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Results for “Cocaine- and Amphetamine-Regulated Transcript Protein”

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PubMed1999

Sequence variants in the human cocaine and amphetamine-regulated transcript (CART) gene in subjects with early onset obesity.

OBJECTIVE: The cocaine and amphetamine-regulated transcript (CART) is expressed in the brain of rodents and humans, and intracerebroventricular injection of the peptide in rats reduces food intake. The objective of the present study was to chromosomally map the CART gene and to examine the coding region of the gene for variability in obese subjects. METHODS: The coding region of the CART gene was analyzed by single-strand conformation polymorphism analysis in 84 subjects with early onset obesity. The prevalence of identified mutations was estimated in a cohort of 757 subjects with juvenile onset obesity [body mass index (BMI) = 35.7+/-5.7 kg/m2+/-standard deviation (S)] and in 890 random control subjects (BMI = 26.1+/-3.6 kg/m2+/-S). Furthermore, using radiation hybrid mapping we mapped the chromosomal localization of the human CART gene. RESULTS: Radiation hybrid mapping co-localized the CART gene with a recently published human obesity locus at chromosome 5q13-14 corresponding also to an obesity locus at the similar syntenic region in mice. We identified two silent polymorphisms in the 3'UTR region of the gene (position 1457 deletion of A and position 1475 A-->G substitution) and the prevalence of these was determined among obese and control subjects. However, none of the variants were associated with either obesity or weight gain during an average follow-up period of 27.4+/-8.4 years (S). CONCLUSION: Mutations in the coding region of the CART gene are unlikely to be involved in body weight control in Danish Caucasians with early onset obesity.

Adolescent↗

PubMed2001

Effect of LPS administration on the expression of POMC, NPY, galanin, CART and MCH mRNAs in the rat hypothalamus.

Anorexia and weight loss are manifestations of inflammation seen both in patients and in experimental animal models such as the lipopolysaccharide (LPS)-treated rat. Using in situ hybridization, the levels of mRNAs encoding proopiomelanocortin (POMC), neuropeptide Y (NPY), galanin, melanin-concentrating hormone (MCH) and cocaine- and amphetamine-regulated transcript (CART) were investigated in the rat hypothalamus after a single intraperitoneal dose (125 microg/kg) of LPS. Four hours after LPS injection the food intake was significantly decreased. POMC and CART mRNA levels were increased in the arcuate nucleus, and MCH, CART and galanin mRNAs were all decreased in the lateral hypothalamic area in LPS-treated rats. Levels of mRNAs for NPY and galanin in the arcuate nucleus, and for MCH and CART in the zona incerta did not change significantly after LPS treatment. These findings support the hypothesis that LPS-induced factors mediate signalling to the POMC/CART neurons in the arcuate nucleus which could lead to reduced food intake by decreasing MCH, CART and galanin synthesis in target lateral hypothalamic neurons.

Animals↗

PubMed2000

In vitro stimulation of the prepubertal rat gonadotropin-releasing hormone pulse generator by leptin and neuropeptide Y through distinct mechanisms.

