A possible role of neuropeptide Y, agouti-related protein and leptin receptor isoforms in hypothalamic programming by perinatal feeding in the rat

Abstract

Aim/hypothesis: Perinatal overfeeding predisposes humans and rats to obesity and diabetes in later life. One classical model for studying the effect of early feeding is manipulation of the size of rat litters. Rats growing up in small litters gain more weight than rats growing up in normal-sized litters. Interestingly, these obese rats maintain this phenotype in adulthood. Conversely, rats raised in large litters show a delay in growth and a decrease in body weight. The aim of this work was to assess the hypothalamic control mechanisms of food intake regulated by perinatal feeding. Methods: Leptin levels were analysed using RIA. Leptin receptor mRNA levels were analysed using RT-PCR. Neuropeptide mRNA levels were analysed using in situ hybridisation. Results: Perinatally overfed neonatal male rats exhibited hyperleptinaemia and a decrease in hypothalamic mRNA levels of the long isoform of the leptin receptor (OB-Rb), explaining their leptin resistance. Moreover, this obese model showed an increase in the mRNA expression of cocaine-and amphetamine-regulated transcript, neuropeptide Y and agouti-related protein in the hypothalamic arcuate nucleus (ARC). In contrast, perinatally underfed neonatal male rats with hypoleptinaemia showed an increase in hypothalamic mRNA of the short isoforms of the leptin receptor. Furthermore, they exhibited an increase in expression of neuropeptide Y and agoutirelated protein in the ARC. Conclusions/interpretation: Rats overfed during early postnatal life show a leptinresistant state mediated by down-regulation of the hypothalamic OB-Rb. These data, together with the increased expression of neuropeptide Y and agouti-related protein in specific neurons in the ARC, might indicate the existence of regulated programming in this nucleus and may provide a new aetiopathogenic concept in susceptibility to obesity.

The hypothalamus–adipose axis is a key target of developmental programming by maternal nutritional manipulation

“…In the latter case, these modifications might impair hormonal effects on POMC expression and might account for hypothalamic leptin/insulin resistance (Plagemann et al 2009). This was a very specific effect in that no change was observed in the NPY promoter region, despite increased NPY mRNA expression levels (Ló pez et al 2005).…”

“…First, they displayed neuronal morphometric modifications and altered hypothalamic nuclei activity (Plagemann et al 1999b). Secondly, they exhibited impaired Arc neuron sensitivity, especially to leptin and insulin with higher NPY mRNA expression levels (Ló pez et al 2005).…”

Perinatal overfeeding in rats results in increased levels of plasma leptin but unchanged cerebrospinal leptin in adulthood

“…1,2 In both rodents and humans, perinatal nutrition predisposes to metabolic alterations, such as diabetes and obesity. 1,[3][4][5][6][7][8][9][10][11] One classical model to study the effect of early overnutrition is the manipulation of the size of the rat litters in the first days of life, called 'programming'. 7,[11][12][13] Rats growing up in small litters (SL) gain more weight than rats growing up in normal litters (NL) and this phenotype is maintained throughout their lives.…”

“…1,[3][4][5][6][7][8][9][10][11] One classical model to study the effect of early overnutrition is the manipulation of the size of the rat litters in the first days of life, called 'programming'. 7,[11][12][13] Rats growing up in small litters (SL) gain more weight than rats growing up in normal litters (NL) and this phenotype is maintained throughout their lives. 7,11,14 The specific physiological mechanisms underlying fetal/neonatal programming are not completely known.…”

“…7,[11][12][13] Rats growing up in small litters (SL) gain more weight than rats growing up in normal litters (NL) and this phenotype is maintained throughout their lives. 7,11,14 The specific physiological mechanisms underlying fetal/neonatal programming are not completely known. It has been recently reported that during the juvenile state (24-days old), perinatal overfed rats show hyperleptinemia and leptin resistance to peripheral leptin, related with the downregulation of the long isoform of the leptin receptor (OB-Rb) in the hypothalamus.…”