamide Riboside Supplementations Sex-Dependently Affect Beige Transcriptional Programming of Preadipocytes in Mouse Adipose Tissue

Abstract

Nutritional programming of the thermogenic and fuel oxidation capacity of white adipose tissue (WAT) through dietary interventions in early life is a potential strategy to enhance future metabolic health. We previously showed that mild neonatal supplementations with the polyphenol resveratrol (RSV) and the vitamin B3 form nicotinamide riboside (NR) have sex-dependent, long-term effects on the thermogenic/oxidative phenotype of WAT of mice in adulthood, enhancing this phenotype selectively in male animals. Here, we tested the hypothesis that these dietary interventions may impact the commitment of progenitor cells resident in the developing WAT toward brown-like (beige) adipogenesis. NMRI mice received orally from postnatal day 2–20 (P2–20) a mild dose of RSV or NR, in independent experiments; control littermates received the vehicle. Sex-separated primary cultures were established at P35 from the stromovascular fraction of inguinal WAT (iWAT) and of brown adipose tissue (BAT). Expression of genes related to thermogenesis and oxidative metabolism was assessed in the differentiated cultures, and in vivo in the iWAT depot of young (P35) animals. Neonatal RSV and NR treatments had little impact on the animals’ growth during early postnatal life and the expression of thermogenesis- and oxidative metabolism-related genes in the iWAT depot of young mice. However, the expression of brown/beige adipocyte marker genes was upregulated in the iWAT primary cultures from RSV supplemented and NR supplemented male mice, and downregulated in those from supplemented female mice, as compared to cultures derived from sex-matched control littermates. RSV supplementation had similar sex-dependent effects on the expression of thermogenesis-related genes in the BAT primary cultures. A link between the sex-dependent short-term effects of neonatal RSV and NR supplementations on primary iWAT preadipocyte differentiation observed herein and their previously reported sex-dependent long-term effects on the thermogenic/oxidative capacity of adult iWAT is suggested. The results provide proof-of-concept that the fate of preadipocytes resident in WAT of young animals toward the beige adipogenesis transcriptional program can be modulated by specific food bioactives/micronutrients received in early postnatal life.

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

“…RSV and NR are both described as activators of SIRT1 (though through different mechanisms) [51,56,57], and SIRT1 has epigenetic activity, as it impacts global and gene-specific DNA methylation [58][59][60] and interacts with and deacetylates components of the DNA methylation machinery [60][61][62]. Still, RSV and NR have additional, non-overlapping biological targets for interaction besides SIRT1, and in fact, it is to be noted that effects of neonatal RSV and NR treatments observed in our previous studies [6,8] and in this work are similar, but not identical.…”

“…Early life supplementation with RSV or NR resulted in increased Prdm16 mRNA levels in iWAT in adulthood in male mice, with a similar degree of induction for both treatments and after NFD or HFD feeding conditions (1.6-1.9-fold induction relative to expression levels in the corresponding controls) [6]. Moreover, Prdm16 gene expression was also found induced in iWAT of young male mice neonatally treated with NR, and in the primary adipocyte cultures derived from it [8]. These results added to the role of PRDM16 as a brown adipocyte lineage-determining factor [14] and reported DNA methylation-dependent regulation of Prdm16 gene expression [17], prompted us to assess for eventual effects of the experimental neonatal supplementations on the methylation profile of Prdm16.…”

“…In good concordance, 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]. However, whether epigenetic changes affecting brown/beige adipocyte marker genes are involved in this programming has not been addressed.…”

“…Slc27a1 up-regulation is especially evident under NFD conditions in the RSV mice (3.2-fold induction under NFD vs. 1.45-fold induction under HFD, relative to levels in corresponding controls), and under HFD conditions in the NR mice (2-fold induction vs. 1.15-fold induction under NFD) [6]. Furthermore, primary adipocytes derived from the stromal vascular fraction isolated from iWAT of young RSV-treated and NR-treated male mice also have Slc27a1 gene expression up-regulated relative to corresponding primary adipocytes from control littermates [8]. These previous results, together with reports linking Slc27a1 and its protein product FATP1 to thermogenesis, mitochondria function and WAT browning [10][11][12], made a priori Slc27a1 an interesting gene to study its eventual epigenetic modification in response to the experimental treatments applied.…”

“…Slc27a1 (solute carrier family 27 member 1) and Prdm16 (PR domain containing 16) are two browning-related genes that are induced in WAT of male mice treated neonatally with RSV or NR and derived primary cultures [6,8]. The protein product of Slc27a1 is fatty acid transport protein 1 (FATP1), an integral membrane protein that mediates the cellular uptake of long-chain fatty acids and can channel the uptaken fatty acids toward oxidation in mitochondria [9].…”