Corticosteroid-induced hyperammonaemic encephalopathy in a woman with late-onset ornithine transcarbamylase deficiency.

Ornithine transcarbamylase deficiency (OTCD) is a rare, X linked disorder that can manifest in late adulthood in heterozygous females as severe hyperammonaemia following environmental stressors. We present a case of hyperammonaemic encephalopathy that was triggered by glucocorticoid administration in an adult woman with heterozygous OTCD with clinical response to haemodialysis, ammonia scavengers and a high-calorie, low-protein diet.

Maternal malnutrition associated with postnatal sugar consumption increases inflammatory response and prostate disorders in rat offspring.

Maternal malnutrition can alter developmental biology, programming health and disease in offspring. The increase in sugar consumption during the peripubertal period, a worldwide concern, also affects health through adulthood. Studies have shown that maternal exposure to a low protein diet (LPD) is associated with an increase in prostate disease with aging. However, the combined effects of maternal LPD and early postnatal sugar consumption on offspring prostate disorders were not investigated. The effects on aging were evaluated using a maternal gestational model with lactational LPD (6% protein) and sugar consumption (10%) from postnatal day (PND) 21-90, associating the consequences on ventral prostate (VP) rats morphophysiology on PND540. An increase was shown in mast cells and in the VP of the CTR + SUG and Gestational and Lactational Low Protein (GLLP) groups. In GLLP + SUG, a significant increase was shown in TGF-ß1 expression in both the systemic and intra-prostatic forms, and SMAD2/3p had increased. The study identified maternal LPD and sugar consumption as risk factors for prostatic homeostasis in senility, activating the TGFß1-SMAD2/3 pathway, a signaling pathway with potential markers for prostatic disorders.

Evaluating change in diet with pegvaliase treatment in adults with phenylketonuria: Analysis of phase 3 clinical trial data.

Phenylketonuria (PKU), a genetic disorder characterized by phenylalanine hydroxylase (PAH) deficiency and phenylalanine (Phe) accumulation, is primarily managed with a protein-restricted diet and PKU-specific medical foods. Pegvaliase is an enzyme substitution therapy approved for individuals with PKU and uncontrolled blood Phe concentrations (>600 µmol/L) despite prior management. This analysis assessed the effect of pegvaliase on dietary intake using data from the Phase 3 PRISM-1 (NCT01819727), PRISM-2 (NCT01889862), and 165-304 (NCT03694353) clinical trials. Participants (N = 250) had a baseline diet assessment, blood Phe ≥600 µmol/L, and had discontinued sapropterin; they were not required to follow a Phe-restricted diet. Outcomes were analyzed by baseline dietary group, categorized as >75%, some (>0% but ≤75%), or no protein intake from medical food. At baseline, mean age was 29.1 years, 49.2% were female, mean body mass index was 28.4 kg/m2, and mean blood Phe was 1237.0 µmol/L. Total protein intake was stable up to 48 months for all 3 baseline dietary groups. Over this time, intact protein intake increased in all groups, and medical protein intake decreased in those who consumed any medical protein at baseline. Of participants consuming some or >75% medical protein at baseline, 49.1% and 34.1% were consuming no medical protein at last assessment, respectively. Following a first hypophenylalaninemia (HypoPhe; 2 consecutive blood Phe measurements <30 µmol/L) event, consumption of medical protein decreased and consumption of intact protein increased. Substantial and sustained Phe reductions were achieved in all 3 baseline dietary groups. The probability of achieving sustained Phe response (SPR) at ≤600 µmol/L was significantly greater for participants consuming medical protein versus no medical protein in an unadjusted analysis, but no statistically significant difference between groups was observed for probability of achieving SPR ≤360 or SPR ≤120 µmol/L. Participants with alopecia (n = 49) had longer pegvaliase treatment durations, reached HypoPhe sooner, and spent longer in HypoPhe than those who did not have alopecia. Most (87.8%) had an identifiable blood Phe drop before their first alopecia episode, and 51.0% (n = 21/41) of first alopecia episodes with known duration resolved before the end of the HypoPhe episode. In conclusion, pegvaliase treatment allowed adults with PKU to lower their blood Phe, reduce their reliance on medical protein, and increase their intact and total protein intake. Results also suggest that HypoPhe does not increase the risk of protein malnutrition in adults with PKU receiving pegvaliase.