Leptin may act as a negative feedback signal to the brain in the control of appetite through suppression of neuropeptide Y (NPY) secretion and stimulation of cocaine- and amphetamine-regulated transcript (CART), a new anorectic peptide. We aimed at studying whether leptin, NPY, and CART have related effects on the hypothalamic control of the pituitary-gonadal system and the developmental changes in NPY and CART effects. Using retrochiasmatic hypothalamic explants from prepubertal 15-day-old male rats, the GnRH interpulse interval (mean +/- SD: 62 +/- 5 min) was significantly reduced by 10(-7) M of leptin (46 +/- 3.3 min) as well as 10(-7) M of NPY (47 +/- 4.4 min) and 10(-6) M of CART (46 +/- 2.7 min), whereas the GnRH pulse amplitude was not affected. The stimulatory effects of different NPY receptor agonists [human PYY 3-36, porcine NPY 13-36, human (D-Trp 32) NPY, porcine (Leu 31 Pro 34) NPY, human pancreatic polypeptide (PP)], as well as the absent effects of rat PP were consistent with the involvement of the Y5-receptor subtype in mediation of NPY effects. Incubation with 10(-7) M of a Y5-receptor selective antagonist prevented the effect of NPY (61 +/- 4 vs. 46 +/- 2 min), whereas leptin and CART effects were not (47 +/- 3 vs. 46 +/- 3 min and 46 +/- 3 vs. 46 +/- 2 min, respectively), suggesting that NPY was not involved in leptin and CART effects. Using an anti-CART antiserum (1:1000), the reduction of GnRH interpulse interval caused by leptin was partially prevented (56.2 +/- 4 vs. 47.9 +/- 3.8 min), whereas the reduction of GnRH interval caused by NPY was not affected (45.9 +/-2.5 vs. 47.8 +/- 3.7). The GnRH interpulse interval was decreased by 10(-7) M of NPY at 5 days (72 +/- 3.8 vs. 91.9 +/- 3.5) as well as at 15 days, whereas such an effect was not observed anymore at 25 and 50 days. Similar effects were observed using 10(-6) M of CART-peptide. Using 10(-6) M of the Y5-receptor antagonist, the GnRH interpulse interval was significantly increased at 15 days (66.6 +/- 2.7 min), 25 days (56.5 +/- 39.9 min), and 50 days (52.5 vs. 38.2 min), whereas no change was observed at 5 days. Using the anti-CART antiserum, a significant increase of GnRH interpulse interval was observed at 25 days only. In conclusion, the stimulatory effects of leptin and NPY on the frequency of pulsatile GnRH secretion before puberty involve two distinct mechanisms. NPY causes acceleration of GnRH pulsatility via the Y5-receptor subtype, which is not involved in leptin effects while the CART is involved in leptin effects on GnRH secretion but not in NPY effects. The reduction of pulsatility by the Y5 antagonist provides evidence of endogenous NPY involvement in the control of GnRH secretion from the time of onset of puberty.

Aging↗

PubMed1999

CART peptide-immunoreactive neurones in the nucleus accumbens in monkeys: ultrastructural analysis, colocalization studies, and synaptic interactions with dopaminergic afferents.

Cocaine- and amphetamine-regulated transcript (CART) is a novel mRNA whose level of expression was found to be increased in the striatum after acute administration of psychomotor stimulants in rats. To define better the potential role of CART peptides in behavioural and physiologic changes induced by psychomotor stimulants, we analyzed the distribution, ultrastructural features, synaptic connectivity, and transmitter content of CART peptide-immunoreactive neurones in the nucleus accumbens in monkeys. Medium-sized CART peptide-immunoreactive neurones within a rich plexus of labelled varicosities were found mostly in the medial division of the shell of the nucleus accumbens in monkeys. At the electron microscope level, CART peptide immunoreactivity was exclusively associated with neuronal structures that included perikarya, dendrites, spines as well as nerve terminals packed with electron-lucent and dense-core vesicles. Most CART peptide-containing somata displayed the ultrastructural features of striatal output neurones. The majority of labelled terminals formed symmetric axodendritic synapses and displayed gamma-aminobutyric acid (GABA) immunoreactivity. CART peptide-immunoreactive somata were not immunoreactive for parvalbumin and somatostatin, two markers of striatal interneurones, nor for calbindin D-28k, a marker of a subpopulation of projection neurones. In double-immunostained sections, CART peptide-immunoreactive dendrites were found to be contacted by tyrosine hydroxylase-positive terminals which displayed the ultrastructural features of dopamine-containing boutons. These findings strongly suggest that CART peptides may be a cotransmitter with GABA in a subpopulation of projection neurones in the monkey accumbens. Furthermore, the fact that CART peptide-immunoreactive neurones receive direct synaptic inputs from dopaminergic afferents and are particularly abundant in the caudomedial division of the shell of the nucleus accumbens suggest that CART peptides might be involved in neuronal and behavioural changes that underlie addiction to psychomotor stimulants and feeding in primates.

