Background
The body's energy homeostasis is maintained by a highly complex and integrated neurohormonal system that minimizes fluctuations in energy balance. Neurohormones are formed by neurosecretory cells and liberated by nerve impulses (e.g., norepinephrine). Their contribution towards this energy balance includes hormonal secretion sometimes in proportion to the body fat mass and the central nervous system (CNS) targets on which these hormones act.
Of the CNS targets, a complex array of hypothalamic neuropeptides constitutes the appetite regulation system. Of these neuropeptides, NPY, a 36-amino acid orexigenic peptide, is released at the nerve terminals. In the adult rat, NPY has been observed to play a key role in affecting hyperphagia (gluttony) with resultant obesity. Various hormones orchestrate the synthesis and release of this neuropeptide. For example, pancreatic insulin and leptin released by adipocytes have been reported to suppress the synthesis and release of hypothalamic NPY, thereby potentially forming a feedback system in regulating appetite, feeding behavior, and energy balance.
A previous study demonstrated that disturbances in the fetal metabolic environment of diabetic rat or an intrauterine growth-restricted (IUGR) fetus can also alter postnatal brain NPY mRNA and peptide concentrations. This, and other research, demonstrated the presence and regulation of NPY in the fetal and neonatal hypothalamus, yet the exact functional role of this peptide during the early stages of development remains to be ascertained. Accordingly, the functional relevance of a postnatal increase in hypothalamic NPY as seen in the IUGR fetus/newborn is unknown.
A New Study
Researchers have speculated that high levels of intracerebroventricular NPY during the critical stages of postnatal development will have an immediate positive effect on body weight gain, reflecting increased milk intake and a permanent influence on adult appetite, feeding behavior, and body weight gain pattern. To test this hypothesis, they undertook the present investigation and examined the effect of intracerebroventricular NPY on newborn body weight gain and adult food intake and body weight gain pattern.
The authors of "Postnatal Intracerebroventricular Exposure to Neuropeptide Y Causes Weight Loss in Female Adult Rats" are Amit Varma, Jing He, Lisa Weissfeld, and Sherin U. Devaskar, all from the University of Pittsburgh Schools of Medicine and Public Health, Pittsburgh, PA; and with the cooperation of the Department of Pediatrics, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA. Their findings appear in the June 2003 edition of the American Journal of Physiology--Regulatory, Integrative and Comparative Physiology.
Methodology
Gestationally timed pregnant Sprague-Dawley rats were allowed to deliver, and the number of pups in a litter was culled or expanded to 10 to minimize the effect of litter size on postnatal nutrition and body weight. The litters (n = 400 pups from 40 litters) of pups were arbitrarily divided into two major groups, of which one of the groups received intracerebroventricular NPY (1 µg NPY/2.5-µl dose) daily between two and seven days of age (n = 200 pups). The second group received 2.5 µl of vehicle (n = 200 pups).
The 2-7 days of age were chosen for intervention, because this is the critical period of hypothalamic development that has previously been observed to have permanent effects lasting into adulthood. All intracerebroventricular injections were performed using the conventional stereotaxic coordinates for the adult rat lateral ventricle. Individual pups in each litter were weighed daily between 8 and 10 AM. On weaning of the pups at 21 days, body weight was assessed once every 10 days until 120 days of age. Food intake was measured over a 24-h period by weighing the rat chow at the beginning and end of the 24-h period, accounting for spillage and evaporation.
At 120 days of age, the female animals in the neonatal NPY- or vehicle-treated groups were further divided into two groups each, one that received 10 µg of NPY/2.5-µl dose and the other that received an equal volume of vehicle, thereby leading to a total of four adult experimental groups. These four groups were NPY-NPY, NPY-vehicle, vehicle-NPY, and vehicle-vehicle. All animals were anesthetized with a combination of ketamine (40 mg/kg) and xylazine (8 mg/kg). The 120-day-old animals subjected to stereotaxic surgery were weighed before surgery and every day between 8 and 10 AM, spanning a total of three days. In addition, food intake was measured over a 24-hour period daily spanning a three-day period beginning on 121 days and lasting through 123 days.
Results
The following results were observed:
After injecting intracerebroventricular NPY on a daily basis between days 2-7 of life, the researchers observed an immediate increase in body weight gain within 24 hours of initiating treatment compared with the vehicle treatment group (NPY = 1.58 ± 0.07 vs. vehicle = 1.2 ± 0.03 g;). This 32 percent increase in body weight resolved in 48 hours and was no longer evident throughout the suckling phase despite ongoing NPY administration until day 7. However, beginning on day 60, a significant decline in body weight gain and food intake was observed in females that persisted through 120 days. In contrast, no statistically significant change in either the food intake or body weight gain pattern was observed in males.
The newborn animals that received NPY demonstrated hyperinsulinemia at three days of age, with no change in glucose and leptin concentrations. This hyperinsulinemia persisted until 120 days of age in the female progeny, with continuing euglycemia. The leptin levels in the NPY-treated group were not statistically different from the vehicle group. However, given the decline in female adult body weight of the NPY treatment group, plasma leptin concentrations at this age in females, if expressed per unit body weight (g), are significantly increased in the NPY vs. the vehicle group. Similar changes were absent in the male progeny. LH synthesized and released into the circulation by the pituitary in response to hypothalamic LH-releasing hormone (LHRH) and measured as plasma LH concentrations was altered in response to exogenous NPY. Neonatal exogenous intracerebroventricular NPY administration increased plasma LH concentrations at 21, 60, and 120 days, particularly in the females. The 120-day-old and not the 21-day-old males expressed a similar increase in plasma LH concentrations. LH in 35- and 60-day-old male adults was not assessed.
Conclusions
The researchers conclude that the concentrations of fetal/postnatal endogenous NPY content, either as an associated change or an end result of disturbances in circulating insulin and/or leptin concentrations, contribute toward the predetermination of adult appearance and behavior. These observations collectively make fetal/neonatal nutrition/metabolism extremely important, thereby presenting avenues for intervention before the adult onset of altered eating behavior and phenotype.
The researchers also conclude that postnatal exogenous administration of NPY causes central and peripheral changes. The central effect consists of a direct suppression of endogenous hypothalamic NPY concentrations and the indirect effect consists of neonatal hyperinsulinemia and/or hyperleptinemia that in turn chronically suppress hypothalamic NPY concentrations.
This effect is permanent, causing a decline in food intake and body weight gain only in female adults. The cause for this sex-specific "neuropeptide imprinting" effect akin to the previously described "hormonal/metabolic imprinting" effect remains to be further investigated.
Source: June 2003 edition of the American Journal of Physiology--Regulatory, Integrative and Comparative Physiology.
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