Metabolic Responses to Protein Restriction During Pregnancy in Rat and Translation Initiation Factors in the Mother and Fetus

Parimi, Prabhu S.; Cripe-Mamie, Chantal; Kalhan, Satish C.

doi:10.1203/01.pdr.0000136277.10365.84

Cited by 21 publications

(13 citation statements)

References 37 publications

(38 reference statements)

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“…Maternal protein restriction (60 g protein/kg diet) throughout pregnancy in rats decreased maternal serum concentration of the branched chain amino acids (valine, isoleucine and leucine) by 29-36%, and the threonine concentration was reduced by 80% compared with the control group fed on 180 g protein/kg diet (Rees et al 1999). Similar results have been reported in rats showing significantly decreased maternal serum concentrations of the branched-chain amino acids and/or the total essential amino acids under maternal protein restriction (Bhasin et al 2009;Parimi et al 2004;Rees et al 2006). BeWo cells have been used to study the effects of amino acid restriction on amino acid transport (Jones et al 2006), in which DMEM Glutamax 1 was used as control, while the amino acid deprivation medium was a balanced salt solution containing no nonessential, and 50% essential amino acids used in MEM.…”

Section: Discussionsupporting

confidence: 79%

Low amino acids affect expression of 11β-HSD2 in BeWo cells through leptin-activated JAK-STAT and MAPK pathways

et al. 2011

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Maternal protein restriction diminishes placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) activity and causes fetal growth restriction in mammals. However, it is unknown whether such effect was caused directly by nutrient deficiency, or indirectly through the mediation of maternal hormones. In the present study, a human placental cell line (BeWo) was cultured in F12K as control and F12 as low amino acids (LAA) media for 48 h to investigate the effects of amino acids deficiency on 11β-HSD2 expression and activity. Despite a significant up-regulation of 11β-HSD2 mRNA expression in LAA cells, 11β-HSD2 activity and protein content were decreased by 38 and 54%, respectively (P<0.05), indicating a mechanism of post-transcriptional regulation. Among 5 miRNAs targeting 11β-HSD2, miR-498 was expressed significantly higher in LAA cells. Leptin concentration was significantly lower (P<0.01) in LAA medium. The mRNA expression of both isoforms of leptin receptor was significantly higher in LAA cells, although no difference was detected at protein level. To further clarify whether leptin is involved in mediating the effect of LAA on 11β-HSD2 activity, leptin was supplemented to LAA medium, whereas three specific inhibitors of leptin signaling pathways, WP1066 for JAK-STAT, PD98059 for MAPK and LY294002 for PI3K, respectively were added to control medium. Leptin restored the diminished 11β-HSD2 activity in LAA cells, whereas WP1066 (5 nM) and PD98059 (50 nM) significantly decreased 11β-HSD2 activity in control cells. In conclusion, the present results indicate that LAA diminishes 11β-HSD2 expression and activity in BeWo cells through leptin-activated JAK-STAT and MAPK pathways.

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Section: Discussionsupporting

confidence: 79%

Low amino acids affect expression of 11β-HSD2 in BeWo cells through leptin-activated JAK-STAT and MAPK pathways

et al. 2011

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“…The concentration of methionine in the plasma was measured by HPLC (15). An aliquot of plasma was treated with perchloric acid to remove [ 14 C]O 2 .…”

Section: Discussionmentioning

confidence: 99%

“…Blood samples (0.5 ml) were obtained in heparinized syringes at 240, 270, 300, and 330 min. Respiratory calorimetry measurements were done using an open canopy system as described previously (15).…”

Section: Isotopic Tracer Studiesmentioning

confidence: 99%

Metabolic and Genomic Response to Dietary Isocaloric Protein Restriction in the Rat

