Nutritional programming affects hypothalamic organization and early response to leptin.
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.
Coupé
Bérengère
B
Institut National de la Recherche Agronomique, Unité Mixte de Recherche 1280 Physiologie des Adaptations Nutritionnelles, Université de Nantes, Nantes, France.
Amarger
Valérie
V
Grit
Isabelle
I
Benani
Alexandre
A
Parnet
Patricia
P
D054369:Agouti-Related Protein / Q000032:analysis / Q000235:genetics; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000503:physiopathology; D001835:Body Weight / Q000235:genetics / Q000502:physiology; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D019175:DNA Methylation; D002149:Energy Intake; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics / Q000503:physiopathology*; D005786:Gene Expression Regulation; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D009412:Nerve Fibers / Q000502:physiology / Q000648:ultrastructure; D009419:Nerve Tissue Proteins / Q000235:genetics; D009478:Neuropeptide Y / Q000235:genetics; D010286:Paraventricular Hypothalamic Nucleus / Q000503:physiopathology; D011333:Pro-Opiomelanocortin / Q000235:genetics; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D051381:Rats; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D000521:alpha-MSH / Q000032:analysis; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein
C515197:AGRP protein, rat; D054369:Agouti-Related Protein; D020738:Leptin; D009419:Nerve Tissue Proteins; D009478:Neuropeptide Y; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein; D000521:alpha-MSH; D012313:RNA; D011333:Pro-Opiomelanocortin; D004247:DNA