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1.  Differential Pathways to Adult Metabolic Dysfunction following Poor Nutrition at Two Critical Developmental Periods in Sheep 
PLoS ONE  2014;9(3):e90994.
Epidemiological and experimental studies suggest early nutrition has long-term effects on susceptibility to obesity, cardiovascular and metabolic diseases. Small and large animal models confirm the influence of different windows of sensitivity, from fetal to early postnatal life, on offspring phenotype. We showed previously that undernutrition in sheep either during the first month of gestation or immediately after weaning induces differential, sex-specific changes in adult metabolic and cardiovascular systems. The current study aims to determine metabolic and molecular changes that underlie differences in lipid and glucose metabolism induced by undernutrition during specific developmental periods in male and female sheep. Ewes received 100% (C) or 50% nutritional requirements (U) from 1–31 days gestation, and 100% thereafter. From weaning (12 weeks) to 25 weeks, offspring were then fed either ad libitum (CC, UC) or were undernourished (CU, UU) to reduce body weight to 85% of their individual target. From 25 weeks, all offspring were fed ad libitum. A cohort of late gestation fetuses were studied after receiving either 40% nutritional requirements (1–31 days gestation) or 50% nutritional requirements (104–127 days gestation). Post-weaning undernutrition increased in vivo insulin sensitivity, insulin receptor and glucose transporter 4 expression in muscle, and lowered hepatic methylation at the delta-like homolog 1/maternally expressed gene 3 imprinted cluster in adult females, but not males. Early gestational undernutrition induced lower hepatic expression of gluconeogenic factors in fetuses and reduced in vivo adipose tissue insulin sensitivity in adulthood. In males, undernutrition in early gestation increased adipose tissue lipid handling mechanisms (lipoprotein lipase, glucocorticoid receptor expression) and hepatic methylation within the imprinted control region of insulin-like growth factor 2 receptor in adulthood. Therefore, undernutrition during development induces changes in mechanisms of lipid and glucose metabolism which differ between tissues and sexes dependent on the period of nutritional restriction. Such changes may increase later life obesity and dyslipidaemia risk.
doi:10.1371/journal.pone.0090994
PMCID: PMC3946277  PMID: 24603546
2.  Site Distribution at the Edge of the Palaeolithic World: A Nutritional Niche Approach 
PLoS ONE  2013;8(12):e81476.
This paper presents data from the English Channel area of Britain and Northern France on the spatial distribution of Lower to early Middle Palaeolithic pre-MIS5 interglacial sites which are used to test the contention that the pattern of the richest sites is a real archaeological distribution and not of taphonomic origin. These sites show a marked concentration in the middle-lower reaches of river valleys with most being upstream of, but close to, estimated interglacial tidal limits. A plant and animal database derived from Middle-Late Pleistocene sites in the region is used to estimate the potentially edible foods and their distribution in the typically undulating landscape of the region. This is then converted into the potential availability of macronutrients (proteins, carbohydrates, fats) and selected micronutrients. The floodplain is shown to be the optimum location in the nutritional landscape (nutriscape). In addition to both absolute and seasonal macronutrient advantages the floodplains could have provided foods rich in key micronutrients, which are linked to better health, the maintenance of fertility and minimization of infant mortality. Such places may have been seen as ‘good (or healthy) places’ explaining the high number of artefacts accumulated by repeated visitation over long periods of time and possible occupation. The distribution of these sites reflects the richest aquatic and wetland successional habitats along valley floors. Such locations would have provided foods rich in a wide range of nutrients, importantly including those in short supply at these latitudes. When combined with other benefits, the high nutrient diversity made these locations the optimal niche in northwest European mixed temperate woodland environments. It is argued here that the use of these nutritionally advantageous locations as nodal or central points facilitated a healthy variant of the Palaeolithic diet which permitted habitation at the edge of these hominins’ range.
