Role Of Hypothalamic Neuropeptides Research Articles

The Role of Hypothalamic Neuropeptides in Regulation of Liver Functions in Health and Disease

The communication between brain and peripheral tissues is mediated by neuropeptides that coordinate the functions of each organ with the activities of the entire body in specific environmental conditions. Hypothalamic neuropeptides act as neurotransmitters and hormones to regulate the physiology of food intake, digestion, and metabolism, having a direct or indirect impact on the liver. Investigations on liver pathologies found that dysfunctions of neuropeptides and their receptors are associated with liver disorders such as non-alcoholic fatty liver disease, steatohepatitis, cholestasis, cirrhosis, and liver cancer. In this article, we reviewed neuropeptides that regulate energy homeostasis and lipid and glucose metabolism in the liver and are associated with liver injuries. Firstly, peptides involved in regulatory processes in the brain and liver, such as neuropeptide Y, agouti-related protein, and the galanin family, are related to obesity and its comorbidities, including type 2 diabetes and metabolic syndrome, are presented. Secondly, a comprehensive review of neuropeptides such as secretin, vasoactive intestinal peptide, substance P, and somatostatin, which are involved in liver injuries unrelated to obesity; i.e., cholestasis-induced biliary hyperplasia, cirrhosis, hepatocellular carcinoma, and cholangiocarcinoma, is also presented. The cellular and molecular mechanisms underlining liver injuries related to the dysfunction of these neuropeptides and receptors are also described.

EVIDENCE OF APOPTOSIS IN PARVOCELLULAR NUCLEI OF HYPOTHALAMUS IN DIABETES MELLITUS

Diabetes mellitus (DM) causes great socio-economic damage, which is determined by medical expenses and expenditure on social security to patients due to invalidity and loss of labour capacity. Researchers are studying the role of hypothalamic neuropeptides and their involvement in the regulation of pancreatic islet function. In view of the above, the aim of our study was to establish the features of morphofunctional changes in the arcuate nucleus (AN) and ventromedial nucleus (VN) of the hypothalamus in streptozotocin-induced diabetes mellitus (SIDM).
 Histological, immunohistochemical, electron-microscopic, biochemical and statistical research methods were used.
 Polymorphic changes were noted in AN and VN at early stages of development of SIDM (on the 14th day). In AN, the area of neurons and their nuclei became larger, the numerical density of dark functionally more active neurons increased, and dinuclear light neuroendocrine cells (NC) appeared. In light and dark NCs of AN, there was a significant increase in the bulk density of neurosecretory granules – by 2-4 times compared with the control, in VN – by 1.2-2 times.
 Such morphofunctional changes in parvocellular nuclei of the hypothalamus and the increase in the bulk density of neurosecretory granules in their NCs indicate boosted synthesis of neurohormones which directly affect the adenohypophysis and improving functional activity of NCs in AN and VN.
 On the 70th day of SIDM in AN and VN of the hypothalamus, there was a decrease in the numerical density of neurons due to light NC and increase in the numerical density of vacuolated, dark pycnomorphic and apoptotic neurons. The apoptotic index in the studied nuclei of the hypothalamus increased by 2-4 times compared with the control. The area of the profile field of NC increased and the area of nuclei decreased, which led to the reduced nuclear-cytoplasmic index and indicated a decrease in their functional activity and was confirmed by a decrease in the bulk density of neurosecretory granules in NC by 1.9-2.1 times in AN and by 2.7-4.7 times in VN. At the ultrastructural level, pronounced destructive processes such as vacuolar dystrophy, development of satelliteosis and neuronophagia were observed in light NCs.
 Thus, prolonged hyperglycemia in SIDM in parvocellular nuclei of the hypothalamus causes neuronal death to a lesser extent due to apoptosis, and to a greater extentdue due to hydropic dystrophy and colliquative necrosis, especially in the long term of the experiment (on the 70th day), and leads to the development of diabetic neuroendocrinopathy.