Animals↗

PubMed2002

Neurochemical phenotype of hypothalamic neurons showing Fos expression 23 h after intracranial AgRP.

Agouti-related protein (AgRP) is coexpressed with neuropeptide Y (NPY) in a population of neurons in the arcuate nucleus (ARC) of the hypothalamus and stimulates food intake for up to 7 days if injected intracerebroventricularly. The prolonged food intake stimulation does not seem to depend on continued competition at the melanocortin-4 receptor (MC4R), because the relatively specific MC4R agonist MTII regains its ability to suppress food intake 24 h after AgRP injection. Intracerebroventricular AgRP also stimulates c-Fos expression 24 h after injection in several brain areas, so the neurons exhibiting delayed Fos expression might be particularly important in feeding behavior. Thus we aimed to identify the neurochemical phenotype of some of these neurons in select hypothalamic areas, using double-label immunohistochemistry. AgRP-injected rats ingested significantly more chow (10.2 +/- 0.6 g) vs. saline controls (3.4 +/- 0.7 g) in the first 9 h (light phase) after injection. In the lateral hypothalamus (particularly the perifornical area) 23 h after injection, AgRP induced significantly more Fos vs. saline in orexin-A (OXA) neurons (25.6 +/- 4.9 vs. 4.8 +/- 3.1%), but not in melanin-concentrating hormone (MCH) or cocaine- and amphetamine-regulated transcript (CART) neurons. In the ARC, AgRP induced significantly more Fos in CART (40.6 +/- 5.9 vs. 13.4 +/- 1.8%) but not NPY neurons. In the paraventricular nucleus, there was no significant difference in Fos expression induced by AgRP vs. saline in oxytocin and CART neurons. We conclude that the long-lasting hyperphagia induced by AgRP is correlated with and possibly partially mediated by hyperactive OXA neurons in the lateral hypothalamus and CART neurons in the ARC, but not by NPY and MCH neurons. The substantial increase in light-phase food intake by AgRP supports a role for the arousing effects of OXA. Activation of CART neurons in the ARC (which likely coexpress proopiomelanocortin) could indicate attempts to activate counterregulatory decreases in food intake.

Agouti-Related Protein↗

PubMed2002

Cocaine- and amphetamine-regulated transcript peptide-immunoreactivity in adrenergic C1 neurons projecting to the intermediolateral cell column of the rat.

Cocaine- and amphetamine-regulated transcript (CART) peptide-immunoreactivity was detected in neurons of the rostral ventrolateral medulla (RVLM), but few in the caudal ventrolateral medulla (CVLM). Double-labeling the medullary sections with sheep polyclonal phenylethanolamine N-methyltransferase-antiserum (PNMT) or monoclonal tyrosine hydroxylase-antibody and rabbit polyclonal CART peptide-antiserum revealed that nearly all adrenergic cells in the C1 area were CART peptide-positive and vice versa; tyrosine hydroxylase-positive cells in the A1 area were not. In the thoracolumbar spinal cord, neurons in the intermediolateral cell column (IML) and other sympathetic autonomic nuclei were CART peptide-positive; some of these were contacted by immunoreactive fibers arising from the lateral funiculus. By immuno-electron microscopy, axon terminals containing closely packed agranular CART peptide-immunoreactive vesicles appeared to make synaptic contacts with immunoreactive dendrites and soma in the IML, albeit the incidence of such contacts was low. Microinjection of the retrograde tracer Fluorogold into the lateral horn area of the T1-T3 spinal segments labeled a population of neurons in the C1 area, many of which were also CART peptide-positive. The results indicate that CART peptide-immunoreactivity is expressed in C1 adrenergic neurons, some of which project to the thoracolumbar spinal cord. The presence of this novel peptide in C1 adrenergic neurons underscores the multiplicity of putative transmitters that may be involved in signaling between putative cardiovascular neurons in the medulla oblongata and sympathetic preganglionic neurons (SPNs) in the spinal cord.

