Maternal omega-3 fatty acid deficiency affects fetal thermogenic development and postnatal musculoskeletal growth in mice.

Maternal omega-3 (n-3) polyunsaturated fatty acids (PUFAs) deficiency can affect offspring's adiposity and metabolism by modulating lipid and glucose metabolism. However, the impact of n-3 PUFA deficiency on the development of fetal thermogenesis and its consequences is not reported. Using an n-3 PUFA deficient mice, we assessed fetal interscapular brown adipose tissue (iBAT), body fat composition, insulin growth factor-1 (IGF-1), glucose transporters (GLUTs), and expression of lipid storage & metabolic proteins in the offspring. The n-3 PUFA deficiency did not change the pups' calorie intake, organ weight, and body weight. However, the offspring's skeletal growth was altered due to excess fat to lean mass, reduced tibia & femur elongation, dysregulated IGF-1 in the mother and pups (P< .05). Localization of uncoupling protein 1 (UCP1) in iBAT exhibited a reduced expression in the deficient fetus. Further, UCP1, GLUT1, GPR120 were downregulated while FABP3, ADRP, GLUT4 expressions were upregulated in the BAT of the deficient offspring (P< .05). The deficiency decreased endogenous conversion of the n-3 LCPUFAs from their precursors and upregulated SCD1, FASN, and MFSD2A mRNAs in the liver (P< .05). An altered musculoskeletal growth in the offspring is associated with impaired browning of the fetal adipose, dysregulated thermogenesis, growth hormone, and expression of glucose and fatty acid metabolic mediators due to maternal n-3 PUFA deficiency. BAT had higher metabolic sensitivity compared to WAT in n-3 PUFA deficiency. Maternal n-3 PUFA intake may prevent excess adiposity by modulating fetal development of thermogenesis and skeletal growth dynamics in the mice offspring.

Maternal n-3 PUFA deficiency alters uterine artery remodeling and placental epigenome in the mice.

The maternal n-3 polyunsaturated fatty acid (PUFA) deficiency on decidual vascular structure and angiogenesis in mice placenta was investigated. Namely, we studied uterine artery remodeling, fatty acid metabolism, and placental epigenetic methylation in this animal model. Weanling female Swiss albino mice were fed either alpha-linolenic acid (18:3 n-3, ALA) deficient diets (0.13% energy from ALA) or a sufficient diet (2.26% energy from ALA) throughout the study. The dietary n-3 PUFA deficiency altered uteroplacental morphology and vasculature by reversing luminal to vessel area and increased luminal wall thickness at 8.5-12.5gD. Further, placentas (F0 and F1) showed a significant decrease in the expression of VCAM1, HLAG proteins and an increase in MMP9, KDR expression. The conversion of ALA to long-chain (LC) n-3 PUFAs was significantly decreased in plasma and placenta during the n-3 deficiency state. Reduced n-3 LCPUFAs increased the placental expression of intracellular proteins FABP3, FABP4, and ADRP to compensate decreased availability of these fatty acids in the n-3 deficient mice. The N-3 PUFA deficiency significantly increased the 5-methylcytosine levels in the placenta but not in the liver. The alteration in DNA methylation continued to the next generation in the placental epigenome with augmented expression of DNMT3A and DNMT3B. Our study showed that maternal n-3 PUFA deficiency alters placental vascular architecture and induces epigenetic changes suggesting the importance of n-3 PUFA intake during the development of the fetus. Moreover, the study shows that the placenta is the susceptible target for epigenetic alteration in maternal deficiency n-3 fatty acids.

Curcumin stimulates angiogenesis through VEGF and expression of HLA-G in first-trimester human placental trophoblasts.

Curcumin has a protective role in placental diseases like preeclampsia and preterm birth. Very little is known about its functional effects on growth, angiogenesis, and epigenetic activities of human first trimester placenta. HTR8/SVneo trophoblasts cells were used as model for human first trimester placenta. Effects of curcumin (≥80%) in these cells were investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), radioactive thymidine uptake, quantitative real-time polymerase chain reaction (qRT-PCR), promoter DNA methylation, qRT-PCR array, tube formation, wound healing, and immunoblot assays. PC3 (prostate cancer), JEG-3 (trophoblast), and HMEC-1 (endothelial) cells were used as control in various experiments. Unlike in PC3 cells, curcumin stimulated growth, proliferation, and viability in HTR8/SVneo cells. Curcumin increased tube formation, and messenger RNA (mRNA) expression of angiogenic factors such as vascular endothelial growth factor A (VEGFA) and protein expression of proangiogenic factor VEGF receptor-2 and fatty acid-binding protein-4 (FABP4) in these cells. Curcumin-stimulated tube formation was associated with an increased expression of VEGFR2 and FABP4. The stimulatory effects of curcumin were inhibited by VEGFR2 (SU5416) and FABP4 (BMS309403) inhibitors. Curcumin also significantly increased both mRNA and protein expression of HLA-G in HTR8/SVneo cells. Curcumin increased mRNA expression of DNMT3A and NOTCH signaling system whereas down-regulated mRNA expression of HSD11ß2. Curcumin enhanced hypomethylation of gene promoters against oxidative stress and DNA damage pathway mediators. Curcumin promotes cell growth, migration, and thus angiogenic potential of these cells. Increased expression of HLA-G by curcumin, hitherto unknown, is a novel finding since HLA-G not only favors the immune environment for invasive trophoblasts but also positively modulates angiogenesis.

Dietary incorporation of whey protein isolate and galactooligosaccharides exhibits improvement in glucose homeostasis and insulin resistance in high fat diet fed mice.

BACKGROUND: This study was planned to investigate the effectiveness of the whey protein isolate (WPI) of high purity and a galactooligosaccharides (GOS) preparation on glucose homeostasis and insulin resistance in high fat diet (HFD) (45.47% energy from fat) fed conditions in C57BL/6J mice. METHODS: Fasting blood glucose level, serum insulin, and glucagon-like peptide-1 (enzyme-linked immunosorbent assay) were measured; also, homeostasis model assessment of insulin resistance (HOMA-IR) was determined in different treatment groups. mRNA expression of gluconeogenesis genes in liver and small intestine tissues was analyzed by quantitative real time-polymerase chain reaction. RESULTS: Dietary incorporation of WPI and GOS was observed to significantly resist (P < 0.001) the HFD-induced increase in blood glucose levels indicating a mitigating effect on glycemic load. It is important to note that no additive effects of administration of WPI and GOS could be observed. The administration of WPI and GOS exhibited maximum resistance (37.8%) to the rise in insulin level. Thus, the resistance to the increase in HOMA-IR was also noticed on the dietary incorporation of two functional ingredients . The positive effects on mRNA expression of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase could be detected in liver only. CONCLUSION: Both types of functional components exhibit potential to improve glucose homeostasis under HFD fed conditions. Resistance to HFD-induced hyperinsulinemia and HOMA-IR is also recorded .