doi:10.1371/journal.pone.0081476
PMCID: PMC3858259  PMID: 24339935
3.  Maternal fat intake in rats alters 20:4n-6 and 22:6n-3 status and the epigenetic regulation of Fads2 in offspring liver☆☆☆★ 
Poor prenatal nutrition, acting through epigenetic processes, induces persistent changes in offspring phenotype. We investigated the effect of maternal fat intake on polyunsaturated fatty acid (PUFA) status and on the epigenetic regulation of Fads2, encoding Δ6 desaturase (rate limiting in PUFA synthesis), in the adult offspring. Rats (n=6 per dietary group) were fed either 3.5% (w/w), 7% (w/w) or 21% (w/w) butter or fish oil (FO) from 14 days preconception until weaning. Offspring (n=6 males and females per dietary group) were fed 4% (w/w) soybean oil until postnatal day 77. 20:4n-6 and 22:6n-3 levels were lower in liver phosphatidylcholine (PC) and phosphatidylethanolamine and plasma PC (all P<.0001) in offspring of dams fed 21% than 3.5% or 7% fat regardless of type. Hepatic Fads2 expression related inversely to maternal dietary fat. Fads2 messenger RNA expression correlated negatively with methylation of CpGs at −623, −394, −84 and −76 bases relative to the transcription start site (all P<.005). Methylation of these CpGs was higher in offspring of dams fed 21% than 3.5% or 7% fat; FO higher than butter. Feeding adult female rats 7% fat reduced 20:4n-6 status in liver PC and Fads2 expression and increased methylation of CpGs −623, −394, −84 and −76 that reversed in animals switched from 7% to 4% fat diets. These findings suggest that fat exposure during development induces persistent changes, while adults exhibit a transient response, in hepatic PUFA status in offspring through epigenetic regulation of Fads2. Thus, epigenetic regulation of Fads2 may contribute to short- and long-term regulation of PUFA synthesis.
doi:10.1016/j.jnutbio.2012.09.005
PMCID: PMC3698442  PMID: 23107313
Maternal dietary fat; Early life programming; Liver; Arachidonic acid; Docosahexaenoic acid; Δ6 desaturase
4.  Tissue-Specific 5′ Heterogeneity of PPARα Transcripts and Their Differential Regulation by Leptin 
PLoS ONE  2013;8(6):e67483.
The genes encoding nuclear receptors comprise multiple 5′untranslated exons, which give rise to several transcripts encoding the same protein, allowing tissue-specific regulation of expression. Both human and mouse peroxisome proliferator activated receptor (PPAR) α genes have multiple promoters, although their function is unknown. Here we have characterised the rat PPARα promoter region and have identified three alternative PPARα transcripts, which have different transcription start sites owing to the utilisation of distinct first exons. Moreover these alternative PPARα transcripts were differentially expressed between adipose tissue and liver. We show that while the major adipose (P1) and liver (P2) transcripts were both induced by dexamethasone, they were differentially regulated by the PPARα agonist, clofibric acid, and leptin. Leptin had no effect on the adipose-specific P1 transcript, but induced liver-specific P2 promoter activity via a STAT3/Sp1 mechanism. Moreover in Wistar rats, leptin treatment between postnatal day 3–13 led to an increase in P2 but not P1 transcription in adipose tissue which was sustained into adulthood. This suggests that the expression of the alternative PPARα transcripts are in part programmed by early life exposure to leptin leading to persistent change in adipose tissue fatty acid metabolism through specific activation of a quiescent PPARα promoter. Such complexity in the regulation of PPARα may allow the expression of PPARα to be finely regulated in response to environmental factors.
doi:10.1371/journal.pone.0067483
PMCID: PMC3692471  PMID: 23825665
5.  Epigenetic Gene Promoter Methylation at Birth Is Associated With Child’s Later Adiposity 
Diabetes  2011;60(5):1528-1534.
OBJECTIVE
Fixed genomic variation explains only a small proportion of the risk of adiposity. In animal models, maternal diet alters offspring body composition, accompanied by epigenetic changes in metabolic control genes. Little is known about whether such processes operate in humans.
RESEARCH DESIGN AND METHODS
Using Sequenom MassARRAY we measured the methylation status of 68 CpGs 5′ from five candidate genes in umbilical cord tissue DNA from healthy neonates. Methylation varied greatly at particular CpGs: for 31 CpGs with median methylation ≥5% and a 5–95% range ≥10%, we related methylation status to maternal pregnancy diet and to child’s adiposity at age 9 years. Replication was sought in a second independent cohort.