Lifelong dietary protein restriction accelerates skeletal muscle loss and reduces muscle fibre size by impairing proteostasis and mitochondrial homeostasis.

The early life environment significantly affects the development of age-related skeletal muscle disorders. However, the long-term effects of lactational protein restriction on skeletal muscle are still poorly defined. Our study revealed that male mice nursed by dams fed a low-protein diet during lactation exhibited skeletal muscle growth restriction. This was associated with a dysregulation in the expression levels of genes related to the ribosome, mitochondria and skeletal muscle development. We reported that lifelong protein restriction accelerated loss of type-IIa muscle fibres and reduced muscle fibre size by impairing mitochondrial homeostasis and proteostasis at 18 months of age. However, feeding a normal-protein diet following lactational protein restriction prevented accelerated fibre loss and fibre size reduction in later life. These findings provide novel insight into the mechanisms by which lactational protein restriction hinders skeletal muscle growth and includes evidence that lifelong dietary protein restriction accelerated skeletal muscle loss in later life.

The deleterious effects of maternal protein deprivation on the brainstem are minimized with moderate physical activity by offspring during early life.

Maternal protein malnutrition during developmental periods might impair the redox state and the brain's excitatory/inhibitory neural network, increasing central sympathetic tone. Conversely, moderate physical exercise at an early age reduces the risk of chronic diseases. Thus, we hypothesized that a moderate training protocol could reduce the harmful effects of a low-protein maternal diet on the brainstem of young male offspring. We used a rat model of maternal protein restriction during the gestational and lactation period followed by an offspring's continuous treadmill exercise. Pregnant rats were divided into two groups according to the protein content in the diet: normoprotein (NP), receiving 17% of casein, and low protein (LP), receiving 8% of casein until the end of lactation. At 30 days of age, the male offspring were further subdivided into sedentary (NP-Sed and LP-Sed) or exercised (NP-Ex and LP-Ex) groups. Treadmill exercise was performed as follows: 4 weeks, 5 days/week, 60 min/day at 50% of maximal running capacity. The trained animals performed a treadmill exercise at 50% of the maximal running capacity, 60 min/day, 5 days/week, for 4 weeks. Our results indicate that a low-protein diet promotes deficits in the antioxidant system and a likely mitochondrial uncoupling. On the other hand, physical exercise restores the redox balance, which leads to decreased oxidative stress caused by the diet. In addition, it also promotes benefits to GABAergic inhibitory signaling. We conclude that regular moderate physical exercise performed in youthhood protects the brainstem against changes induced by maternal protein restriction.

Efficacy and Safety of a High-Energy, Low-Protein Formula Replacement Meal for Pre-Dialysis Chronic Kidney Disease Patients: A Randomized Controlled Trial.

High-energy, low-protein formulas (HE-LPFs) are commonly used as oral nutritional supplements (ONSs) to help provide extra calories to patients who are adhering to a low-protein diet (LPD) after diagnosis with chronic kidney disease (CKD). This randomized controlled trial aimed to evaluate the efficacy and safety of an HE-LPF as either a partial or a total replacement for one meal in pre-dialysis CKD patients. Stage 4-5 CKD patients received either a once-daily HE-LPF (HE-LPF group) or normal food (control group) for a period of 4 weeks while following an LPD. Overall, 73 patients who completed the study were included in the intention-to-treat population. After analyzing the 3-day food records, the HE-LPF group experienced a significant decrease in the percentage of energy derived from protein (p < 0.05) and an increase in the percentage of energy derived from fat (p < 0.05) compared to the control group. The two groups had no significant differences in body weight, body composition, grip strength, renal function, electrolytes, or metabolic markers. The HE-LPF group had a high adherence (94.9% at week 4), and no adverse effects were observed. HE-LPFs are safe to employ as meal replacements for pre-dialysis CKD patients adhering to an LPD.

Amino acid supplementation counteracts negative effects of low protein diets on tail biting in pigs more than extra environmental enrichment.