Kalhan¹,

Uppal²,

Moorman³

et al. 2011

Journal of Biological Chemistry

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We have examined hepatic, genomic, and metabolic responses to dietary protein restriction in the non-pregnant Sprague-Dawley rat. Animals were pair-fed either a 6 or 24% casein-based diet for 7-10 days. At the end of the dietary period, a microarray analysis of the liver was performed, followed by validation of the genes of interest. The rates of appearance of phenylalanine, methionine, serine, and glucose and the contribution of pyruvate to serine and glucose were quantified using tracer methods. Plasma and tissue amino acid levels, enzyme activities, and metabolic intermediates were measured. Protein restriction resulted in significant differential expression of a number of genes involved in cell cycle, cell differentiation, transport, transcription, and metabolic processes. RT-PCR showed that the expression of genes involved in serine biosynthesis and fatty acid oxidation was higher, and those involved in fatty acid synthesis and urea synthesis were lower in the liver of protein-restricted animals. Free serine and glycine levels were higher and taurine levels lower in all tissues examined. Tracer isotope studies showed an ϳ50% increase in serine de novo synthesis. Pyruvate was the primary (ϳ90%) source of serine in both groups. Transmethylation of methionine was significantly higher in the protein-restricted group. This was associated with a higher S-adenosylmethionine/Sadenosylhomocysteine ratio and lower cystathione ␤-synthase and cystathionine ␥-lyase activity. Dietary isocaloric protein restriction results in profound changes in hepatic one-carbon metabolism within a short period. These may be related to high methylation demands placed on the organism and caused by possible changes in cellular osmolarity as a result of the efflux of the intracellular taurine.The metabolic and biochemical impact of qualitative and quantitative changes in dietary protein intake continues to be of interest because of their implications for public health and because of a number of studies showing a strong relationship between protein intake during pregnancy with cardiovascular function, hypertension, and glucose intolerance in the offspring (1-3). Studies in humans, primarily focused on whole body protein, nitrogen metabolism, and protein accretion, show that both high and low protein intake can impact these processes (4 -7). However, how humans adapt to protein deprivation or the biochemical mechanisms involved has not been examined. In the context of pregnancy, both high protein intake (in humans) and protein restriction in rodents have been shown to cause fetal metabolic programming and consequently altered physiological response in the offspring in adulthood (8 -11). In the rodent, dietary protein restriction during pregnancy results in growth retardation, impaired beta cell function and mass, impaired insulin sensitivity, hypertension, and other pathological responses in the offspring (1, 2). These have been associated with a change in the hypothalamic-pituitary-adrenal axis, changes in the renin-angiotensin system, and ...

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“…In a previous study in rat, we had examined the effect of isocaloric protein restriction on the metabolism of the mother and translation initiation factors as indices of protein synthesis in the maternal and fetal liver (Parimi et al, 2004). These data showed that protein restriction in pregnancy resulted in a higher rate of oxygen consumption and lower levels of branched chain amino acids, lysine and histidine early in gestation suggestive of a lower rate of whole body protein turnover as was seen in the non- pregnant animals (Kalhan et al, 2011).…”

Section: One Carbon Metabolism and The Health Of The Mother Fetusmentioning

confidence: 99%

One carbon metabolism in pregnancy: Impact on maternal, fetal and neonatal health

Kalhan

2016

Molecular and Cellular Endocrinology

102

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One carbon metabolism or methyl transfer, a crucial component of metabolism in all cells and tissues, supports the critical function of synthesis of purines, thymidylate and methylation via multiple methyl transferases driven by the ubiquitous methyl donor s-adenosylmethionine. Serine is the primary methyl donor to the one carbon pool. Intracellular folates and methionine metabolism are the critical components of one carbon transfer. Methionine metabolism requires vitamin B12, B6 as cofactors and is modulated by endocrine signals and is responsive to nutrient intake. Perturbations in one carbon transfer can have profound effects on cell proliferation, growth and function. Epidemiological studies in humans and experimental model have established a strong relationship between impaired fetal growth and the immediate and long term consequences to the health of the offspring. It is speculated that during development, maternal environmental and nutrient influences by their effects on one carbon transfer can impact the health of the mother, impair growth and reprogram metabolism of the fetus, and cause long term morbidity in the offspring. The potential for such effects is underscored by the unique responses in methionine metabolism in the human mother during pregnancy, the absence of transsulfuration activity in the fetus, ontogeny of methionine metabolism in the placenta and the unique metabolism of serine and glycine in the fetus. Dietary protein restriction in animals and marginal protein intake in humans causes characteristic changes in one carbon metabolism. The impact of perturbations in one carbon metabolism on the health of the mother during pregnancy, on fetal growth and the neonate are discussed and their possible mechanism explored.

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Metabolic Responses to Protein Restriction During Pregnancy in Rat and Translation Initiation Factors in the Mother and Fetus

Cited by 21 publications

References 37 publications

Low amino acids affect expression of 11β-HSD2 in BeWo cells through leptin-activated JAK-STAT and MAPK pathways

Low amino acids affect expression of 11β-HSD2 in BeWo cells through leptin-activated JAK-STAT and MAPK pathways

Metabolic and Genomic Response to Dietary Isocaloric Protein Restriction in the Rat

One carbon metabolism in pregnancy: Impact on maternal, fetal and neonatal health

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