Maternal n-3 PUFA supplementation promotes fetal brown adipose tissue development through epigenetic modifications in C57BL/6 mice

Brown adipose tissue (BAT) is a crucial regulator of energy expenditure. Emerging evidence suggests that n-3 PUFA potentiate brown adipogenesis in vitro. Since the pregnancy and lactation is a critical time for brown fat formation, we hypothesized that maternal supplementation of n-3 PUFA promotes BAT development in offspring. Female C57BL/6 mice were fed a diet containing n-3 PUFA (3%) derived from fish oil (FO), or an isocaloric diet devoid of n-3 PUFA (Cont) during pregnancy and lactation. Maternal n-3 PUFA intake was delivered to the BAT of neonates significantly reducing the n-6/n-3 ratio. The maternal n-3 PUFA exposure was linked with upregulated brown-specific gene and protein profiles and the functional cluster of brown-specific miRNAs. In addition, maternal n-3 PUFA induced histone modifications in the BAT evidenced by 1) increased epigenetic signature of brown adipogenesis, i.e., H3K27Ac and H3K9me2, 2) modified chromatin-remodeling enzymes, and 3) enriched the H3K27Ac in the promoter region of Ucp1. The offspring received maternal n-3 PUFA nutrition exhibited a significant increase in whole-body energy expenditure and better maintenance of core body temperature against acute cold treatment. Collectively, our results suggest that maternal n-3 PUFA supplementation potentiates fetal BAT development via the synergistic action of miRNA production and histone modifications, which may confer long-lasting metabolic benefits to offspring.     

PI3K/Akt is involved in brown adipogenesis mediated by growth differentiation factor-5 in association with activation of the Smad pathway

We have previously demonstrated promotion by growth differentiation factor-5 (GDF5) of brown adipogenesis for systemic energy expenditure through a mechanism relevant to activating the bone morphological protein (BMP) receptor/mothers against decapentaplegic homolog (Smad)/peroxisome proliferator-activated receptor gamma co-activator 1α (PGC-1α) pathway. Here, we show the involvement of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in brown adipogenesis mediated by GDF5. Overexpression of GDF5 in cells expressing adipocyte protein-2 markedly accelerated the phosphorylation of Smad1/5/8 and Akt in white and brown adipose tissues. In brown adipose tissue from heterozygous GDF5^Rgsc451 mutant mice expressing a dominant-negative (DN) GDF5 under obesogenic conditions, the basal phosphorylation of Smad1/5/8 and Akt was significantly attenuated. Exposure to GDF5 not only promoted the phosphorylation of both Smad1/5/8 and Akt in cultured brown pre-adipocytes, but also up-regulated Pgc1a and uncoupling protein-1 expression in a manner sensitive to the PI3K/Akt inhibitor Ly294002 as well as retroviral infection with DN-Akt. GDF5 drastically promoted BMP-responsive luciferase reporter activity in a Ly294002-sensitive fashion. Both Ly294002 and DN-Akt markedly inhibited phosphorylation of Smad5 in the nuclei of brown pre-adipocytes. These results suggest that PI3K/Akt signals play a role in the GDF5-mediated brown adipogenesis through a mechanism related to activation of the Smad pathway.