RESULTS
In cohort 1, retinoid X receptor-α (RXRA) chr9:136355885+ and endothelial nitric oxide synthase (eNOS) chr7:150315553+ methylation had independent associations with sex-adjusted childhood fat mass (exponentiated regression coefficient [β] 17% per SD change in methylation [95% CI 4–31], P = 0.009, n = 64, and β = 20% [9–32], P < 0.001, n = 66, respectively) and %fat mass (β = 10% [1–19], P = 0.023, n = 64 and β =12% [4–20], P = 0.002, n = 66, respectively). Regression analyses including sex and neonatal epigenetic marks explained >25% of the variance in childhood adiposity. Higher methylation of RXRA chr9:136355885+, but not of eNOS chr7:150315553+, was associated with lower maternal carbohydrate intake in early pregnancy, previously linked with higher neonatal adiposity in this population. In cohort 2, cord eNOS chr7:150315553+ methylation showed no association with adiposity, but RXRA chr9:136355885+ methylation showed similar associations with fat mass and %fat mass (β = 6% [2–10] and β = 4% [1–7], respectively, both P = 0.002, n = 239).
CONCLUSIONS
Our findings suggest a substantial component of metabolic disease risk has a prenatal developmental basis. Perinatal epigenetic analysis may have utility in identifying individual vulnerability to later obesity and metabolic disease.
doi:10.2337/db10-0979
PMCID: PMC3115550  PMID: 21471513
6.  Vascular Dysfunction Induced in Offspring by Maternal Dietary Fat Involves Altered Arterial Polyunsaturated Fatty Acid Biosynthesis 
PLoS ONE  2012;7(4):e34492.
Nutrition during development affects risk of future cardiovascular disease. Relatively little is known about whether the amount and type of fat in the maternal diet affect vascular function in the offspring. To investigate this, pregnant and lactating rats were fed either 7%(w/w) or 21%(w/w) fat enriched in either18:2n-6, trans fatty acids, saturated fatty acids, or fish oil. Their offspring were fed 4%(w/w) soybean oil from weaning until day 77. Type and amount of maternal dietary fat altered acetylcholine (ACh)-mediated vaso-relaxation in offspring aortae and mesenteric arteries, contingent on sex. Amount, but not type, of maternal dietary fat altered phenylephrine (Pe)-induced vasoconstriction in these arteries. Maternal 21% fat diet decreased 20:4n-6 concentration in offspring aortae. We investigated the role of Δ6 and Δ5 desaturases, showing that their inhibition in aortae and mesenteric arteries reduced vasoconstriction, but not vaso-relaxation, and the synthesis of specific pro-constriction eicosanoids. Removal of the aortic endothelium did not alter the effect of inhibition of Δ6 and Δ5 desaturases on Pe-mediated vasoconstriction. Thus arterial smooth muscle 20:4n-6 biosynthesis de novo appears to be important for Pe-mediated vasoconstriction. Next we studied genes encoding these desaturases, finding that maternal 21% fat reduced Fads2 mRNA expression and increased Fads1 in offspring aortae, indicating dysregulation of 20:4n-6 biosynthesis. Methylation at CpG −394 bp 5′ to the Fads2 transcription start site predicted its expression. This locus was hypermethylated in offspring of dams fed 21% fat. Pe treatment of aortae for 10 minutes increased Fads2, but not Fads1, mRNA expression (76%; P<0.05). This suggests that Fads2 may be an immediate early gene in the response of aortae to Pe. Thus both amount and type of maternal dietary fat induce altered regulation of vascular tone in offspring though differential effects on vaso-relaxation, and persistent changes in vasoconstriction via epigenetic processes controlling arterial polyunsaturated fatty acid biosynthesis.
