Effects of maternal HF diet and absence of TRPC1 gene on mouse placental growth and fetal intrauterine growth retardation (IUGR).

Placental tissue intracellular calcium (Ca2+) regulates placental development and growth. Maternal high-fat diet (HFD) results in placental lipid accumulation, increased inflammation, reduced nutrient transport expression, and intrauterine growth restriction (IUGR). Currently, whether maternal HFD differentially affects placental and fetal growth and development under reduced Ca2+ influx is not yet known. We hypothesized that maternal HFD feeding decreases placental growth and development resulting in IUGR and that reduction of Ca2+ influx in the placenta worsens maternal HFD-induced placental dysfunction and IUGR. Three-week-old female B6129SF2/J wild type (WT) and transient receptor potential canonical 1 (TRPC1) protein deficient (KO) mice were fed normal fat (NF, 16 kcal % fat) and high fat (HF, 45 kcal % fat) diets for 12 weeks prior to mating with NF diet fed male mice. Fetuses and placentae were examined at mid- (D12) and late- (D18) gestation. At D12, maternal HFD had no effects on placental or fetal weight changes in WT and TRPC1 KO mice while absence of TRPC1 resulted in decreased placental and fetal weights. At D18, maternal HFD increased placental weights in both TRPC1 KO and WT mice, in part, by moderately increasing placental tissue triacylglyceride (TAG, P=.0632). At D12, mRNA expression of key placental growth factors including IGF1, PLGF, and VEGF were increased in WT compared to TRPC1 KO mice while IGF2 and VEGF mRNA expression were increased at D18. Results presented in our study demonstrated that maternal HFD increased placental weight, in part, due to increased lipid concentration resulting in IUGR and via an additive adverse effect of genotype and maternal HFD. Future studies are needed to determine the signaling mechanism underlying Ca2+ influx reduction-induced placental dysfunction and IUGR.

Corrigendum: Lipidomic Analysis of TRPC1 Ca2+-Permeable Channel-Knock Out Mouse Demonstrates a Vital Role in Placental Tissue Sphingolipid and Triacylglycerol Homeostasis Under Maternal High-Fat Diet.

[This corrects the article DOI: 10.3389/fendo.2022.854269.].

Effect of a maternal high-fat diet with vegetable substitution on fetal brain transcriptome.

Maternal dietary conditions play a major role in fetal growth and brain development. The primary aim of this study was to determine the effects of 5% of energy substitution by vegetables in a maternal dietary fat on placental and fetal weight and on fetal brain gene expression. Two-month-old female C57BL/6 mice were fed 16% (normal-fat, NF), 45% fat (HF), or HF substituted with vegetables (5% energy, HF+VS) diets for 12 weeks. Dams were then bred with NF diet-fed male mice. Placenta and fetal weights were measured at gestational age 19 (D19). RNA was isolated from fetal whole brains and sequenced using Illumina HiSeq. HF+VS diet prevented maternal HF diet-induced decreases in placental weight at D19. Feeding of a maternal HF diet was associated with 79 differentially expressed genes (DEGs), while maternal vegetable substitution was associated with 131 DEGs. The vegetable substitution diet decreased Apold1 (P=.0319), Spata2l (P=.0404), and Celsr1 (P<.03) expression compared to HF diet. Enrichment analysis of HF vs. HF+VS DEGs identified that synapse organization and regulation of embryonic development were significantly represented. KEGG enrichment analysis identified a significant representation of DEGs in the ubiquitin mediated proteolysis pathway in HF vs. HF+VS, and chemokine signaling pathway in NF vs. HF. These findings suggest that at D19, in a rodent model, a maternal HF diet alters placental and fetal growth, and that vegetable supplementation renders a protective effect against these changes.

Lipidomic Analysis of TRPC1 Ca2+-Permeable Channel-Knock Out Mouse Demonstrates a Vital Role in Placental Tissue Sphingolipid and Triacylglycerol Homeostasis Under Maternal High-Fat Diet.

