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.

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.

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