Animals↗

PubMed2000

Quantification and synthesis of cocaine- and amphetamine-regulated transcript peptide (79-102)-like immunoreactivity and mRNA in rat tissues.

The distribution of cocaine- and amphetamine-regulated transcript peptide (79-102)-like immunoreactivity (CART-LI) was quantified in brain and peripheral tissues of male and female Wistar rats, and male obese (fa/fa) and heterozygous (Fa/+) Zucker rats using a specific RIA. CART-LI tissue levels have not been quantified previously. The assay, using cocaine- and amphetamine-regulated transcript (CART) (79-102) as a standard and radioactive tracer and an antibody to CART (79-102) fragment, detected CART-LI in all brain regions examined, the anterior and posterior pituitary, the spinal cord and throughout the gastrointestinal tract of both male and female Wistar rats. The highest concentrations were found in the hypothalamus, duodenum, anterior pituitary and posterior pituitary (50.6+/-4.4, 26.1+/-4.2, 50.0+/-1.3 and 373.0+/-55.2 pmol/g wet tissue respectively, means+/- s.e.m., n=6-10 male animals). There was no significant variation between the sexes. The concentrations of CART-LI in hypothalami and anterior and posterior pituitaries from fa/fa rats were significantly (P<0002) lower than those of Fa/+ controls (35.9+/-2.1 vs 53.9+/-4.9,<0.6 vs 1.8+/-0.4 and 114+/-9.1 vs 255.5+/- 20.9 pmol/g wet tissue respectively, means+/- s.e.m., n=7). Gel permeation chromatography of regions of rat brain and gastrointestinal tract showed possible differential processing between regions. CART-LI was released from hypothalamic tissue slices in a calcium-dependent fashion by potassium-induced depolarisation. Northern blot analysis detected CART mRNA in the hypothalamus, anterior pituitary, brain stem, cerebellum and spinal cord. The pattern o! f distribution of CART mRNA and CART-LI in various neural and other tissues is in accord with a role for CART as a neurotransmitter.

Animals↗

PubMed1998

Cocaine- and amphetamine-regulated transcript peptide immunohistochemical localization in the rat brain.

Cocaine- and amphetamine-regulated transcript (CART) is a brain-enriched mRNA with a protein product(s) that is a candidate brain neurotransmitter. We have developed antisera to CART peptide fragment 106-129 and have demonstrated specific immunoreactivity (IR) at the light microscopic level throughout the brain, spinal cord, and retina. All brain nuclei previously shown to express CART mRNA are now shown to contain CART peptide IR. Although it is premature to define CART peptide(s) as a neurotransmitter(s), the localization found here suggests an involvement of CART in many processes. CART peptide staining in the nucleus accumbens and basolateral amygdala continue to suggest a role in drug-induced reward and reinforcement. Staining in the olfactory bulbs, the cortical barrels, the retina and its projection areas, the thalamic nuclei, the lateral and dorsal horns of the spinal cord, and the nuclei of the solitary tract are compatible with a major role for CART in sensory processing and autonomic regulation. CART peptides appear to colocalize with some classical neurotransmitters and appear to occur in peripheral neurons as well.

Amphetamine↗

PubMed2000

Association of cocaine- and amphetamine-regulated transcript-immunoreactive elements with thyrotropin-releasing hormone-synthesizing neurons in the hypothalamic paraventricular nucleus and its role in the regulation of the hypothalamic-pituitary-thyroid axis during fasting.

