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Nutrition received in early life may impact adult health. The aim of the study was to determine whether high protein feeding in neonatal period would have long term metabolic effects in an animal model of low birth weight infants.Male rat pups born from dams receiving a low protein diet during gestation were separated from their mothers, and equipped with gastrostomy tubes to receive as their sole feeding a milk formula of either adequate protein (AP; n = 14; 8.7 g protein/dL; total energy: 155 kcal/100 g), or high protein content (HP; n = 14; 13.0 g protein/dL; total energy: 171 kcal/100 g) between the 7th (D7) and 21st day (D21) of life. Rats were then weaned to standard chow until sacrificed at adulthood.At D18, HP feeding was associated with higher estimated rates of protein turnover (p = 0.007) and synthesis (p = 0.051), as assessed using l-[U-(13)C]valine infusion. HP milk feeding in early life was associated with an increase in weight gain from puberty through adulthood, along with an increase in food intake, serum insulin (179 ± 58 vs. 55 ± 7 pmol/L; means ± SE), pancreatic β-cell number, plasma triglycerides (95 ± 8 vs. 73 ± 9 mg/dL), serum leptin (9.7 ± 1.0 vs. 5.5 ± 1.2 ng/mL), mesenteric fat mass, and adipocyte size.In an animal model of low birth weight infants, high protein neonatal feeding may have a lasting effect on fat and glucose metabolism, potentially leading to "metabolic syndrome" in adulthood.

Intrauterine growth restriction (IUGR) is closely linked with metabolic diseases, appetite disorders and obesity at adulthood. Leptin, a major adipokine secreted by adipose tissue, circulates in direct proportion to body fat stores, enters the brain and regulates food intake and energy expenditure. Deficient leptin neuronal signalling favours weight gain by affecting central homeostatic circuitry. The aim of this study was to determine if leptin resistance was programmed by perinatal nutritional environment and to decipher potential cellular mechanisms underneath. We clearly demonstrated that 5 months old IUGR rats develop a decrease of leptin sentivity, characterized by no significant reduction of food intake following an intraperitoneal injection of leptin. Apart from the resistance to leptin injection, results obtained from IUGR rats submitted to rapid catch-up growth differed from those of IUGR rats with no catch-up since we observed, for the first group only, fat accumulation, increased appetite for food rich in fat and increased leptin synthesis. Centrally, the leptin resistant state of both groups was associated with a complex and not always similar changes in leptin receptor signalling steps. Leptin resistance in IUGR rats submitted to rapid catch-up was associated with alteration in AKT and mTOR pathways. Alternatively, in IUGR rats with no catch-up, leptin resistance was associated with low hypothalamic expression of LepRa and LepRb. This study reveals leptin resistance as an early marker of metabolic disorders that appears before any evidence of body weight increase in IUGR rats but whose mechanisms could depend of nutritional environment of the perinatal period.

International audience; Intrauterine growth restriction (IUGR) due to maternal protein restriction is associated in rats with an alteration in hypothalamic centers involved in feeding behaviour. In order to gain insight into the mechanism of perinatal maternal undernutrition in the brain, we used proteomics approach to identify hypothalamic proteins that are altered in their expression following protein restriction in utero. We used an animal model in which restriction of the protein intake of pregnant rats (8% vs. 20%) produces IUGR pups which were randomized to a nursing regimen leading to either rapid or slow catch-up growth. We identified several proteins which allowed, by multivariate analysis, a very good discrimination of the three groups according to their perinatal nutrition. These proteins were related to energy-sensing pathways (Eno 1, E2PDH, Acot 1 and Fabp5), redox status (Bcs 1L, PrdX3 and 14-3-3 protein) or amino acid pathway (Acy1) as well as neurodevelopment (DRPs, MAP2, Snca). In addition, the differential expressions of several key proteins suggested possible shunts towards ketone-body metabolism and lipid oxidation, providing the energy and carbon skeletons necessary to lipogenesis. Our results show that maternal protein deprivation during pregnancy only (IUGR with rapid catch-up growth) or pregnancy and lactation (IUGR with slow postnatal growth) modulates numerous metabolic pathways resulting in alterations of hypothalamic energy supply. As several of these pathways are involved in signalling, it remains to be determined whether hypothalamic proteome adaptation of IUGR rats in response to different postnatal growth rates could also interfere with cerebral plasticity or neuronal maturation.

