Observations on the orexigenic hypothalamic neuropeptide Y-system in neonatally overfed weanling rats.

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.

Cholecystokinin-8S levels in discrete hypothalamic nuclei of weanling rats exposed to maternal protein malnutrition.

Perinatal malnutrition and growth retardation at birth are suggested to be important risk factors for the development of overweight and syndrome X in later life. Underlying mechanisms are unknown. Body weight and food intake are regulated, e.g. by hypothalamic neuropeptidergic systems which are thought to be highly vulnerable to persisting malorganization due to perinatal malnutrition. To investigate possible consequences for hypothalamic cholecystokinin-8S (CCK-8S) in the offspring, pregnant Wistar rats were fed an 8% protein diet during pregnancy and lactation (low-protein group; LP) while control mothers (CO) received a 17% protein isocaloric standard diet. LP offspring displayed underweight at birth (P < 0.05) and during suckling (P < 0.001), while leptin levels were not altered. At weaning, under basal conditions CCK-8S was decreased in LP offspring in the paraventricular hypothalamic nucleus and arcuate hypothalamic nucleus (P < 0.05), as well as in the dorsomedial hypothalamic nucleus, lateral hypothalamic area and ventromedial hypothalamic nucleus (P < 0.01). In summary, these data indicate (1) an inhibition of the satiety peptide CCK-8S in main regulators of body weight and food intake in low-protein malnourished newborn rats; (2) no direct relationship of hypothalamic CCK-8S to circulating leptin at this age; and (3) no neurochemical signs of hypothalamic CCKergic dysregulation in this animal model at the age of weaning.

Hypothalamic neuropeptide Y levels in weaning offspring of low-protein malnourished mother rats.

Maternal low-protein malnutrition during gestation and lactation (LP) is an animal model frequently used for the investigation of long-term deleterious consequences of perinatal growth retardation. Hypothalamic neuropeptides are decisively involved in the central nervous regulation of body weight and metabolism. We investigated neuropeptide Y (NPY) in distinct hypothalamic nuclei in the offspring of LP mother rats at the end of the critical hypothalamic differentiation period (20th day of life). Weanling LP offspring were underweight (P< 0.001) and hypoinsulinaemic (P< 0.05), while leptin levels were unchanged. NPY was significantly increased in the paraventricular hypothalamic nucleus (PVN) (P< 0.01) and lateral hypothalamic area (P< 0.05) in LP offspring. In contrast, NPY was unchanged in the ventromedial hypothalamic nucleus (VMN). These observations indicate a leptin-independent stimulation of the orexigenic ARC-PVN axis in undernourished LP rats at weaning. Furthermore a disturbed NPYergic regulation of the VMN is suggested, possibly contributing to alterations of the hypothalamic regulation of body weight and metabolism in LP offspring during life.