Because cocaine- and amphetamine-regulated transcript (CART) coexists with alpha-melanocyte stimulating hormone (alpha-MSH) in the arcuate nucleus neurons and we have recently demonstrated that alpha-MSH innervates TRH-synthesizing neurons in the hypothalamic paraventricular nucleus (PVN), we raised the possibility that CART may also be contained in fibers that innervate hypophysiotropic thyrotropin-releasing hormone (TRH) neurons and modulate TRH gene expression. Triple-labeling fluorescent in situ hybridization and immunofluorescence were performed to reveal the morphological relationships between pro-TRH mRNA-containing neurons and CART- and alpha-MSH-immunoreactive (IR) axons. CART-IR axons densely innervated the majority of pro-TRH mRNA-containing neurons in all parvocellular subdivisions of the PVN and established asymmetric synaptic specializations with pro-TRH neurons. However, whereas all alpha-MSH-IR axons in the PVN contained CART-IR, only a portion of CART-IR axons in contact with pro-TRH neurons were immunoreactive for alpha-MSH. In the medial and periventricular parvocellular subdivisions of the PVN, CART was co-contained in approximately 80% of pro-TRH neuronal perikarya, whereas colocalization with pro-TRH was found in <10% of the anterior parvocellular subdivision neurons. In addition, >80% of TRH/CART neurons in the periventricular and medial parvocellular subdivisions accumulated Fluoro-Gold after systemic administration, suggesting that CART may serve as a marker for hypophysiotropic TRH neurons. CART prevented fasting-induced suppression of pro-TRH in the PVN when administered intracerebroventricularly and increased the content of TRH in hypothalamic cell cultures. These studies establish an anatomical association between CART and pro-TRH-producing neurons in the PVN and demonstrate that CART has a stimulatory effect on hypophysiotropic TRH neurons by increasing pro-TRH gene expression and the biosynthesis of TRH.

Animals↗

PubMed2001

A role for dietary fat in leptin receptor, OB-Rb, function.

Leptin is a hormone believed to control appetite and regulate body weight via receptors in the hypothalamus. Much is known about the structure of the functional, or long, form of the leptin receptor, OB-Rb. However, the mechanism by which the receptor regulates leptin's biological action is unknown. Both the type and amount of dietary fat have been shown to affect factors involved in OB-Rb binding and signaling, as well as the morphology of hypothalamic cell membranes. Thus, the following review article examines possible mechanisms by which dietary fat may affect OB-Rb functioning at the hypothalamic level. Dietary fat can alter the fatty acid make-up of membranes, such as the polyunsaturated:saturated fat ratio, changing membrane fluidity and possibly leading to an enhancement or impairment of the structure and/or function of any membrane-associated receptor complexes. Dietary fat also interferes in biochemical pathways involving leptin, OB-Rb, and other neurons containing neuropeptides under OB-Rb's control, such as neuropeptide Y (NPY), proopiomelanocortin (POMC), and cocaine- and amphetamine-regulated transcript (CART). Increased monounsaturated fat increases cyclic adenosine monophosphate (cAMP) levels, possibly reducing mitogen-activated protein kinase (MAPK) activation and interrupting leptin signaling through Janus kinase/signal tranducers and activators of transcription (JAK/STAT) pathways. Dietary induced alterations in hypothalamic cell membranes, SNS activity, or other factors involved in OB-Rb function form a possible basis for the control of leptin's effects on body composition and appetite. Improving the biological activity of leptin by diet modification may exist as a practical strategy for the treatment of obesity and related disorders.

Animals↗

PubMed2000

Separate systems for serotonin and leptin in appetite control.

Appetite control involves an integration of the drive signals arising form energy stores in the body with the satiety signals generated by periodic episodes of food consumption. Serotonin (5-hydroxytryptamine, 5-HT) has been implicated in the processes of within-meal satiation and postmeal satiety (5-HT1B and 5-HT2C postsynaptic receptors) which are concerned with the signals arising form the pattern of food intake. Central nervous system (CNS) 5-HT is sensitive to circulating levels of the precursor tryptophan, certain macronutrients and peripheral satiety factors such as cholecystokinin (CCK) and enterostatin. Hypothalamic 5-HT receptor systems inhibit neuropeptide Y (NPY), a potent stimulator of hunger and food intake. In contrast to the linking of 5-HT with the consequences of food ingestion, the hormone leptin (OB protein) is regarded as a signal linking adipose tissue status with a number of key CNS circuits. Leptin itself stimulates CNS leptin receptors (OB-r receptor) which link with pro-opiomelanocortin (POMC)/ MC-4 receptors. The effects of leptin may also be modulated by factors such as the corticotrophin-releasing factor (CRF), cocaine and amphetamine-regulated transcript (CART), orexins and galanin. Very little evidence exists to support any direct link between the actions of 5-HT and leptin, suggesting that they are separate systems. 5-HT is a part of an integrated network for short-acting satiety signals (episodic in nature), and leptin is a hormonal indicator of long-term (tonic) energy reserves. At a conceptual level, these may represent the distinction between 'satiety' and 'drive'. Interestingly, both 5-HT and leptin modulate the action of NPY, which may form a part of a common output pathway for the expression of appetite.

