Observations on the Orexigenic Hypothalamic Neuropeptide Y‐System in Neonatally Overfed Weanling Rats

Abstract

Early postnatal overnutrition is a risk factor for obesity in juvenile and adult life. Underlying pathophysiological mechanisms are still unclear. Hypothalamic neuropeptides are decisively involved in the regulation of body weight and food intake. In this study, we investigated consequences of early postnatal overnutrition, as compared to normo-and undernutrition, on NPY within the arcuate nucleus and paraventricular nucleus (PVN). The normal litter size of Wistar rats was adjusted on the third day of life from 10 pups (normal litters, NL; normonutrition) to only three newborns (small litters, SL; overnutrition) or 18 pups per mother (large litters, LL; undernutrition). SL rats developed clear overweight until the day 21 of life (P<0.0001), as well as hyperleptinaemia (P<0.001), and hyperinsulinaemia (P<0.01). LL rats were underweight and had decreased leptin and insulin concentrations. Using radioimmunoassay, NPY contents were determined in hypothalamic micropunches, and immunocytochemistry for NPY was performed in serial hypothalamic sections on day 21 of life. While in the underweight, hypoleptinaemic, and hypoinsulinaemic LL rats increased concentrations of NPY in the arcuate nucleus and PVN were observed, no decrease in NPY content was found in the overweight, hyperleptinaemic, and hyperinsulinaemic SL rats. Moreover, the percentage of NPY-immunopositive neurones per total number of neurones was increased not only in the LL rats, but also in the SL rats. Since the NPY system is functionally mature already at this age, these findings might indicate an acquired resistance of the hypothalamic NPY system to increased levels of insulin and/or leptin in early postnatally overfed SL rats.

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

“…The number of animals of each sex in the three kinds of litter was balanced. No mortality was found in the NL and SL groups, but in contrast with previous reports [19] mortality in the LL groups was 20 ±4.6% before day 11; after this time no mortality was detected in that group. Animals were separated from their mothers at day 24 (not at day 21 as in previous reports [19,22]) in order to ensure complete weaning [23] due to the known delay to weaning observed in LL pups [19,22].…”

“…Their increase in body weight was accompanied by an increase in body length. Even with this increased body length, their relative body weight (body weight/body length) was significantly higher than the relative body weight of rats with normal feeding (NL), indicating an obese phenotype [10,19]. This is further demonstrated by the high leptin levels observed in these rats, indicating a large amount of adipose tissue [5,48].…”

“…This effect could be explained in terms of milk intake [10,45]. The key aspect of the overfed model is that these rats maintain the obese phenotype throughout their lives [19,22,44]. These data suggest that perinatal feeding is a crucial factor in the development of obesity [22,46,47].…”

“…On day 2 of life, newborns were randomly distributed among the mothers. To induce early postnatal over-, under-or normal feeding, the litter size was adjusted on day 2 of life to four to five rats in each litter (small litters, SL, n=50 pregnant mothers, early postnatal overfeeding), 22 to 24 rats in each litter (large litters, LL, n=9 pregnant mothers, early postnatal underfeeding), or 12 newborns in each litter (normal litters, NL [control], n=25 pregnant mothers, normal feeding) [19,22]. The number of animals of each sex in the three kinds of litter was balanced.…”

“…Several studies suggest the existence of alterations in the hypothalamic feeding-regulation systems in the postnatal overfeeding model. It has already been shown that these rats are hyperleptinaemic with central leptin resistance [15][16][17][18] and hyperinsulinaemic with central insulin resistance [19,20]. However, there are no data about the mechanisms underlying this programmed leptin resistance and the possible changes induced by early nutrition on the expression of hypothalamic neuropeptides.…”