Dietary overload lithium decreases the adipogenesis in abdominal adipose tissue of broiler chickens.

To investigate the toxic effects of dietary overload lithium on the adipogenesis in adipose tissue of chicken and the role of hypothalamic neuropeptide Y (NPY) in this process, one-day-old male chicks were fed with the basal diet added with 0 (control) or 100mg lithium/kg diet from lithium chloride (overload lithium) for 35days. Abdominal adipose tissue and hypothalamus were collected at day 6, 14, and 35. As a percentage of body weight, abdominal fat decreased (p<0.001) at day 6, 14, and 35, and feed intake and body weight gain decreased during day 7-14, and day 15-35 in overload lithium treated broilers as compared to control. Adipocyte diameter and DNA content in abdominal adipose tissue were significantly lower in overload-lithium treatment than control at day 35, although no significant differences were observed at day 6 and 14. Dietary overload lithium decreased (p<0.01) transcriptional expression of preadipocyte proliferation makers ki-67 (KI67), microtubule-associated protein homolog (TPX2), and topoisomerase 2-alpha (TOP2A), and preadipocyte differentiation transcriptional factors peroxisome proliferator-activated receptor-γ (PPARγ), and CCAAT/enhancer binding protein (C/EBP) α mRNA abundance in abdominal adipose tissue. In hypothalamus, dietary overload lithium influenced (p<0.001) NPY, and NPY receptor (NPYR) 6 mRNA abundance at day 6 and 14, but not at day 35. In conclusion, dietary overload lithium decreased the adipogenesis in abdominal adipose tissue of chicken, which was accompanied by depressing transcriptional expression of adipogenesis-associated factors. Hypothalamic NPY had a potential role in the adipogenesis in abdominal adipose tissue of broilers with a short-term overload lithium treatment.

The Role of Hypothalamic Neuropeptides in Neurogenesis and Neuritogenesis.

The hypothalamus is a source of neural progenitor cells which give rise to different populations of specialized and differentiated cells during brain development. Newly formed neurons in the hypothalamus can synthesize and release various neuropeptides. Although term neuropeptide recently undergoes redefinition, small-size hypothalamic neuropeptides remain major signaling molecules mediating short- and long-term effects on brain development. They represent important factors in neurite growth and formation of neural circuits. There is evidence suggesting that the newly generated hypothalamic neurons may be involved in regulation of metabolism, energy balance, body weight, and social behavior as well. Here we review recent data on the role of hypothalamic neuropeptides in adult neurogenesis and neuritogenesis with special emphasis on the development of food intake and social behavior related brain circuits.

Changes in free amino acid and monoamine concentrations in the chick brain associated with feeding behavior.

Domesticated chicks are precocial and therefore have relatively well-developed feeding behavior. The role of hypothalamic neuropeptides in food-intake regulation in chicks has been reported for decades. However, we hypothesized that nutrients and their metabolites in the brain may be involved in food intake in chicks because these animals exhibit a very frequent feeding pattern. Therefore, the purpose of this study was to examine the feeding behavior of chicks as well as the associated changes in free amino acid and monoamine concentrations in the chick brain. The feeding behavior of chicks was recorded continuously for 6 h. The next day, brain and blood samples were collected when the chicks either attempted to have food (hungry group) or turned food down (satiated group), in order to analyze the concentrations of the free amino acids and monoamines. We confirmed that the feeding behavior of neonatal chicks was characterized by short resting periods between very brief times spent on food intake. Several free amino acids in the mesencephalon were significantly lower in the satiated group than in the hungry group, while l-histidine and l-glutamine were significantly higher. Notably, there was no change in the free amino acid concentrations in other brain regions or plasma. As for monoamines, serotonin and norepinephrine were significantly lower in the mesencephalon of the hungry group compared with the satiated group, but 5 hydroxyindolacetic acid (5-HIAA) was higher. In addition, serotonin and norepinephrine levels were significantly higher in the brain stem of the hungry chicks compared with the satiated group, but levels of 5-HIAA and homovanillic acid were lower. Levels of both dopamine and its metabolite, 3,4-dihydroxyphenylacetic acid, were significantly higher in the diencephalon and telencephalon of the chicks in the hungry group. In conclusion, the changes in the free amino acids and monoamines in the brain may have some role in the feeding behavior of neonatal chicks.