Low protein (LP) diets may increase the occurrence of damaging behaviours, like tail biting, in pigs. We investigated the effect of supplementing a LP diet with indispensable amino acids (IAA) or environmental enrichment on tail biting. Undocked pigs (n = 48 groups of 12) received either a normal protein diet (NP), a LP, LP with supplemented IAA (LP+), or LP diet with extra environmental enrichment (LP-E+) during the starter, grower, and finisher phase. Performance, activity, behaviour, and body damage were recorded. LP and LP-E+ had a lower feed intake, growth, and gain-to-feed ratio, and were more active than NP and LP+ pigs. LP-E+ pigs interacted most often with enrichment materials, followed by LP, LP+, and NP pigs. LP pigs showed more tail biting than all other groups during the starter phase and the finisher phase (tendency) compared to NP and LP+ pigs. Thus, LP-E+ only reduced tail biting in the starter phase, whereas LP+ tended to do so throughout. Tail damage was more severe in LP pigs than in NP and LP+, with LP-E+ in between. In conclusion, IAA supplementation was more effective than extra environmental enrichment in countering the negative effects of a low protein diet on tail biting in pigs.

Maternal low-protein diet alters hepatic lipid accumulation and gene expression related to glucose metabolism in young adult mouse offspring fed a postweaning high-fat diet.

Maternal consumption of low-protein (LP) diet during pregnancy has been demonstrated to increase the chances of adult offspring developing metabolic syndrome, and this risk can be exacerbated when the postnatal diets do not align with the prenatal conditions. However, in our previous study, focusing on serum parameters and gene expression patterns within adipose tissue, we discovered the presence of "healthy obesity" in young adult offspring from dams that were fed an LP, as a response to a postweaning high-fat (HF) diet. Here, we subsequently investigated the role played by the liver and skeletal muscle in alleviation of insulin resistance in male offspring that were fed either control (C/C group) or HF diet (C/HF and LP/HF groups) for 22 weeks. While a postweaning HF diet increased liver weight and hepatic triglyceride (TG) and cholesterol levels in offspring of control dams, these levels were lower in the LP/HF group compared to the C/HF group. Analysis of the liver transcriptome identified 430 differentially expressed genes (DEGs) in the LP/HF and C/HF comparison. Especially, downregulated DEGs were enriched in carbohydrate metabolism and the levels of DEGs were significantly correlated with the levels of markers for serum glucose homeostasis and hepatic lipid accumulation. In the LP/HF group compared to the C/HF group, there was a decrease in the gastrocnemius muscle weight, while no differences were observed in gene expression levels associated with muscle fiber phenotype, mitochondrial function, and inflammation. In conclusion, maternal LP diet induced changes in lipid and glucose metabolism within the liver, similar to what was observed in adipose tissue, while there were no alterations in metabolic functions in the skeletal muscle in young offspring mice fed an HF diet. Further research that investigating the enduring impact of nutritional transition on offspring is essential to gain a comprehensive grasp of developmental programming throughout their entire lifespan.

The role of a low protein diet supplemented with ketoanalogues on kidney progression in pre-dialysis chronic kidney disease patients.

In slowing kidney progression, numerous pre-dialysis chronic kidney disease (CKD) patients could not adhere to the well-established dietary pattern, including a very low protein diet, 0.3-0.4 g/kg/day, plus a full dose ketoanalogues (KAs) of amino acids. We evaluated the role of a low protein diet (LPD), 0.6-0.8 g/kg/day, combined with KAs (LPD-KAs) on CKD progression. We extracted data in the retrospective cohort using electronic medical records (n = 38,005). Participants with LPD-KAs for longer than six months were identified. An unmatched control group, LPD alone, was retrieved from the same database. Cox proportional hazard models were performed to examine the associations between LPD-KAs and outcomes. The primary outcome was either a rapid estimated glomerular filtration rate (eGFR) decline > 5 mL/min/1.73m2/year or commencing dialysis. Other secondary outcomes include changes in proteinuria, serum albumin, and other metabolic profiles were also assessed. A total of 1042 patients were finally recruited (LPD-KAs = 543). Although patients with LPD-KAs had significantly lower eGFR and a prevalence of diabetes, age, and dietary protein intake were comparable between LPD-KAs (0.7 ± 0.2 g/kg/day) and LPD alone groups (0.7 ± 0.3 g/kg/day, p = 0.49). During a median follow-up of 32.9 months, patients treated with LPD-KAs had a significantly lower risk of kidney function decline (HR 0.13; 95% CI 0.09-0.19, p < 0.001) and dialysis initiation (HR 0.24; 95% CI 0.12-0.49, p < 0.001) than LPD alone after adjusting for confounders. The annual rate of eGFR decline in patients receiving LPD-KAs was 4.5 [3.4-5.5] mL/min/1.73m2 compared with 7.7 [6.0-9.4] mL/min/1.73m2 in LPD alone (p = 0.001). According to KAs dose-response analysis, the daily dose of ≤ 5 tablets was conversely associated with a higher risk of the primary endpoint, whereas the association disappeared among patients receiving a dose of > 6 tablets. The spot urine protein creatinine ratio and serum phosphate levels were not significantly different between groups. LPD-KAs could retard kidney progression compared with LPD alone. This favorable effect was significant among CKD patients receiving a daily KAs dose of more than six tablets. Future randomized controlled trials should be performed to verify these findings.