The transient receptor potential canonical channel 1 (TRPC1) is a ubiquitous Ca2+-permeable integral membrane protein present in most tissues, including adipose and placenta, and functionally regulates energetic homeostasis. We demonstrated that elimination of TRPC1 in a mouse model increased body adiposity and limited adipose accumulation under a high fat diet (HFD) even under conditions of exercise. Additionally, intracellular Ca2+ regulates membrane lipid content via the activation of the protein kinase C pathway, which may impact placental membrane lipid content and structure. Based upon this we investigated the effect of HFD and TRPC1 elimination on neutral lipids (triacylglycerol and cholesteryl ester), membrane lipids (phosphatidylcholine and phosphatidylethanolamine), and other multifunctional lipid species (unesterified cholesterol, sphingomyelins, ceramides). The concentration of unesterified cholesterol and sphingomyelin increased with gestational age (E12.5 to E 18.5.) indicating possible increases in plasma membrane fluidity. Diet-dependent increases ceramide concentration at E12.5 suggest a pro-inflammatory role for HFD in early gestation. TRPC1-dependent decreases in cholesterol ester concentration with concomitant increases in long-chain polyunsaturated fatty acid -containing triacylglycerols indicate a disruption of neutral lipid homeostasis that may be tied to Ca2+ regulation. These results align with changes in lipid content observed in studies of preeclamptic human placenta.

DNA methylation dataset of bovine embryonic fibroblast cells treated with epigenetic modifiers and divergent energy supply.

Fetal programming is established early in life, likely through epigenetic mechanisms that control gene expression. Micronutrients can act as epigenetic modifiers (EM) by modulating the genome through mechanisms that include DNA methylation and post-translational modification of chromatin. Among the EM, methionine, choline, folate, and vitamin B12 have been suggested as key players of DNA methylation. However, the effects of supplementing these four EM, involved in the methionine folate cycle on DNA methylation, are still under investigation. This manuscript provides the genome-wide DNA methylation dataset (GSE180362) of bovine embryonic fibroblast cells exposed to different supplementation levels of glucose and methionine, choline, folate, and vitamin B12 (collectively named as Epigenetic Modifiers - EM). The DNA methylation was measured using MSP-I digestion and Reduced Representation Bisulfite Sequencing. Bioinformatics analyses included data quality control, read mapping, methylation calling, and differential methylation analyses. Supplementary file S1 and data analysis codes are within this article. To our knowledge, this is the first dataset investigating the effects of four EM in bovine embryonic fibroblast DNA methylation profiles. Furthermore, this data and its findings provide information on putative candidate genes responsive to DNA methylation due to EM supplementation.

Epigenetic Modifier Supplementation Improves Mitochondrial Respiration and Growth Rates and Alters DNA Methylation of Bovine Embryonic Fibroblast Cells Cultured in Divergent Energy Supply.

Epigenetic modifiers (EM; methionine, choline, folate, and vitamin B12) are important for early embryonic development due to their roles as methyl donors or cofactors in methylation reactions. Additionally, they are essential for the synthesis of nucleotides, polyamines, redox equivalents, and energy metabolites. Despite their importance, investigation into the supplementation of EM in ruminants has been limited to one or two epigenetic modifiers. Like all biochemical pathways, one-carbon metabolism needs to be stoichiometrically balanced. Thus, we investigated the effects of supplementing four EM encompassing the methionine-folate cycle on bovine embryonic fibroblast growth, mitochondrial function, and DNA methylation. We hypothesized that EM supplemented to embryonic fibroblasts cultured in divergent glucose media would increase mitochondrial respiration and cell growth rate and alter DNA methylation as reflected by changes in the gene expression of enzymes involved in methylation reactions, thereby improving the growth parameters beyond Control treated cells. Bovine embryonic fibroblast cells were cultured in Eagle's minimum essential medium with 1 g/L glucose (Low) or 4.5 g/L glucose (High). The control medium contained no additional OCM, whereas the treated media contained supplemented EM at 2.5, 5, and 10 times (×2.5, ×5, and ×10, respectively) the control media, except for methionine (limited to ×2). Therefore, the experimental design was a 2 (levels of glucose) × 4 (levels of EM) factorial arrangement of treatments. Cells were passaged three times in their respective treatment media before analysis for growth rate, cell proliferation, mitochondrial respiration, transcript abundance of methionine-folate cycle enzymes, and DNA methylation by reduced-representation bisulfite sequencing. Total cell growth was greatest in High ×10 and mitochondrial maximal respiration, and reserve capacity was greatest (p < 0.01) for High ×2.5 and ×10 compared with all other treatments. In Low cells, the total growth rate, mitochondrial maximal respiration, and reserve capacity increased quadratically to 2.5 and ×5 and decreased to control levels at ×10. The biological processes identified due to differential methylation included the positive regulation of GTPase activity, molecular function, protein modification processes, phosphorylation, and metabolic processes. These data are interpreted to imply that EM increased the growth rate and mitochondrial function beyond Control treated cells in both Low and High cells, which may be due to changes in the methylation of genes involved with growth and energy metabolism.