Role of hypothalamic neuropeptides in feed intake regulation of livestock species (literary review)

Energy balance is the net result of the energy intake (nutrition) and expenditure (basic metabolic rate). The purpose of the daily feed intake is to provide energy and nutrients for maintenance, production and fill and maintain energy storages in form of glycogen and fat. Animals can adjust their feed intake to ensure their energy demand. Food intake regulation in animals and human is a very complex process, in which the digestive system, the central nervous system, the joining hormonal and non-hormonal factors, and the integrating hypothalamus take part. This review primarily focuses on the action mechanism of some important appetite regulating neuropeptides, and their impacts on the performance traits of the economically significant animal species.

Nutrition and hypothalamic neuropeptides in sheep: histochemical studies.

The identification and role of neuropeptides in the control of food intake and energy balance have been extensively studied in rodents, and for more than ten years, similar studies have been performed in sheep. As a photoperiodic ruminant, sheep are an interesting alternative animal model to rodents. In this review, we summarize the results obtained in sheep concerning the distribution of peptide-containing neurones in the hypothalamus and their central role in the control of food intake and energy balance, and compared them with relevant data from rodents. Even if the general organization and the role of hypothalamic neuropeptides are similar in sheep and rodents, numerous differences have been observed between these two species. In sheep, the magnocellular neurones of the paraventricular and supraoptic nuclei are characterized by the low density and the lack of galanin- and neuropeptide-Y-containing neurones, respectively. The sheep pituitary stalk presents neurones containing neuropeptides such as neuropeptide-Y or beta-endorphin, which are also found in the deep part of the infundibular nucleus. In this structure, several neuronal populations, including galanin, agouti-gene related peptide, somatostatin, are sensitive to energy balance variations, undernutrition or overfeeding, which may specifically modify neuropeptide levels in discrete neuronal subgroups. This feature is well illustrated by the number of neuropeptide-Y labelled neurones, that increases in the lateral part of the infundibular nucleus of undernourished ewes and decreases in the ventral part of overfed ewes. Conversely, after 24 hours of food deprivation, the number of neuropeptide-Y-immunolabelled neurones is unchanged in the sheep infundibular nucleus, whereas increased levels of this neuropeptide are described, in rats, by radioimmuno-assay. In conclusion, our review shows that peptide-containing neurone systems, involved in the regulation of food intake and energy balance in sheep, are generally similar to those observed in other species, but they present specific differences according to the physiological characteristics of the animal model.

Role of hypothalamic neuropeptide Y (NPY) in the change of feeding behavior induced by repeated treatment of amphetamine

Neuropeptide Y (NPY), an orexigenic peptide, is involved in the control of food intake. Repeated administration of amphetamine (AMPH), an anorectic agent, results in an anorectic effect on day 1 and a tolerant anorectic effect on the followings. In an attempt to know the role of hypothalamic NPY in these effects of AMPH, contents of hypothalamic NPY were determined by radioimmunoassay at first. In AMPH-treated groups, the contents of hypothalamic NPY decreased rapidly on day 1 but restored gradually to the normal level on the following days as observed in repeated AMPH. An involvement of hypothalamic NPY in the feeding change of repeated AMPH can thus be considered. Moreover, daily injection of NPY antisense oligonucleotide into brain (10 μg/10μl/day, i.c.v.) to inhibit the gene expression of hypothalamic NPY were performed at 1 hour before daily 2 mg/kg AMPH. The reversion of food intake from the anorectic level to the normal level (tolerant anorexia) was abolished by this antisense pretreatment. It is suggested that hypothalamic NPY may play a role in the change of feeding behavior induced by repeated AMPH administration.

