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

Abstract

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.

Maternal Eicosapentaenoic Acid Feeding Decreases Placental Lipid Deposition and Improves the Homeostasis of Oxidative Stress Through a Sirtuin‐1 (SIRT1) Independent Manner

“…Here, the decrease in placental and fetal lipid deposition by EPA supplementation may be attributable to the promotion of placental lipolysis while inhibiting lipogenesis, and increases in the expression of fatty acid transport genes and fatty acid oxidation. Previous studies have found that n‐3 PUFA promotes brown adipogenesis and adaptive thermogenesis via epigenetic modulation of PGC1α, UCP1, PRDM16, transcription in adipose tissues . Consistent with earlier reports, it was observed here that supplementation with EPA increased placental PGC1α and UCP1 expression and reduced HFD‐induced mitochondrial swelling, which may be of benefit for placental nutrient transport.…”

Alpha-Linolenic Acid-Enriched Butter Promotes Fatty Acid Remodeling and Thermogenic Activation in the Brown Adipose Tissue

“…To determine the FA profile in the BAT, the total lipids were extracted, as we previously described [15]. Briefly, approximately~100 mg of BAT was minced, and the extracted total lipids were converted into fatty acid methyl ester.…”

“…The BAT samples were fixed in 10% buffered formalin, embedded in paraffin, and cut into 5 µm sections. After deparaffinization, BAT sections were stained with hematoxylin and eosin (H&E) staining as previously described [15].…”

“…In contrast, the intake of fish oil, a significant source of n-3 long-chain (LC) polyunsaturated fatty acids (PUFA), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), potentiates the cell-autonomous brown adipocyte differentiation from murine brown precursor cells [13,14]. Additionally, maternal fish oil supplementation during pregnancy promotes prenatal BAT formation in vivo, which may decrease the risk of childhood obesity by augmenting BAT-mediated energy expenditure [15]. Moreover, we have demonstrated that fish oil consumption facilitates the thermogenic potential of BAT, resulting in improved insulin sensitivity against diet-induced obesity and insulin resistance [12,13].…”

Field and laboratory methods for quantifying brown adipose tissue thermogenesis

“…Additionally, environmental factors during development may influence the trajectory of BAT growth across the life course. For example, maternal diet during gestation and lactation and childhood cold exposure may alter BAT development and have consequences for energy expenditure in adulthood (Argentato, de Cássia César, Estadella, & Pisani, ; Fan, Toney, Jang, Ro, & Chung, ; Levy, ).…”