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

Madhu Asnani-Kishnani,Andreu Palou,Joan Ribot,Ana M Rodríguez,Alba Serrano,M Luisa Bonet

doi:10.3389/fphys.2019.00083

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.

Highlights

Brown adipocytes in canonical brown adipose tissue (BAT) depots in mammals express uncoupling protein 1 (UCP1) and a high oxidative capacity and mitochondria content, which distinguishes them metabolically from white adipocytes in typical white adipose tissue (WAT) depots
Adipocytes differentiated from the inguinal WAT (iWAT) stromovascular fraction (SVF) of RSV female mice showed a generalized decreased expression of transcripts of brown and beige adipocyte marker genes, as well as of Pparg, when compared to primary adipocytes from control female mice (Figure 1A)
Ucp1 expression is the hallmark of the brown and beige adipocyte phenotype, and Slc27a1 encodes a fatty acid transport protein (FATP1) that is highly expressed in BAT and other tissues actively oxidizing fatty acids and that is required for BAT thermogenesis (Wu et al, 2006)

Summary

Introduction

Brown adipocytes in canonical BAT depots in mammals express uncoupling protein 1 (UCP1) and a high oxidative capacity and mitochondria content, which distinguishes them metabolically from white adipocytes in typical WAT depots. Beige adipocytes share with brown adipocytes a common core thermogenesis gene signature including inducible UCP1 expression, which allows for the regulated dissipation as heat of the energy contained in fatty acid and glucose fuel molecules (Bartelt and Heeren, 2014). The emergence of beige adipocytes in WAT is termed WAT browning or beigeing. BAT activation and WAT browning are both viewed as potential therapeutic targets in the management of obesity and related metabolic disorders such as hyperlipidemia and diabetes (Bonet et al, 2013; Harms and Seale, 2013)

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