Role of hypothalamic neuropeptide Y and orexigenic peptides in anorexia associated with experimental colitis in the rat

Role of hypothalamic neuropeptide Y and orexigenic peptides in anorexia associated with experimental colitis in the rat

Role of hypothalamic neuropeptide Y and orexigenic peptides in anorexia associated with experimental colitis in the rat

Neuropeptide Y (NPY) is thought to play a crucial role in the normal hypothalamic response to starvation. After a period of food restriction, increased release of NPY induces hunger and hyperphagia, and helps to restore body weight to its set point. Persistent anorexia in rats with experimental colitis implies failure of this adaptive feeding response. In vivo NPY release and regional hypothalamic NPY concentrations were measured in rats with trinitrobenzenesulphonic acid (TNBS)-induced colitis, healthy controls and animals pair-fed to match the food intake of the colitic group. Food intake in the colitic group was assessed after administration of NPY and two other potent orexigenic peptides: melanin-concentrating hormone (MCH) and hypocretin (orexin-A). Food intake was decreased by 30-80% below control values for 5 days in the colitic rats. In both the pair-fed and colitic groups, release of NPY in the paraventricular nucleus was significantly increased compared with free-feeding controls. Intraventricular or intrahypothalamic administration of NPY, MCH or hypocretin elicited a feeding response in healthy controls, but not in the colitic group. In summary, animals with TNBS-colitis and anorexia show an appropriate increase in hypothalamic NPYergic activity. However, the failure of NPY and other orexigenic peptides to increase feeding in the colitic group indicates suppression of feeding, either by inhibition of a common downstream hypothalamic neuronal pathway or by induction of one or more potent anorexigenic agents.

Role of hypothalamic neuropeptide Y in feeding and obesity

The 36-amino-acid peptide, neuropeptide Y (NPY), is the most abundant peptide in the rat brain. When administered into the brain, NPY produces a variety of physiological actions including a pronounced stimulation of feeding in satiated rats. Elevations in hypothalamic NPY have been reported after food deprivation and in genetically obese rodents. NPY is believed to produce its actions through a portfolio of G-protein coupled receptors, Y1, Y2, Y4 and Y5. Studies using peptide analogs, receptor knockout animals and specific receptor antagonists suggest the Y1 and Y5 receptors are important in mediating the effects of NPY on food intake in rats. Development of specific receptor antagonists with improved pharmacokinetic properties will be required to determine the importance of NPY in human obesity and appetite disorders.

Role of hypothalamic neuropeptide Y neurons in the defective thermogenic response to acute cold exposure in fatty Zucker rats

The fatty Zucker rat has impaired heat production and fails to mount an adequate thermogenic response to cold exposure, partly because of decreased sympathetic drive to thermogenesis in brown adipose tissue. Neuropeptide Y, synthesized in neurons of the hypothalamic arcuate nucleus and released in the paraventricular nucleus, stimulates feeding and inhibits brown adipose tissue activity. The neuropeptide Y neurons are overactive in fatty Zucker rats and are thought to contribute to hyperphagia, reduced energy expenditure and obesity. We have examined the relationship between thermogenic activity in brown adipose tissue (measured as uncoupling protein messenger RNA levels) and hypothalamic neuropeptide Y and neuropeptide Y messenger RNA levels in response to cold exposure (4°C) for 2.5 and 18 h, in fatty and lean Zucker rats. In lean Zucker rats, cold exposure at 4°C for 2.5 and 18 h significantly increased uncoupling protein messenger RNA levels by 3.5-fold ( P<0.01) and 3.3-fold ( P<0.01), respectively, compared with warm-maintained controls. Exposure to cold for 18 h also increased neuropeptide Y concentrations in the paraventricular nucleus ( P<0.01) and ventromedial nucleus ( P<0.001) in lean rats, with no change in neuropeptide Y messenger RNA after either 2.5 or 18 h. By contrast, fatty Zucker rats showed no significant changes in uncoupling protein messenger RNA ( P>0.05) at either duration of cold exposure. There were also no significant changes in neuropeptide Y levels in any region nor in neuropeptide Y messenger RNA, with cold exposure for either period ( P>0.05). In lean rats, cold exposure therefore stimulates brown fat uncoupling protein messenger RNA and also increases neuropeptide Y concentrations in its hypothalamic sites of release. We suggest that increased brown fat thermogenic capacity induced by cold in lean rats may be mediated, at least in part, by decreased neuropeptide Y release in the paraventricular nucleus, resulting in its accumulation in this site. Defective thermogenic responses in fatty rats may result from central dysregulation of brown adipose tissue due to sustained and non-suppressible overactivity of hypothalamic neuropeptide Y neurons.