The Epigenetic Legacy of Maternal Protein Restriction: Renal Ptger1 DNA Methylation Changes in Hypertensive Rat Offspring.

Nutrient imbalances during gestation are a risk factor for hypertension in offspring. Although the effects of prenatal nutritional deficiency on the development of hypertension and cardiovascular diseases in adulthood have been extensively documented, its underlying mechanisms remain poorly understood. In this study, we aimed to elucidate the precise role and functional significance of epigenetic modifications in the pathogenesis of hypertension. To this end, we integrated methylome and transcriptome data to identify potential salt-sensitive hypertension genes using the kidneys of stroke-prone spontaneously hypertensive rat (SHRSP) pups exposed to a low-protein diet throughout their fetal life. Maternal protein restriction during gestation led to a positive correlation between DNA hypermethylation of the renal prostaglandin E receptor 1 (Ptger1) CpG island and high mRNA expression of Ptger1 in offspring, which is consistently conserved. Furthermore, post-weaning low-protein or high-protein diets modified the Ptger1 DNA hypermethylation caused by fetal malnutrition. Here, we show that this epigenetic variation in Ptger1 is linked to disease susceptibility established during fetal stages and could be reprogrammed by manipulating the postnatal diet. Thus, our findings clarify the developmental origins connecting the maternal nutritional environment and potential epigenetic biomarkers for offspring hypertension. These findings shed light on hypertension prevention and prospective therapeutic strategies.

Diet enriched in saturated fatty acids induces liver oxidative stress and elicits inflammatory pathways prior to metabolic disruption in perinatal protein undernutrition.

The impact of diets high in saturated fatty acids in individuals who have undergone maternal protein restriction is not clear. Here, we tested the hypothesis that a saturated fatty acid-enriched hyperlipidic diet (HL) affects liver expression of genes of the redox balance and inflammatory pathway in postweaning rat offspring subjected to maternal protein restriction. Pregnant Wistar rats received either a control (C; 19% protein) or low protein (LP; 8% protein) diet during gestation and lactation. At weaning, pups received either C or HL diets up to 90 days of life. The LP+HL group showed an upregulation of transcription of peroxisome proliferator-activated receptor γ (+48%) and peroxisome proliferator-activated receptor γ coactivator α (+96%) compared with the LP+C group (P < .05), respectively. Similarly, gene expression of the markers of inflammation, nuclear factor-kappa B1 (+194%) and tumor necrosis factor-α (+192%), was enhanced (P < .05). Although other antioxidant enzymes were not modified in gene expression, catalase (CAT) was 66% higher in LP+HL compared with LP+C. In contrast, CAT protein content in the liver was 50% lower in LP groups compared with C, and superoxide dismutase 2 (SOD2) was twice as high in LP groups compared with C. Postweaning HL after maternal protein restriction induces hepatic metabolic adaptation characterized by enhanced oxidative stress, unbalanced expression in the antioxidant enzymes SOD1, SOD2 and CAT, and activation of inflammatory pathways but does not impact circulating markers of lipid metabolism and liver function.

Personalized Low-Protein Diet Prescription in CKD Population: Merging Evidence From Randomized Trials With Observational Data.