International audience; Intrauterine growth restriction (IUGR), along with postnatal growth trajectory, is closely linked with metabolic diseases and obesity at adulthood. The present study reports the time-dependent metabolomic response of male offspring of rat dams exposed to maternal adequate protein diet during pregnancy and lactation (CC) or protein deprivation during pregnancy only (IUGR with rapid catch-up growth, RC) or through pregnancy and lactation (IUGR with slow postnatal growth, RR). Plasma LC-HRMS metabolomic fingerprints for 8 male rats per group, combined with multivariate statistical analysis (PLS-DA and HCA), were used to study the impact of IUGR and postnatal growth velocity on the offspring metabolism in early life (until weaning) and once they reached adulthood (8 months). Compared with CC rats, RR pups had clear-cut alterations in plasma metabolome during suckling, but none at adulthood; in contrast, in RC pups, alterations in metabolome were minimal in early life but more pronounced in the long run. In particular, our results pinpoint transient alterations in proline, arginine, and histidine in RR rats, compared to CC rats, and persistent differences in tyrosine and carnitine, compared to RC rats at adulthood. These findings suggest that the long-term deregulation in feeding behavior and fatty acid metabolism in IUGR rats depends on postnatal growth velocity

High-protein (HP) milk formulas are routinely used in infants born with a low birth weight (LBW) to enhance growth and ensure a better verbal IQ development. Indirect evidence points to a link between an HP intake during early life and the prevalence of obesity in later life. We hypothesized that HP milk supplementation to LBW pups during early postnatal life would impact hypothalamic appetite neuronal pathways development with consequences, at adulthood, on energy homeostasis regulation. Rat pups born with a LBW were equipped with gastrostomy tubes on the fifth day of life. They received a milk formula with either normal protein (NP, 8.7 g protein/dl) or high protein content (HP; 13.0 g protein/dl) and were subsequently weaned to a standard, solid diet at postnatal day 21. Rats that had been fed HP content milk gained more weight at adulthood associated with an increase of plasma insulin, leptin and triglycerides concentrations compared to NP rats. Screening performed on hypothalamus in development from the two groups of rats identified higher gene expression for cell proliferation and neurotrophin markers in HP rats. Despite these molecular differences, appetite neuronal projections emanating from the arcuate nucleus did not differ between the groups. Concerning feeding behavior at adulthood, rats that had been fed HP or NP milk exhibited differences in the satiety period, resting postprandial duration and nocturnal meal pattern. The consequences of HP milk supplementation after LBW will be discussed in regard to neural development and metabolic anomalies

On line 1945-7170 Print 0013-7227; Nutritional programming, taking place in utero or early after birth, is closely linked with metabolic and appetite disorders in adulthood. Following the hypothesis that nutritional programming impacts hypothalamic neuronal organization, we report on discrepancies of multiple molecular and cellular early events that take place in the hypothalamus of rats submitted to intrauterine growth restriction (IUGR). Expression screening performed on hypothalami from IUGR rats at birth and at postnatal d 12 identified changes in gene expression of neurodevelopmental process (cell differentiation and cytoskeleton organization). Additionally, a slight reduction of agouti-related protein and a strong reduction of {alpha}-MSH-immunoreactive efferent fibers were demonstrated in the paraventricular nucleus of IUGR rats. Rapid catch-up growth of IUGR rats, 5 d after birth, had a positive effect on neurodevelopmental factors and on neuronal projections emanating from the arcuate nucleus. The molecular and cellular anomalies detected in IUGR rats can be related to the reduced and delayed plasma leptin surge from d 0-16 when compared with control and IUGR rats with catch-up growth. However, the ability of leptin to activate intracellular signaling in arcuate nucleus neurons was not reduced in IUGR rats. Other mechanism such as epigenetic regulation of the major appetite-regulating neuropeptides genes was analyzed in parallel with their mRNA expression during postnatal development. This study reveals the importance of an early catch-up growth that reduces abnormal organization of hypothalamic pathways involved in energy homeostasis, whereas protein restriction, maintained during postnatal development leads to an important immaturity of the hypothalamus.