doi:10.1371/journal.pone.0034492
PMCID: PMC3317992  PMID: 22509311
7.  Effect of sex and dietary fat intake on the fatty acid composition of phospholipids and triacylglycerol in rat heart 
Variations in the fatty acid composition of lipids in the heart alter its function and susceptibility to ischaemic injury. We investigated the effect of sex and dietary fat intake on the fatty acid composition of phospholipids and triacylglycerol in rat heart. Rats were fed either 40 or 100 g/kg fat (9:1 lard:soybean oil) from weaning until day 105. There were significant interactive effects of sex and fat intake on the proportions of fatty acids in heart phospholipids, dependent on phospholipid classes. 20:4n-6, but not 22:6n-3, was higher in phospholipids in females than males fed a low, but not a high, fat diet. There was no effect of sex on the composition of triacylglycerol. These findings suggest that sex is an important factor in determining the incorporation of dietary fatty acids into cardiac lipids. This may have implications for sex differences in susceptibility to heart disease.
doi:10.1016/j.plefa.2010.07.006
PMCID: PMC3000522  PMID: 20719489
Heart; Fatty acids; Phophospholipids; Triacylglycerol; Sex; Rat
8.  Physical Inactivity Differentially Alters Dietary Oleate and Palmitate Trafficking 
Diabetes  2009;58(2):367-376.
OBJECTIVE— Obesity and diabetes are characterized by the incapacity to use fat as fuel. We hypothesized that this reduced fat oxidation is secondary to a sedentary lifestyle.
RESEARCH DESIGN AND METHODS— We investigated the effect of a 2-month bed rest on the dietary oleate and palmitate trafficking in lean women (control group, n = 8) and the effect of concomitant resistance/aerobic exercise training as a countermeasure (exercise group, n = 8). Trafficking of stable isotope–labeled dietary fats was combined with muscle gene expression and magnetic resonance imaging–derived muscle fat content analyses.
RESULTS— In the control group, bed rest increased the cumulative [1-13C]oleate and [d31]palmitate appearance in triglycerides (37%, P = 0.009, and 34%, P = 0.016, respectively) and nonesterified fatty acids (NEFAs) (37%, P = 0.038, and 38%, P = 0.002) and decreased muscle lipoprotein lipase (P = 0.043) and fatty acid translocase CD36 (P = 0.043) mRNA expressions. Plasma NEFA-to-triglyceride ratios for [1-13C]oleate and [d31]palmitate remained unchanged, suggesting that the same proportion of tracers enters the peripheral tissues after bed rest. Bed rest did not affect [1-13C]oleate oxidation but decreased [d31]palmitate oxidation by −8.2 ± 4.9% (P < 0.0001). Despite a decreased spontaneous energy intake and a reduction of 1.9 ± 0.3 kg (P = 0.001) in fat mass, exercise training did not mitigate these alterations but partially maintained fat-free mass, insulin sensitivity, and total lipid oxidation in fasting and fed states. In both groups, muscle fat content increased by 2.7% after bed rest and negatively correlated with the reduction in [d31]palmitate oxidation (r2 = 0.48, P = 0.003).
CONCLUSIONS— While saturated and monounsaturated fats have similar plasma trafficking and clearance, physical inactivity affects the partitioning of saturated fats toward storage, likely leading to an accumulation of palmitate in muscle fat.
doi:10.2337/db08-0263
PMCID: PMC2628610  PMID: 19017764
9.  Nutrition in early life, and risk of cancer and metabolic disease: alternative endings in an epigenetic tale? 
The British journal of nutrition  2008;101(5):619-630.
There is substantial evidence which shows that constraints in the early life environment is an important determinant of risk of metabolic and cardiovascular disease. There is emerging evidence that higher birth weight, which reflects a more abundant prenatal environment, is associated with increased risk of cancer, in particular breast cancer and childhood leukaemia. Using specific examples from epidemiology and experimental studies, this review discusses the hypothesis that increased susceptibility to cardiovascular, metabolic disease and cancer have a common origin in developmental changes induced in the developing fetus by aspects of the intra uterine environment including nutrition which involve stable changes to the epigenetic regulation of specific genes. However, the induction of specific disease risk is dependent upon the nature of the environmental challenge and interactions between the susceptibility set by the altered epigenome and the environment throughout the life course.
doi:10.1017/S0007114508145883
PMCID: PMC2649281  PMID: 19079817
10.  Feeding pregnant rats a protein-restricted diet persistently alters the methylation of specific cytosines in the hepatic PPARα promoter of the offspring 
The British journal of nutrition  2008;100(2):278-282.