Nutritional therapy is a cornerstone of the clinical management of chronic kidney disease (CKD). Nevertheless, randomized controlled trials often have failed to show a relevant benefit of low-protein diets in nonselected CKD populations in terms of slowing the progression of kidney disease and need for dialysis. The more the target population is selected, the less the results can be generalizable to implement in clinical practice. On the contrary, observational studies, especially if performed with patient-centered, flexible approaches, point toward an extensive implementation of dietary protein restriction in different and unselected CKD populations. The observational evidence cannot be disregarded anymore. The most recent guidelines advise implementing low-protein diets or even very-low-protein diets in all CKD patients as early as stage 3. However, the lack of data from large randomized controlled trials on unselected CKD populations as well as on specific subpopulations, such as diabetic or obese patients, which nowadays comprise the majority of CKD subjects, reduces the generalizability of the recommendations. For some patient populations, such as those encompassing very old, nephrotic, or pregnant patients, the literature is even more limited because of the lower prevalence of these conditions and diffused prejudices against reducing protein intake. This pragmatic review discusses the need for integrating information derived from randomized trials with evidence derived from observational studies to guide feasible strategies for more successful implementation of low-protein diets in the treatment of all segments of the CKD population.

Hepatic and Skeletal Muscle Autophagy Marker Levels in Rat Models of Prenatal and Postnatal Protein Restriction.

Fetal growth restriction (FGR) leads to adult-onset metabolic syndrome. Intrauterine and early postnatal caloric restriction ameliorates the risk in animal models. To understand the underlying mechanism, we compared autophagic marker levels between offspring with FGR and those with prenatal and early postnatal protein restriction (IPPR). We postulated that FGR would impair, whereas IPPR would help regulate, autophagy in neonatal rats. This study involved control (Con), FGR offspring (Pre), and IPPR offspring groups (Pre + Post); n = 5/group. We assessed the abundance of autophagy markers in the liver and skeletal muscles. At birth, the Pre group pups had lower levels of some autophagy-related proteins, with increased p62 expression and a low microtubule-associated protein light chain beta (LC3-II:LC3-I) ratio. This finding suggests a lower hepatic autophagy flux in FGR offspring than the Con group. The hepatic levels of autophagy proteins were considerably decreased in the Pre and Pre + Post groups at 21 days of age compared to the Con group, but the LC3-II:LC3-I ratio was higher in the Pre + Post group than in the Con and Pre groups. The muscle levels of beclin-1, LC3-II, and p62 were lower in the Pre group pups, with no difference in the LC3-II:LC3-I ratio among the groups. An imbalance in the nutritional environment is associated with downstream autophagic flux, thus suggesting that FGR offspring will have impaired autophagic flux, and that post-natal nutrition restriction might help reduce this risk.

The Role of Protein Restriction in the Progression of Chronic Kidney Disease.

Even though nephrology has made much progress, reducing the progression of the chronic kidney disease remains, in fact, one of the biggest challenges. Long before the renal replacement therapy (RRT), it was known that limiting the protein could help almost all uremia symptoms. Although it was proposed as early as the 1960s, it only became widely used in the 1980s. By lowering the urea and other nitrogen wastes and lowering the metabolic acidosis, oxidative stress, and insulin resistance, limiting the amount of protein in your diet can help improve uremic symptoms. Also, limiting the protein in the diet positively controls the cardiovascular complications, including the arterial blood pressure and proteinuria reduction, which are risk factors for CKD progression. This mini-review examines the impact of protein restriction on the possibility of slowing CKD progression in depth.

Low Protein Programming Causes Increased Mitochondrial Fusion and Decreased Oxygen Consumption in the Hepatocytes of Female Rats.

The liver is one of the major organs involved in the regulation of glucose and lipid homeostasis. The effectiveness of metabolic activity in hepatocytes is determined by the quality and quantity of its mitochondria. Mitochondrial function is complex, and they act via various dynamic networks, which rapidly adapt to changes in the cellular milieu. Our present study aims to investigate the effects of low protein programming on the structure and function of mitochondria in the hepatocytes of adult females. Pregnant rats were fed with a control or isocaloric low-protein diet from gestational day 4 until delivery. A normal laboratory chow was given to all dams after delivery and to pups after weaning. The rats were euthanized at 4 months of age and the livers were collected from female offspring for investigating the mitochondrial structure, mtDNA copy number, mRNA, and proteins expression of genes associated with mitochondrial function. Primary hepatocytes were isolated and used for the analysis of the mitochondrial bioenergetics profiles. The mitochondrial ultrastructure showed that the in utero low-protein diet exposure led to increased mitochondrial fusion. Accordingly, there was an increase in the mRNA and protein levels of the mitochondrial fusion gene Opa1 and mitochondrial biogenesis genes Pgc1a and Essra, but Fis1, a fission gene, was downregulated. Low protein programming also impaired the mitochondrial function of the hepatocytes with a decrease in basal respiration ATP-linked respiration and proton leak. In summary, the present study suggests that the hepatic mitochondrial dysfunction induced by an in utero low protein diet might be a potential mechanism linking glucose intolerance and insulin resistance in adult offspring.