International audience; Epidemiological studies demonstrated a relationship between low birth weight mainly caused by intrauterine growth restriction (IUGR) and adult metabolic disorders. The concept of metabolic programming centers on the idea that nutritional and hormonal status during the key period of development determines the long-term control of energy balance by programming future feeding behavior and energy expenditure. The present study examined the consequence of early or late "catch-up growth" after IUGR on feeding behavior and metabolic cues of male offspring of rat dams exposed to protein restriction during gestation and/or lactation. Our results suggest that early catch-up growth may be favorable for fasting metabolic parameters at weaning, as no differences were observed on plasma leptin, triglyceride, glucose, and insulin levels compared with controls. In contrast, if pups remained malnourished until weaning, low insulin concentration was detected and was accompanied by hyperphagia associated with a large increase in hypothalamic NPY and AgRP mRNA expression. At adult age, on a regular chow diet, only the meal structure was modified by fetal programming. The two IUGR groups demonstrated a reduced meal duration that enhanced the speed of food ingestion and consequently increased the rest period associated to the satiety state without changes in the hypothalamic expression of appetite neuropeptides. Our findings demonstrate that in IUGR, regardless of postnatal growth magnitude, metabolic programming occurred in utero and was responsible for both feeding behavior alteration and postprandial higher insulin level in adults. Additionally, catch-up growth immediately after early malnutrition could be a key point for the programming of postprandial hyperleptinemia.

Les nouveau-nes de petit poids de naissance ayant souffert d’un retard de croissance intra-uterin (RCIU) sont une population a haut risque pour developper un « syndrome metabolique » (obesite, hypertension, insulino-resistance) a l’âge adulte. Ces bebes sont generalement nourris avec des laits « enrichis » en proteines afin de leur assurer une croissance de rattrapage. Or le risque de pathologies cardiovasculaires ou d’obesite a l’âge adulte est correle a la vitesse de croissance dans les toutes premieres semaines de vie. Notre hypothese est qu’une alimentation hyperproteique prescrite en periode neonatale chez des nouveau-nes RCIU pourrait avoir des consequences nefastes sur la sante a l’âge adulte. Pour etudier les consequences a distance d’une alimentation neonatale hyperproteique, des ratons RCIU, nes de meres carencees en proteines durant la gestation (60 % de carence) ont ete equipes au 5eme jour de vie (J5) d’une canule de gastrostomie posee de facon percutanee (modele de ratons « pup in the cup »). Ils ont recu, de J5 (pose de la canule) a J21 (jour du sevrage) et de facon randomisee, soit un lait « normoproteique » (NP : 87,0 g/l, n = 9), soit un lait « hyperproteique » (HP : 130,5 g/l, n = 7). La croissance des rats et les quantites ingerees ont ete suivies regulierement (de J5 a J160, rat adulte). Le lait HP ne modifie pas la croissance des ratons avant le sevrage. Le lait HP presente des effets a distance : (1) un surpoids des rats nourris au lait hyperproteique vs. normoproteique entre J50 et J65, (HP : 329 ± 14 g vs . NP : 307 ± 28 g pour des rats de J60, p = 0,079), lie a une augmentation des quantites ingerees d’aliments (de J50 a J60, HP : 28 ± 3 g/j vs . NP : 25 ±3 g/j, p = 0.079) ; (2) une augmentation, de la masse du pancreas (0,29 ± 0,15 g vs . 0,17 ± 0,06, p = 0.046) et de la masse de la graisse mesenterique (6,3 ±1,4g vs . 4,5 ± 2, 1, p = 0,088) respectivement chez des rats HP vs. NP. Ces donnees preliminaires suggerent qu’un lait hyperproteique, administre a des ratons RCIU durant la periode neonatale, a des effets memoire sur le poids et la masse grasse mesenterique, traduisant des desordres metaboliques. Des mesures de composition corporel le, glucose et insuline plasmatiques, nous permettront de preciser ces perturbations metaboliques.