Induction of an altered phenotype by prenatal under-nutrition involves changes in the epigenetic regulation of specific genes. We investigated the effect of feeding pregnant rats a protein-restricted (PR) diet with different amounts of folic acid on the methylation of individual CpG dinucleotides in the hepatic PPARα promoter in juvenile offspring, and the effect of the maternal PR diet on CpG methylation in adult offspring. Pregnant rats (n 5 / group) were fed 180g / kg casein (Control) or 90g / kg casein (PR) with 1mg / kg folic acid, or 90g / kg casein and 5 mg / kg folic acid (PRF). Offspring were killed on postnatal d34 (n 5 males and females / group) and d80 (n 5 males / group). Methylation of 16 CpG dinucleotides in the PPARα promoter was measured by pyrosequencing. Mean PPARα promoter methylation in the PR offspring (4.5%) was 26% lower than Controls (6.1%) due to specific reduction at CpG dinucleotides 2 (40%), 3 (43%), 4 (33%) and 16 (48 %) (P < 0.05). There was no significant difference in methylation at these CpGs between Control and PRF offspring. Methylation of CpGs 5 and 8 was higher (47% and 63%, respectively, P < 0.05) in the PRF offspring than Control or PR offspring. The methylation pattern in d80 PR offspring was comparable to d34 PR offspring. These data show for the first time that prenatal nutrition induces differential changes to the methylation of individual CpG dinucleotides in juvenile rats which persist in adults.
doi:10.1017/S0007114507894438
PMCID: PMC2564112  PMID: 18186951
Fetal programming; epigenetic; rat; PPARα
11.  The nature of the growth pattern and of the metabolic response to fasting in the rat are dependent upon the dietary protein and folic acid intakes of their pregnant dams and post-weaning fat consumption 
The British journal of nutrition  2007;99(3):540-549.
The nutritional cues which induce different phenotypes from a single genotype in developing offspring are poorly understood. How well prenatal nutrient availability before birth predicts that after birth may also determine the offspring's response to later metabolic challenge. We investigated the effect of feeding pregnant rats diets containing 180 g/ kg (Control) or 90 g/ kg (PR) protein and either 1 or 5 mg/kg folic acid on growth and metabolic response to fasting in their offspring, and also the effect of diets with different fat contents (40 g/kg (Fat4) or 100g/kg (Fat10) after weaning. Offspring of dams fed the PR diet with 5 mg/kg folic acid were significantly lighter than other offspring. The PR offspring fed the Fat4 diet had lower plasma triacylglycerol (TAG) than the Control offspring, but this relationship was reversed when offspring were fed Fat10. Increasing the folic acid content of the Control or PR maternal diets induced opposing effects on plasma TAG, non-esterified fatty acids, β-hydroxybutyrate and glucose concentrations in offspring fed Fat4. The effect was accentuated in offspring fed the Fat10 diet such that these metabolites were increased in the Control offspring, but reduced in the PR offspring. These data show for the first time that maternal dietary folic acid intake alters offspring phenotype depending upon dietary protein intake, and that this effect is modified by fat intake after weaning. Prevention by increased folic acid intake of an altered metabolic phenotype by maternal protein-restriction may be at the expense of somatic growth.
doi:10.1017/S0007114507815819
PMCID: PMC2493056  PMID: 17761015
Low protein diet; fetal programming; folic acid; Growth; Metabolism
12.  Epigenetic regulation of transcription: A mechanism for inducing variations in phenotype (fetal programming) by differences in nutrition during early life? 
The British journal of nutrition  2007;97(6):1036-1046.
There is considerable evidence for the induction of different phenotypes by variations in the early life environment, including nutrition, which in humans is associated with graded risk of metabolic disease; fetal programming. It is likely that induction of persistent changes to tissue structure and function by differences in the early life environment involves life-long alterations to the regulation of gene transcription. This view is supported by both studies of humans and animal models. The mechanism which underlies such changes to gene expression is now beginning to be understood. In this review we discuss the role of changes in the epigenetic regulation of transcription, specifically DNA methylation and covalent modification of histones, in the induction of an altered phenotype by nutritional constraint in early life. Demonstration of altered epigenetic regulation of genes in phenotype induction suggests the possibility of interventions to modify long-term disease risk associated with unbalanced nutrition in early life.
doi:10.1017/S0007114507682920
PMCID: PMC2211525  PMID: 17381976
Epigenetic; fetal programming; metabolic disease; DNA methylation; DNA methyltransferase
13.  Dietary protein restriction of pregnant rats in the F0 generation induces altered methylation of hepatic gene promoters in the adult male offspring in the F1 and F2 generations 
The British journal of nutrition  2007;97(3):435-439.