Postnatal exercise protects offspring from high-fat diet-induced reductions in subcutaneous adipocyte beiging in C57Bl6/J mice.

Maternal low-protein and postnatal high-fat (HF) diets program offspring obesity and type 2 diabetes mellitus (T2DM) risk by epigenetically reducing beige adipocytes (BAs) via increased G9a protein expression (Histone3 Lysine9 dimethyl transferase), an inhibitor of the BA marker fibroblast growth factor 21 (FGF21). Conversely, offspring exercise reduces fat mass and white adipocytes, but the mechanisms are not yet understood. This work investigated whether exercise reduces offspring obesity and T2DM risk caused by a maternal HF diet via regulation of G9a and FGF21 expression that would convert white to BA. Two-month-old female C57Bl/6J mice (F0) were fed a 16% (normal fat; NF) or a 45% HF diet for 3 months prior to breeding, and subsequent gestation and lactation. Male offspring (F1) were fed the same NF and HF diets and further divided into either sedentary (S) or voluntary wheel running (Ex) groups for an additional 3 months yielding eight groups: NF (maternal treatment condition)-NF-S (postweaning treatment conditions), NF-HF-S, NF-NF-Ex, NF-HF-Ex, HF-NF-S, HF-HF-S, HF-NF-Ex, and HF-HF-Ex. Subcutaneous adipose tissue was collected for protein and mRNA analysis of FGF21, peroxisome proliferator-activated receptor-gamma coactivator (PGC-1 alpha, inducer of FGF21), G9a, E4BP4 (G9a coactivator), and protein expression of H3K9 demethylases (KDM4C). Postnatal HF diet decreased FGF21 positive BA numbers regardless of maternal diets and postnatal exercise. Under sedentary conditions, postnatal HF diet increased protein expression of FGF21 transcription inhibitors G9a and E4BP4 compared to NF diet resulting in decreased FGF21 expression. In contrast, postnatal HF diet and exercise decreased G9a and E4BP4 protein expression while decreasing FGF21 expression compared to NF diet. Under exercised condition, postnatal HF diet-induced KDM4C protein expression while no changes in KDM4C protein expression were induced by postnatal HF diet under sedentary conditions. These findings suggest that the postnatal diet exerts a greater impact on offspring adiposity and BA numbers than maternal diets. These data also suggest that offspring exercise induces KDM4C to counter the increase in G9a that was triggered by maternal and postnatal HF diets. Future studies need to determine whether KDM4C induces methylation status of G9a to alter thermogenic function of BA.

Paternal high-fat diet and exercise regulate sperm miRNA and histone methylation to modify placental inflammation, nutrient transporter mRNA expression and fetal weight in a sex-dependent manner.

We previously have shown that male offspring (F1) of fathers (F0) fed a high-fat (HF) diet and that exercised had greater skeletal muscle insulin signaling and reduced type 2 diabetes mellitus (T2DM) risk compared to fathers fed HF diet and that remained sedentary. The current study extends this work by hypothesizing that F0 HF diet and exercise regulate F1 T2DM risk by alterations in placental tissue growth via changes in sperm miRNA expression. To test these hypotheses, 3-week-old male C57BL/6 mice were fed a normal-fat diet (16% fat) or an HF diet (45% fat) and assigned to either voluntary wheel running exercise or cage activity for 3 months. Results showed that F0 sperm miRNA 193b expression was decreased while miRNA 204 was increased by paternal exercise. Protein expression of dimethylated histone 3 lysine 9 was decreased with F0 HF diet. Placental and fetal tissue weights were decreased by F0 HF diet in F1 males. Placental interleukin-1ß and tumor necrosis factor (TNF)-α mRNA expression was reduced by paternal exercise, while nutrient transporter mRNA expression was decreased by paternal HF diet only in the placentae of F1 females. Treatment of primary placental cell with miRNA 193b inhibited TNF-α mRNA expression, and treatment of TNF-α decreased SLC38a2 mRNA expression. Moreover, paternal exercise increased body weight at weaning in a female offspring. These results demonstrate that placental tissue weight, placental nutrient transporter gene expression and fetal weights are altered by paternal exercise, while placental inflammatory gene expression is influenced by paternal exercise in offspring in a sex-specific manner.

Nutrients and Immunometabolism: Role of Macrophage NLRP3.