Role of hypothalamic neuropeptide Y gene expression in body weight regulation.

Hypothalamic neuropeptide Y (NPY) may be involved in the hyperphagia that follows food deprivation associated with significant weight loss. However, it is unclear whether NPY is involved in body weight regulation under more physiological circumstances. Consequently, we measured body weight, food intake, arcuate nucleus (ARC) NPY mRNA, serum glucose, and insulin in male Wistar rats after 48 h of food deprivation and various refeeding protocols. Food deprivation produced a twofold increase in NPY mRNA, whereas 3 days of ad libitum refeeding returned body weight and NPY mRNA to control. If hyperphagia was prevented for 5 days during refeeding, then neither body weight nor NPY mRNA normalized. There were strong negative correlations between ARC NPY mRNA and both loss of body weight and serum insulin levels. These data suggest that hypothalamic NPY gene expression plays a role in control of body weight under physiological conditions. The data further suggest that NPY mRNA may be decreased by peripheral insulin levels.

Immunocytochemical localization of neuropeptides in the hypothalamus of the Japanese long-fingered bat, Miniopterus schreibersii fuliginosus

To elucidate the role of hypothalamic neuropeptides in regulation of reproductive phenomena of seasonally breeding feral mammals, we used Japanese long-fingered bats, Miniopterus schreibersii fuliginosus, for immunocytochemical study of distribution of the following neuropeptides in the hypothalamus: arginin vasopressin, oxytocin, luteinizing hormone-releasing hormone, somatostatin, corticotropin-releasing factor, and growth hormone-releasing factor. The size, shape and location of supraoptic, paraventricular, suprachiasmatic, and arcuate nuclei of the bat were determined. Arginin vasopressin-and oxytocin-immunoreactive magnocellular neurons were found in the supraoptic and paraventricular nuclei, where they exhibited separate distribution into two distinct groups. Parvocellular arginin vasopressin neurons occurred only in the suprachiasmatic nucleus. The hibernating bats exhibited slightly increased numbers of vasopressin and oxytocin neurons in the supraoptic and paraventricular nuclei. The pregnant bat displayed further increased numbers of vasopressin and oxytocin neurons in both nuclei. Somatostatin-immunoreactive neurons in the paraventricular nucleus were also immunopositive to anti-oxytocin serum, while those in the ventromedial and arcuate nuclei reacted solely to anti-somatostatin serum. They projected to the anterior median eminence and infundibular stalk. Luteinizing hormone-releasing hormone-immunoreactive perikarya were scattered throughout the basal hypothalamus, being particularly abundant in the arcuate nucleus. They were larger in size in hibernating bats than those in normal (non-pregnant) and pregnant females. They projected fibers mainly to the internal layer of the median eminence and infundibular stalk. A few luteinizing hormone-releasing hormone-reactive fibers were also observed in the organum vasculosum laminae terminalis, lateral habenular nuclei, pineal stalk, retroflexus fasciculus, and olfactory tubercle. Corticotropin releasing factor-immunoreactive perikarya were distributed in the paraventricular nucleus and medial preoptic area and projected into the external layer of the anterior median eminence, while growth hormone-releasing factor-immunoreactive perikarya occurred only in the arcuate nucleus and projected into the posterior part of the median eminence.