Gestational low dietary protein induces intrauterine inflammation and alters the programming of adiposity and insulin sensitivity in the adult offspring.

Malnutrition associated with low dietary protein can induce gestational inflammation and sets a long-lasting metabolic impact on the offspring even after replenishment. The work investigated whether a low-protein diet (LPD) during pregnancy and lactation induces intrauterine inflammation and predisposes offspring to adiposity and insulin resistance in their adult life. Female Golden Syrian hamsters were fed LPD (10.0% energy from protein) or a control diet (CD, 20.0 % energy from protein) from preconception until lactation. All pups were switched to CD after lactation and continued until the end. Maternal LPD increased intrauterine inflammation by enhancing neutrophil infiltration, amniotic hsCRP, oxidative stress, and mRNA expression of NFκß, IL8, COX2, and TGFß in the chorioamniotic membrane (P<.05). The prepregnancy body weight, placental, and fetal weights, serum AST and ALT were decreased, while blood platelets, lymphocytes, insulin, and HDL were significantly increased in LPD-fed dams (P<.05). A postnatal switch to an adequate protein could not prevent hyperlipidemia in the 6-months LPD/CD offspring. The lipid profile and liver functions were restored over 10 months of protein feeding but failed to normalize fasting glucose and body fat accumulation compared to CD/CD. LPD/CD showed elevated GLUT4 expression & activated pIRS1 in the skeletal muscle and increased expression of IL6, IL1ß, and p65-NFκB proteins in the liver (P<.05). In conclusion, present data suggest that maternal protein restriction may induce intrauterine inflammation and affect liver inflammation in the adult offspring by an influx of fats from adipose that may alter lipid metabolism and reduce insulin sensitivity in skeletal muscle.

Curcumin intake during lactation suppresses oxidative stress through upregulation of nuclear factor erythroid 2-related factor 2 in the kidneys of fructose-loaded female rat offspring exposed to maternal protein restriction.

BACKGROUND: A high-fructose diet causes the progression of chronic kidney disease. Maternal malnutrition during pregnancy and lactation increases oxidative stress, leading to chronic renal diseases later in life. We investigated whether curcumin intake during lactation could suppress oxidative stress and regulate NF-E2-related factor 2 (Nrf2) expression in the kidneys of fructose-loaded female rat offspring exposed to maternal protein restriction. METHODS: Pregnant Wistar rats received diets containing 20% (NP) or 8% (LP) casein and 0 or 2.5 g "highly absorptive curcumin" /kg diet containing-LP diets (LP/LP or LP/Cur) during lactation. At weaning, female offspring received either distilled water (W) or 10% fructose solution (Fr) and were divided into four groups: NP/NP/W, LP/LP/W, LP/LP/Fr, and LP/Cur/Fr. At week 13, glucose (Glc), triacylglycerol (Tg), and malondialdehyde (MDA) levels in the plasma, macrophages number, fibrotic area, glutathione (GSH) levels, glutathione peroxidase (GPx) activity, protein expression levels of Nrf2, heme oxygenase-1 (HO-1), and superoxide dismutase 1 (SOD1) in the kidneys were examined. RESULTS: The plasma levels of Glc, TG, and MDA, the number of macrophages, and the percentage of fibrotic area in the kidneys of the LP/Cur/Fr group were significantly lower than those of the LP/LP/Fr group. The expression of Nrf2 and its downstream molecules HO-1 and SOD1, GSH levels, and GPx activity in the kidneys of the LP/Cur/Fr group were significantly higher than those of the LP/LP/Fr group. CONCLUSIONS: Maternal curcumin intake during lactation may suppress oxidative stress by upregulating Nrf2 expression in the kidneys of fructose-loaded female offspring exposed to maternal protein restriction.