Inflammation is largely mediated by immune cells responding to invading pathogens, whereas metabolism is oriented toward producing usable energy for vital cell functions. Immunometabolic alterations are considered key determinants of chronic inflammation, which leads to the development of chronic diseases. Studies have demonstrated that macrophages and the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome are activated in key metabolic tissues to contribute to increased risk for type 2 diabetes mellitus, Alzheimer disease, and liver diseases. Thus, understanding the tissue-/cell-type-specific regulation of the NLRP3 inflammasome is crucial for developing intervention strategies. Currently, most of the nutrients and bioactive compounds tested to determine their inflammation-reducing effects are limited to animal models. Future studies need to address how dietary compounds regulate immune and metabolic cell reprograming in humans.

Ca2+ entry via TRPC1 is essential for cellular differentiation and modulates secretion via the SNARE complex.

Properties of adipocytes, including differentiation and adipokine secretion, are crucial factors in obesity-associated metabolic syndrome. Here, we provide evidence that Ca2+ influx in primary adipocytes, especially upon Ca2+ store depletion, plays an important role in adipocyte differentiation, functionality and subsequently metabolic regulation. The endogenous Ca2+ entry channel in both subcutaneous and visceral adipocytes was found to be dependent on TRPC1-STIM1, and blocking Ca2+ entry with SKF96365 or using TRPC1-/- knockdown adipocytes inhibited adipocyte differentiation. Additionally, TRPC1-/- mice have decreased organ weight, but increased adipose deposition and reduced serum adiponectin and leptin concentrations, without affecting total adipokine expression. Mechanistically, TRPC1-mediated Ca2+ entry regulated SNARE complex formation, and agonist-mediated secretion of adipokine-loaded vesicles was inhibited in TRPC1-/- adipose. These results suggest an unequivocal role of TRPC1 in adipocyte differentiation and adiponectin secretion, and that loss of TRPC1 disturbs metabolic homeostasis.This article has an associated First Person interview with the first author of the paper.

A Diet Enriched in Palmitate and Deficient in Linoleate Exacerbates Oxidative Stress and Amyloid-ß Burden in the Hippocampus of 3xTg-AD Mouse Model of Alzheimer's Disease.

Epidemiological studies have suggested a positive correlation between saturated fat intake and the risk for developing Alzheimer's disease (AD). While diets-enriched in the saturated free fatty acid (sFFA) palmitate has been shown to induce cognitive dysfunction and AD-like pathology, polyunsaturated fatty acids (PUFA) such as linoleate have been suggested to protect against AD in mouse models. However, the underlying cellular and molecular mechanisms that mediate the deleterious effects of palmitate or the protective effects of linoleate remain to be characterized. We fed 9-month-old cohorts of triple transgenic AD mice (3xTg-AD) and their-matched controls with a palmitate-enriched/linoleate-deficient diet for three months and determined the impact of the diet on oxidative stress, Bace1 promoter transactivation status, and amyloid-ß (Aß) burden. The palmitate-enriched/linoleate-deficient diet causes a profound increase in oxidative stress burden characterized by significant oxidative damage to lipids, proteins, and nucleic acids concomitant with deficits in the endogenous antioxidant defense capacity in the hippocampi of 3xTg-AD mice. These effects were also associated with increased NF-κB transcriptional activity resulting in NF-κB-mediated transactivation of the Bace1 promoter that culminated in higher BACE1 expression and activity, and Aß production. Our study unveils a novel mechanism by which a diet enriched in the sFFA palmitate and deficient in the PUFA linoleate exacerbates AD-like pathology involving signaling cross-talk between oxidative stress and NF-κB activation as a critical underlying factor in upregulating BACE1 activity and increasing Aß burden.

Palmitate-Induced SREBP1 Expression and Activation Underlies the Increased BACE 1 Activity and Amyloid Beta Genesis.