Epidemiological studies and experimental models show that maternal nutritional constraint during pregnancy alters the metabolic phenotype of the offspring and that this can be passed to subsequent generations. In the rat, induction of an altered metabolic phenotype in the liver of the F1 generation by feeding a protein-restricted diet (PRD) during pregnancy involves altered methylation of specific gene promoters. We therefore investigated whether altered methylation of peroxisomal proliferator-activated receptor (PPARα) and glucocorticoid receptor (GR) promoters is passed to the F2 generation. Females rats (F0) were fed a reference diet (RD, 18% protein) or PRD (9% protein) throughout gestation, and AIN76A during lactation. F1 offspring were weaned onto AIN76A. F1 females were mated and fed AIN76A throughout pregnancy and lactation. F1 and F2 males were killed on postnatal d 80. Hepatic PPARα and GR promoter methylation was significantly (P<0.05) lower in the PRD group in the F1 (PPARα 8%; GR 10%) and F2 (PPARα 11%; GR 8%) generations. There were trends (P<0.1) towards higher expression of PPARα, GR, acyl-CoA oxidase and phosphoenolpyruvate carboxykinase (PEPCK) in the F1 and F2 males, although this was only significant for PEPCK. These data show for the first time that altered methylation of gene promoters induced in the F1 generation by maternal protein-restriction during pregnancy is transmitted to the F2 generation. This may represent a mechanism for the transmission of induced phenotypes between generations.
doi:10.1017/S0007114507352392
PMCID: PMC2211514  PMID: 17313703
Fetal programming; transgeneration; epigenetic; liver
14.  Induction of altered epigenetic regulation of the hepatic glucocorticoid receptor in the offspring of rats fed a protein-restricted diet during pregnancy suggests that reduced DNA methyltransferase-1 expression is involved in impaired DNA methylation and changes in histone modifications 
The British journal of nutrition  2007;97(6):1064-1073.
Prenatal nutritional constraint induces an altered metabolic phenotype in the offspring which in humans confers an increased risk of non-communicable disease. Feeding a protein-restricted (PR) diet to pregnant rats causes hypomethylation of specific gene promoters in the offspring and alters phenotype. We investigated how altered epigenetic regulation of the hepatic glucocorticoid receptor (GR) 110 promoter is induced in the offspring. Rats were fed a control (180g casein/kg) or a PR (90g casein/kg) diet throughout pregnancy, and chow during lactation. Offspring were killed at postnatal day 34 (n 5 per maternal dietary group). Methylation-sensitive PCR showed GR110 promoter methylation was 33% lower (P<0.001) and GR expression 84% higher (P<0.05) in the PR offspring. RT PCR showed DNA methyltransferase-1 (Dnmt1) expression was 17% lower (P<0.05) in PR offspring, while Dnmt3a/b and methyl domain binding protein-2 expression was not altered. Thus hypomethylation of the GR110 promoter may result from lower capacity to methylate hemimethylated DNA during mitosis. Histone modifications which facilitate transcription were increased at the GR110 promoter (147 to 921%, P<0.001), while those that suppress methylation were decreased (54%, P<0.01) or similar to controls. In human umbilical cord (n 15), there was a 2-fold difference between the highest and lowest level of GR1-CTotal promoter methylation. Dnmt1, but not Dnmt3a, expression predicted 49% (P = 0.003) of the variation in GR1-CTotal promoter methylation. These findings suggest that induction in the offspring of altered epigenetic regulation of the hepatic GR110 promoter, and hence metabolic phenotype, may be due to reduced Dnmt1 expression.
doi:10.1017/S000711450769196X
PMCID: PMC2211425  PMID: 17433129
Fetal programming; epigenetic; rat; glucocorticoid receptor; histones; human

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