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

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.

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

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.

Programming of the Beige Phenotype in White Adipose Tissue of Adult Mice by Mild Resveratrol and Nicotinamide Riboside Supplementations in Early Postnatal Life.

SCOPE: Resveratrol (RSV) and nicotinamide riboside (NR) are food compounds with anti-obesity actions in adult rodents. Here, the long-term effects of RSV and NR mild supplementation throughout lactation on adiposity-related parameters and the appearance of the beige phenotype in white adipose tissue (WAT) in adulthood are assessed. METHODS AND RESULTS: Newborn mice received orally RSV or NR from day 2 to 20 of life. Control littermates received the vehicle. All animals are weaned onto a chow diet on day 21. On day 90, half the animals of each group are assigned to a high-fat diet (HFD) for 10 weeks, while the other remained on a normal-fat diet. Energy-balance-related parameters, blood parameters, and gene expression and immunohistochemical analysis of WAT are assessed. Treated male mice show an improved response to the HFD, such as delayed body weight gain, a blunted increase in the plasma leptin/adiponectin ratio, and a decreased lipolytic response, together with signs of white-to-brown fat remodeling in inguinal WAT. These effects are absent in female mice. CONCLUSION: RSV and NR supplementations in early postnatal life affect WAT's thermogenic/oxidative transcriptional phenotype and metabolic responses in adulthood, with upregulatory and beneficial effects evidenced in male animals.

Milk Leptin Surge and Biological Rhythms of Leptin and Other Regulatory Proteins in Breastmilk.

A significant number of chronic diseases are linked to perinatal nutrition, and prevention may be associated to naturally occurring components of breast milk. One key hormone in breast milk is leptin, related with the protection from obesity in the adulthood, thus knowing its changes through the day or lactation is crucial. We aimed to investigate the daily rhythms in the milk levels of leptin, together with other two related hormones, ghrelin and adiponectin, during lactation (days 5, 10 and 15) in rat dams, and the relation with morphometric parameters (dams and pups). Summarizing the main results, the existence of biological rhythms, but not daily and maybe circasemidian, was confirmed for the three hormones at the earliest period of lactation. The correlations performed generally showed a possible dependence of milk hormone levels on plasma levels at the early phase of lactation, while with the progression of lactation this dependence may fade and the hormone levels are suggested to be more dependent on mammary gland production/maturation. There was also a correlation between milk leptin and adiponectin levels, especially in the first half of lactation, suggesting a possible parallel regulation. Interestingly, we describe a milk leptin surge around the mid of lactation (at day 10) which may be related with pup's growth (males and females) and with the well-known (in the literature) plasma leptin surge in pups. All this knowledge may be crucial for future applications in the development of formula milk and in relation with the role of leptin surge during lactation.