Numerous cross-sectional and longitudinal studies have implicated saturated fat-enriched diets in the etio-pathogenesis of Alzheimer's disease (AD). Emerging evidence shows that saturated fat-enriched diets, such as palmitate-enriched diets, increase amyloid-beta (Aß) production, the histopathological hallmark of AD. However, the molecular mechanisms that underlie the deleterious effects of palmitate-enriched diets in the augmentation of Aß genesis are yet to be characterized. Sterol response element binding protein 1 (SREBP1) is a transcription factor that is modulated by saturated fatty acids, such as palmitate, and consequently regulates the expression of genes that code for proteins involved in almost all facets of lipid metabolism. Herein, we determined the role of changes in SREBP1 expression and transcriptional activity in the palmitate-induced effects on Aß genesis and BACE1 expression, the enzyme that catalyzes the rate-limiting step in Aß biosynthesis. We demonstrate that palmitate-induced SREBP1 activation directly regulates BACE1 expression at the transcriptional level in the mouse hippocampus and mouse Neuro-2a (N2a) neuroblastoma cells. Chromatin immunoprecipitation (ChIP) studies show that palmitate increases the binding of SREBP1 to the Bace1 promoter region in the mouse hippocampus and mouse N2a neuroblastoma cells. Ectopic expression of the dominant negative SREBP1 mutant and knocking-down SREBP1 expression significantly reduced the palmitate-induced increase in BACE1 expression and subsequent Aß genesis in mouse N2a neuroblastoma cells. Our study unveils SREBP1 activation as a novel molecular player in the palmitate-induced upregulation of BACE1 expression and subsequent Aß genesis.

Tart Cherry Reduces Inflammation in Adipose Tissue of Zucker Fatty Rats and Cultured 3T3-L1 Adipocytes.

Obesity increases adipose tissue inflammation and secretion of pro-inflammatory adipokines, which have systemic effects on the organism's health status. Our objective was to dissect mechanisms of anti-inflammatory effects of tart cherry (TC) in adipose tissue of Zucker fatty rats, and cultured 3T3-L1 adipocytes. Rats were fed either a control diet, or 4% TC powder diets for eight weeks. Body and epididymal fat pad weights were not significantly different between control and TC groups. However, rats fed the TC diet had significantly reduced adipose tissue inflammation (p < 0.05), as determined by reduced mRNA levels of pro-inflammatory markers including interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα), interleukin-1beta (IL-1ß), monocyte chemoattractant protein 1 (MCP-1), inducible nitric oxide synthase (iNOS), and CD-11b, and increased mRNA levels of type-1 arginase (Arg-1) anti-inflammatory marker. Consistent with these in vivo results, TC significantly decreased expression of IL-6 mRNA and protein levels in lipopolysaccharide (LPS) stimulated adipocytes compared to those stimulated with LPS, but no TC. Moreover, both in vivo (rat adipose tissue) and in vitro (3T3-L1 adipocytes), phosphorylation of p65-NF-κB subunit was significantly reduced by TC. Additionally, TC decreased mRNA expression of fatty acid synthase (FASN), and increased expression of peroxisome proliferator-activated receptor alpha (PPARα), master regulator of lipid oxidation, and anti-oxidant markers nuclear factor erythroid-derived 2-related factor (NRFs) in both models. In conclusion, our findings indicate that TC downregulates inflammation in part via the nuclear factor kappa B (NF-κB) pathway in adipose tissue. Thus, TC may serve as a potential intervention to reduce obesity-associated inflammation.

Paternal exercise protects mouse offspring from high-fat-diet-induced type 2 diabetes risk by increasing skeletal muscle insulin signaling.

Paternal obesity increases, while paternal exercise decreases, offspring obesity and type 2 diabetes (T2D) risk; however, no studies have determined whether a paternal high-fat (HF) diet and exercise interact to alter offspring body weight (BW), adiposity and T2D risk. Three-week-old male C57BL/6 mice were fed a normal-fat (NF) diet (16% fat) or an HF diet (45% fat) and assigned to either voluntary wheel running exercise or cage activity for 3 months prior to mating with NF-diet-fed dams. After weaning, male offspring were fed an NF or HF diet for an additional 3 months. F1 male mice whose fathers ate an HF diet had decreased % body fat accompanied by decreased gene expression of beige adipocyte marker FGF21. However, paternal HF-diet-induced reductions in F1 offspring % body fat normalized but did not reduce T2D risk. Exercise was protective against paternal HF-diet-induced insulin resistance by increasing the expression of insulin signaling (GLUT4, IRS1 and PI3K) markers in skeletal muscle resulting in normal T2D risk. When fathers were fed an HF diet and exercised, a postnatal HF diet increased beiging (PPARγ). Thus, these findings show that increases in T2D risk in male offspring when the father consumes an HF diet can be normalized when the father also exercises preconception and that this protection may occur by increases in insulin signaling potential within offspring skeletal muscle. Future studies should further determine the physiological mechanism(s) underlying the beneficial effects of exercise through the paternal lineage.