Maternal Protein Restriction in Rats Alters Postnatal Growth and Brain Lipid Sensing in Female Offspring.

Perinatal nutrition is a key player in the susceptibility to developing metabolic diseases in adulthood, leading to the concept of "metabolic programming". The aim of this study was to assess the impact of maternal protein restriction during gestation and lactation on glucose homeostasis and eating behaviour in female offspring. Pregnant rats were fed a normal or protein-restricted (PR) diet and followed throughout gestation and lactation. Body weight, glucose homeostasis, and eating behaviour were evaluated in offspring, especially in females. Body weight gain was lower in PR dams during lactation only, despite different food and water intakes throughout gestation and lactation. Plasma concentration of leptin, adiponectin and triglycerides increased drastically before delivery in PR dams in relation to fat deposits. Although all pups had identical birth body weight, PR offspring body weight differed from control offspring around postnatal day 10 and remained lower until adulthood. Offspring glucose homeostasis was mildly impacted by maternal PR, although insulin secretion was reduced for PR rats at adulthood. Food intake, satiety response, and cerebral activation were examined after a lipid preload and demonstrated some differences between the two groups of rats. Maternal PR during gestation and lactation does induce extrauterine growth restriction, accompanied by alterations in maternal plasma leptin and adiponectin levels, which may be involved in programming the alterations in eating behaviour observed in females at adulthood.

Impaired placental hemodynamics and function in a non-human primate model of gestational protein restriction.

Maternal malnutrition increases fetal and neonatal morbidity, partly by affecting placental function and morphology, but its impact on placental hemodynamics are unknown. Our objective was to define the impact of maternal malnutrition on placental oxygen reserve and perfusion in vivo in a rhesus macaque model of protein restriction (PR) using advanced imaging. Animals were fed control (CON, 26% protein), 33% PR diet (17% protein), or a 50% PR diet (13% protein, n = 8/group) preconception and throughout pregnancy. Animals underwent Doppler ultrasound and fetal biometry followed by MRI at gestational days 85 (G85) and 135 (G135; term is G168). Pregnancy loss rates were 0/8 in CON, 1/8 in 33% PR, and 3/8 in 50% PR animals. Fetuses of animals fed a 50% PR diet had a smaller abdominal circumference (G135, p < 0.01). On MRI, placental blood flow was decreased at G135 (p < 0.05) and placental oxygen reserve was reduced (G85, p = 0.05; G135, p = 0.01) in animals fed a 50% PR diet vs. CON. These data demonstrate that a 50% PR diet reduces maternal placental perfusion, decreases fetal oxygen availability, and increases fetal mortality. These alterations in placental hemodynamics may partly explain human growth restriction and stillbirth seen with severe PR diets in the developing world.

Cardiovascular and renal profiles in rat offspring that do not undergo catch-up growth after exposure to maternal protein restriction.

Maternal protein restriction is often associated with structural and functional sequelae in offspring, particularly affecting growth and renal-cardiovascular function. However, there is little understanding as to whether hypertension and kidney disease occur because of a primary nephron deficit or whether controlling postnatal growth can result in normal renal-cardiovascular phenotypes. To investigate this, female Sprague-Dawley rats were fed either a low-protein (LP, 8.4% protein) or normal-protein (NP, 19.4% protein) diet prior to mating and until offspring were weaned at postnatal day (PN) 21. Offspring were then fed a non 'growth' (4.6% fat) which ensured that catch-up growth did not occur. Offspring growth was determined by weight and dual energy X-ray absorptiometry. Nephron number was determined at PN21 using the disector-fractionator method. Kidney function was measured at PN180 and PN360 using clearance methods. Blood pressure was measured at PN360 using radio-telemetry. Body weight was similar at PN1, but by PN21 LP offspring were 39% smaller than controls (Pdiet < 0.001). This difference was due to proportional changes in lean muscle, fat, and bone content. LP offspring remained smaller than NP offspring until PN360. In LP offspring, nephron number was 26% less in males and 17% less in females, than NP controls (Pdiet < 0.0004). Kidney function was similar across dietary groups and sexes at PN180 and PN360. Blood pressure was similar in LP and NP offspring at PN360. These findings suggest that remaining on a slow growth trajectory after exposure to a suboptimal intrauterine environment does not lead to the development of kidney dysfunction and hypertension.