Appetite Regulatory Neuropeptides are Expressed in the Sheep Hypothalamus Before Birth (original) (raw)
Related papers
Neonatal development and central appetite regulation
Journal of Pre-Clinical …, 2009
Appetite serves to regulate adequate energy intake to maintain metabolic needs. It is regulated by a close interplay between the digestive tract, adipose tissue and the brain. The role of hypothalamus, as part of the brain, in preserving energy homeostasis should be stressed. The hypothalamus can be subdivided into nuclei consisting of collections of neurones with discrete functions (e.g. arcuate nucleus, known as the infundibular nucleus in humans, paraventricular nucleus, ventromedial nucleus, dorsomedial hypothalamic nucleus, lateral hypothalamic area, etc.). Neuronal projections between these nuclei, as well as to and from other areas in the brain, enable the hypothalamus to integrate signals from the brain, the peripheral circulation and the gastrointestinal tract. What are these signaling substances and when do they appear? How and when do these projections develop? This review focuses on development of brain mechanisms regulating appetite in neonates, mainly rats and mice.
Neuroscience Letters, 2008
Orexin-A and -B are hypothalamic peptides which, in the adult brain, are associated with arousal, increased vigilance, and the seeking and ingestion of food. Because the fetus is mostly asleep, and hunger is a physiological state unlikely to arise until birth, we hypothesized that orexigenic neurons in the lateral and dorso-medial hypothalamic areas (LHA, DMH) and their projections to the locus coeruleus (LC) would develop only near the time of birth. We therefore determined orexin expression in fetal sheep, where birth occurs over a tightly regulated interval of 146-148 days gestation. Immunohistochemistry was used to determine the presence and distribution of orexin-A positive fibres and cells at the level of the hypothalamus and LC in fetal (125-137 and 145+ days gestation age) and newborn sheep brains. Orexin was measured by radioimmunoassay in plasma samples taken from chronically catheterised fetal and newborn sheep, and in CSF taken from fetuses and lambs at postmortem. Orexin-A positive cells bodies were observed in the hypothalamus, and orexin-A fibres were found throughout all hypothalamic, thalamic, and brain stem regions of all the fetal and newborn brains examined. Orexin-A was present in plasma and CSF at similar concentrations in fetal and newborn sheep. The presence of orexin in hypothalamic neurons and CSF throughout late gestation suggests that orexinergic regulation of hunger, appetite and the sleep/wake cycle is inhibited, by mechanisms yet to be identified, until the time of parturition.
The Journal of Physiology, 2005
In the present study, our aim was to determine whether intrafetal glucose infusion increases fetal adiposity, synthesis and secretion of leptin and regulates gene expression of the 'appetite regulatory' neuropeptides neuropepetide Y (NPY), agouti-related peptide (AGRP), pro-opiomelanocortin (POMC) and cocaine-and amphetamine-regulated transcript (CART) and receptors (leptin receptor (OB-Rb) and melancortin 3 receptor (MC3R)) within the fetal hypothalamus. Glucose (50% dextrose in saline) or saline was infused (7.5 ml h −1 ) into fetal sheep between 130 and 140 days gestation (term = 150 ± 3 days gestation). Glucose infusion increased circulating glucose and insulin concentrations, mean lipid locule size (532.8 ± 3.3 µm 2 versus 456.7 ± 14.8 µm 2 ) and total unilocular fat mass (11.7 ± 0.6 g versus 8.9 ± 0.6 g) of the perirenal fat depot. The expression of OB-Rb mRNA was higher in the ventromedial nucleus compared to the arcuate nucleus of the hypothalamus in both glucose and saline infused fetuses (F = 8.04; P < 0.01) and there was a positive correlation between expression of OB-Rb and MC3R mRNA in the arcuate nucleus (r = 0.81; P < 0.005). Glucose infusion increased mRNA expression for POMC, but not for the anorectic neuropeptide CART, or the orexigenic neuropeptides NPY and AGRP, in the arcuate nucleus of the fetal hypothalamus. These findings demonstrate that increased circulating glucose and insulin regulate gene expression of the neuropeptides within the fetal hypothalamus that are part of the neural network regulating energy balance in adult life.