A diet high in carotenoid-rich vegetables and fruits favorably impacts inflammation status by increasing plasma concentrations of IFN-α2 and decreasing MIP-1ß and TNF-α in healthy individuals during a controlled feeding trial.

The health benefits of vegetable and fruit (VF) intake include benefits for diseases that have an inflammatory component, although the relationship between VF intake and systemic inflammatory status is unclear due to the lack of comprehensive analysis of inflammatory markers in most studies. Therefore, our hypothesis was that the consumption of carotenoid-rich vegetables and fruits in the diet would have a beneficial effect on systemic inflammation status. In this study, we determined the association between varying doses of carotenoid-rich VF intake, plasma carotenoids, and a broad array of markers including 26 cytokines and high-sensitivity C-reactive protein. Data were derived from a single-arm controlled clinical feeding trial in which healthy, nonobese individuals received a low-carotenoid prescription for 6 weeks and then consumed a provided high-VF diet for 8 weeks. Proinflammatory cytokines and plasma carotenoids were measured at baseline, at 6 weeks, and at the end of the 8-week feeding period. Maximum likelihood estimation was used to calculate overall correlations between total plasma carotenoid concentrations and the cytokines. Plasma carotenoids decreased during the low-carotenoid treatment and increased during the feeding treatment. Of the inflammatory markers measured, we found increased plasma concentrations of interferon α-2 (P = .003) and decreased macrophage inflammatory protein-1ß (P = .027) and tumor necrosis factor-α (P = .012) after consumption of the carotenoid-rich diet. These results indicate that consumption of VF may be important in the maintenance of beneficial inflammatory homeostasis.

The TRPC1 Ca2+-permeable channel inhibits exercise-induced protection against high-fat diet-induced obesity and type II diabetes.

The transient receptor potential canonical channel-1 (TRPC1) is a Ca2+-permeable channel found in key metabolic organs and tissues, including the hypothalamus, adipose tissue, and skeletal muscle. Loss of TRPC1 may alter the regulation of cellular energy metabolism resulting in insulin resistance thereby leading to diabetes. Exercise reduces insulin resistance, but it is not known whether TRPC1 is involved in exercise-induced insulin sensitivity. The role of TRPC1 in adiposity and obesity-associated metabolic diseases has not yet been determined. Our results show that TRPC1 functions as a major Ca2+ entry channel in adipocytes. We have also shown that fat mass and fasting glucose concentrations were lower in TRPC1 KO mice that were fed a high-fat (HF) (45% fat) diet and exercised as compared with WT mice fed a HF diet and exercised. Adipocyte numbers were decreased in both subcutaneous and visceral adipose tissue of TRPC1 KO mice fed a HF diet and exercised. Finally, autophagy markers were decreased and apoptosis markers increased in TRPC1 KO mice fed a HF diet and exercised. Overall, these findings suggest that TRPC1 plays an important role in the regulation of adiposity via autophagy and apoptosis and that TRPC1 inhibits the positive effect of exercise on type II diabetes risk under a HF diet-induced obesity environment.

Maternal low-protein diet decreases brain-derived neurotrophic factor expression in the brains of the neonatal rat offspring.

Prenatal exposure to a maternal low-protein (LP) diet has been known to cause cognitive impairment, learning and memory deficits. However, the underlying mechanisms have not been identified. Herein, we demonstrate that a maternal LP diet causes, in the brains of the neonatal rat offspring, an attenuation in the basal expression of the brain-derived neurotrophic factor (BDNF), a neurotrophin indispensable for learning and memory. Female rats were fed either a 20% normal protein (NP) diet or an 8% LP 3 weeks before breeding and during the gestation period. Maternal LP diet caused a significant reduction in the Bdnf expression in the brains of the neonatal rats. We further found that the maternal LP diet reduced the activation of the cAMP/protein kinase A/cAMP response element binding protein (CREB) signaling pathway. This reduction was associated with a significant decrease in CREB binding to the Bdnf promoters. We also show that prenatal exposure to the maternal LP diet results in an inactive or repressed exon I and exon IV promoter of the Bdnf gene in the brain, as evidenced by fluxes in signatory hallmarks in the enrichment of acetylated and trimethylated histones in the nucleosomes that envelop the exon I and exon IV promoters, causing the Bdnf gene to be refractory to transactivation. Our study is the first to determine the impact of a maternal LP diet on the basal expression of BDNF in the brains of the neonatal rats exposed prenatally to an LP diet.