Developmental changes in the mammalian gonadotropin-inhibitory hormone (GnIH) ortholog RFamide-related peptide (RFRP) and its cognate receptor GPR147 in the rat hypothalamus.
ABSTRACT The mammalian gonadotropin-inhibitory hormone (GnIH) ortholog RFamide-related peptide (RFRP) is considered to act on gonadotropin-releasing hormone (GnRH) neurons and on the pituitary to inhibit gonadotropin release and synthesis. To understand the functional significance of this neuropeptide, we investigated the physiological changes in RFRP at mRNA and peptide levels, as well as at the mRNA level of its cognate receptor, G protein-coupled receptor 147 (GPR147), in the rat hypothalamus during development. We also investigated the effects of gonadal steroids on mRNA expression levels of these molecules. In male rats, mRNA expressions of both RFRP and GPR147 increased from postnatal days 12 and 16, peaking at postnatal days 35 and 42, respectively. However, their expressions fell at postnatal day 49. In female rats, mRNA expression of RFRP continued to increase throughout development; mRNA expression of GPR147 in female rats increased from postnatal day 16, peaking at postnatal day 28, but decreased from postnatal day 35. The hypothalamic contents of RFRP on postnatal days 28 and 42 were significantly higher than on postnatal day 4 in male rats, and those on postnatal day 42 were significantly higher than those on postnatal days 4 and 28 in females. Neither orchidectomy nor ovariectomy influenced mRNA expression levels of RFRP or GPR147 in the prepubertal period when endogenous sex steroid levels were low in males and females. Administration of estradiol-17β (E2) increased mRNA expression of RFRP in prepubertal females. These results suggest that the hypothalamic RFRP system changes during development. An ovarian sex steroid, E2, may stimulate mRNA expression of RFRP in the prepubertal period when the basal E2 concentration is low.
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ABSTRACT: Hypothalamic neurons, which produce the kisspeptin family of peptide hormones (Kp), are critical for initiating puberty and maintaining estrous cyclicity by stimulating gonadotropin-releasing hormone (GnRH) release. Conversely, RFamide-related peptide-3 (RFRP3) neurons inhibit GnRH activity. It has previously been shown that neonatal exposure to bisphenol A (BPA) can alter the timing of female pubertal onset and induce irregular estrous cycles or premature anestrus. Here we tested the hypothesis that disrupted ontogeny of RFamide signaling pathways may be a mechanism underlying advanced puberty. To test this, we used a transgenic strain of Wistar rats whose GnRH neurons express enhanced green fluorescent protein. Pups were exposed by daily subcutaneous injection to vehicle, 17beta-estradiol (E2), 50 μg/kg BPA, or 50 mg/kg BPA, from Postnatal Day (PND) 0 through PND 3, and then cohorts were euthanized on PNDs 17, 21, 24, 28, and 33 (5-8 animals per age per exposure; males were collected on PNDs 21 and 33). Vaginal opening was advanced by E2 and 50 μg/kg BPA. On PND 28, females exposed to E2 and 50 μg/kg BPA had decreased RFRP-3 fiber density and contacts on GnRH neurons. RFRP3 perikarya were also decreased in females exposed to 50 μg/kg BPA. Data suggest that BPA-induced premature puberty results from decreased inhibition of GnRH neurons.Biology of Reproduction 05/2012; 87(2):28. · 4.03 Impact Factor
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ABSTRACT: Glucocorticoid secretion is a key endocrine response to stress. It has been reported that prenatal stress induces long-lasting alterations in body weight regulation systems, which persist after the stress has ceased. In this study, the long-term effects of prenatal glucocorticoid exposure on body weight changes and the expression of appetite-regulating factors were examined in female rats. Pregnant rats were given normal drinking water (control) or dexamethasone (1μg/mL) dissolved in drinking water (DEX) from day 13 of pregnancy until delivery. Then, the body weight change, serum leptin levels, and hypothalamic NPY mRNA levels of their offspring were examined. The DEX dams gained significantly less body weight during pregnancy than the control dams. The DEX dams' offspring exhibited a significantly lower birth weight than the offspring of the control dams, and the same was true for body weight at postnatal days 20 and 28. The offspring of the DEX dams displayed significantly higher serum leptin levels and significantly lower hypothalamic NPY mRNA levels compared with the offspring of the control dams. Significant inverse correlations were detected between body weight and the serum leptin level, and between the serum leptin level and the hypothalamic NPY mRNA level. On the other hand, a significant positive correlation was detected between body weight and the hypothalamic NPY mRNA level. These results indicate that leptin production is increased in a long-lasting manner in offspring exposed to glucocorticoids during the prenatal period and that this results in attenuated body weight gain and hypothalamic NPY expression during the pre-pubertal period.International journal of developmental neuroscience: the official journal of the International Society for Developmental Neuroscience 04/2014; · 2.03 Impact Factor
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ABSTRACT: Prokineticin 2 (PK2) is highly expressed in several regions of the central nervous system, including the hypothalamus. Recently, it has been suggested that PK2 plays a role in appetite regulation. In adult male rodents, the administration of PK2 decreased food intake, and PK2 mRNA expression was reduced by food deprivation. Usually, the changes in the expression levels of appetite-regulating factors induced in response to fasting are not fully established during the neonatal period. Thus, we investigated the developmental changes in hypothalamic PK2 mRNA expression and the alterations in hypothalamic PK2 mRNA expression induced by fasting during the pre-pubertal period in female rats. The changes in hypothalamic neuropeptide Y (NPY) mRNA expression were also examined because NPY is a potent appetite regulatory factor. Hypothalamic PK2 mRNA expression was extremely high during the early neonatal period (postnatal day (PND) 5) compared with that observed during subsequent periods (PND15, 25, and 42), while hypothalamic NPY mRNA expression did not differ among any of the examined periods. A fasting-induced reduction in hypothalamic PK2 mRNA expression was observed on PND5, but no fasting-induced increase in hypothalamic NPY mRNA expression was seen during the same period. In addition, the fasting-induced reduction in hypothalamic PK2 mRNA expression observed on PND5 was more marked than that seen on PND25. These results suggest that the sensitivity of hypothalamic PK2 expression to undernutrition develops during the early neonatal period, when the responses of other appetite regulatory factors to such pressures remain immature.International journal of developmental neuroscience: the official journal of the International Society for Developmental Neuroscience 01/2014; · 2.03 Impact Factor