Pre- and postnatal calorie restriction perturbs early hypothalamic neuropeptide and energy balance
Journal of Neuroscience Research, 2012
Energy balance is regulated by circulating leptin concentrations and hypothalamic leptin receptor (ObRb) signaling via STAT3 but is inhibited by SOCS3 and PTP1B. Leptin signaling enhances anorexigenic neuropeptides and receptor (POMC, MC3-R, MC4-R) activation while suppressing orexigenic neuropeptides (NPY, AgRP). We investigated in a sex-specific manner the early (PN2) and late (PN21) postnatal hypothalamic mechanisms in response to intrauterine (IUGR), postnatal (PNGR), and combined (IPGR) calorie and growth restriction. At PN2, both male and female IUGR were hypoleptinemic, but hypothalamic leptin signaling in females was activated as seen by enhanced STAT3. In addition, increased SOCS3 and PTP1B supported early initiation of leptin resistance in females that led to elevated AgRP but diminished MC3-R and MC4-R. In contrast, males demonstrated leptin sensitivity seen as a reduction in PTP1B and MC3-R and MC4-R with no effect on neuropeptide expression. At PN21, with adequate postnatal caloric intake, a sex-specific dichotomy in leptin concentrations was seen in IUGR, with euleptinemia in males indicative of persisting leptin sensitivity and hyperleptinemia in females consistent with leptin resistance, both with normal hypothalamic ObRb signaling, neuropeptides, and energy balance. In contrast, superimposition of PNGR upon IUGR (IPGR) led to diminished leptin concentrations with enhanced PTP1B and an imbalance in arcuate nuclear NPY/AgRP and POMC expression that favored exponential hyperphagia and diminished energy expenditure postweaning. We conclude that IUGR results in sex-specific leptin resistance observed mainly in females, whereas PNGR and IPGR abolish this sex-specificity, setting the stage for acquiring obesity after weaning. V V C 2012 Wiley Periodicals, Inc.
PloS one, 2009
Early life nutrition is critical for the development of hypothalamic neurons involved in energy homeostasis. We previously showed that intrauterine and early postnatal overnutrition programmed hypothalamic neurons expressing the appetite stimulator neuropeptide Y (NPY) and suppressor proopiomelanocortin (POMC) in offspring at weaning. However, the long-term effects of such programming and its interactions with post-weaning high-fat-diet (HFD) consumption are unclear. Female Sprague Dawley rats were exposed to chow or HFD for 5 weeks before mating, throughout gestation and lactation. On postnatal day 1, litters were adjusted to 3/litter to induce postnatal overnutrition (vs. 12 in control). At postnatal day 20, half of the rats from each maternal group were weaned onto chow or HFD for 15 weeks. Hypothalamic appetite regulators, and fuel (glucose and lipid) metabolic markers were measured. Offspring from obese dams gained more weight than those from lean dams independent of post-weani...
Brain Research, 2008
Human and animal studies suggest that obesity in adulthood may have its origins partly during prenatal development. One of the underlying causes of obesity is the perturbation of hypothalamic mechanisms controlling appetite. We determined mRNA levels of genes that regulate appetite, namely neuropeptide Y (NPY), pro-opiomelanocortin (POMC) and the leptin receptor isoform Ob-Rb, in the hypothalamus of adult mouse offspring from pregnant dams fed a protein-restricted diet, and examined whether mismatched post-weaning highfat diet altered further expression of these gene transcripts. Pregnant MF1 mice were fed either normal protein (C, 18% casein) or protein-restricted (PR, 9% casein) diet throughout pregnancy. Weaned offspring were fed to adulthood a high-fat (HF; 45% kcal fat) or standard chow (21% kcal fat) diet to generate the C/HF, C/C, PR/HF and PR/C groups. Food intake and body weight were monitored during this period. Hypothalamic tissues were collected at 16 weeks of age for analysis of gene expression by real time RT-PCR. All HF-fed offspring were observed to be heavier vs. C groups regardless of the maternal diet during pregnancy.
Fetal programming of appetite and obesity
Molecular and Cellular Endocrinology, 2001
Obesity and related metabolic disorders are prevalent health issues in modern society and are commonly attributed to lifestyle and dietary factors. However, the mechanisms by which environmental factors modulate the physiological systems that control weight regulation and the aetiology of metabolic disorders, which manifest in adult life, may have their roots before birth. The 'fetal origins' or 'fetal programming' paradigm is based on the observation that environmental changes can reset the developmental path during intrauterine development leading to obesity and cardiovascular and metabolic disorders later in life. The pathogenesis is not based on genetic defects but on altered genetic expression as a consequence of an adaptation to environmental changes during fetal development. While many endocrine systems can be affected by fetal programming recent experimental studies suggest that leptin and insulin resistance are critical endocrine defects in the pathogenesis of programming-induced obesity and metabolic disorders. However, it remains to be determined whether postnatal obesity is a consequence of programming of appetite regulation and whether hyperphagia is the main underlying cause of the increased adiposity and the development of metabolic disorders.
Maternal nutrition and the programming of obesity: The brain
Organogenesis, 2008
The increasing incidence of obesity in the developed and developing world in the last decade has led to a need to define our understanding of the physiological mechanisms which can predispose individuals to weight gain in infancy, childhood and adulthood. There is now a considerable body of evidence which has shown that the pathway to obesity may begin very early in life, and that exposure to an inappropriate level of nutrition during prenatal and/or early postnatal development can predispose individuals to obesity in later life The brain is at the heart of the regulation of appetite and food preferences, and it is increasingly being recognized that the development of central appetitive structures is acutely sensitive to the nutritional environment both before and immediately after birth. This review will summarize the body of work which has highlighted the critical role of the brain in the early origins of obesity and presents some perspectives as to the potential application of these research findings in the clinical setting.