Animals↗

PubMed1999

Leptin: fundamental aspects.

The discovery of leptin, the product of the ob gene, has led to major developments in understanding the regulation of energy balance. It is now recognised that leptin is produced in several organs additional to white adipose tissue, including brown fat, the placenta and fetal tissues (such as heart and bone/cartilage). The hormone has multiple functions-in inhibiting food intake, in the stimulation/maintenance of energy expenditure, as a signal to the reproductive system and as a 'metabolic' hormone influencing a range of processes (for example, insulin secretion, lipolysis, sugar transport). The production of leptin by white fat is subject to a number of regulatory influences, including insulin and glucocorticoids (which are stimulatory), and fasting and beta-adrenoceptor agonists (which are inhibitory). A key role in the regulation of leptin production by white fat is envisaged for the sympathetic system, operating through beta3-adrenoceptors. The leptin receptor gene is widely expressed, with the several splice variants exhibiting different patterns of expression. The long form variant (Ob-Rb) is expressed particularly in the hypothalamus, although it is being increasingly identified in other tissues. Leptin exerts its central effects through several neuroendocrine systems, including neuropeptide Y, glucagon-like peptide-1, melanocortins, corticotrophin releasing hormone (CRH) and cocaine- and amphetamine-regulated transcript (CART). In essence, the leptin system now appears highly complex, the hormone being involved in a range of physiological processes in a manner far transcending the initial lipostatic concept. This complexity may reduce the potential of the leptin system as a target for anti-obesity therapy.

Adipose Tissue↗

PubMed1999

Neuropeptide Y innervation and neuropeptide-Y-Y1-receptor-expressing neurons in the paraventricular hypothalamic nucleus of the mouse.

The paraventricular hypothalamic nucleus (PVH) serves as integrator and link between the neuroendocrine and autonomic nervous systems. Neuropeptide-Y (NPY)-producing neurons in the arcuate nucleus project to the PVH, where neurons expressing NPY Y1 receptor (Y1R) have been demonstrated. This projection has been suggested to be involved in the regulation of parameters related to energy metabolism, e.g. food intake and thermoregulation. The present study aimed at characterizing this pathway and chemically defining Y1R-expressing neurons by means of immunohistochemistry. The densely distributed NPY-immunoreactive (ir) terminals in the PVH co-stained for agouti gene-related protein (AGRP) mainly in the medial parvocellular regions, indicating an origin in the arcuate nucleus. This was in contrast to noradrenergic/adrenergic terminals in the PVH, which were less frequently seen to contain NPY-like immunoreactivity. Furthermore, AGRP-ir terminals were seen forming abundant close appositions on Y1R-ir cell bodies. Double staining revealed co-existence of Y1R-like immunoreactivity and immunoreactivities for thyrotropin-releasing hormone (TRH) and, to a minor extent, cocaine- and amphetamine-regulated transcript peptide in parvocellular neurons. No Y1R-like immunoreactivity was noted in parvocellular neurons expressing corticotropin-releasing hormone or in magnocellular neurons expressing vasopressin or oxytocin. The present results suggest that the arcuatoparaventricular NPY projection targets the TRH neurons preferentially via the Y1R, whereas the NPYergic regulation of corticotropinergic and magnocellular neurons may be relayed through other subtypes of NPY receptors. This study further defines the link between NPY-induced feeding and the hypothalamus-pituitary-thyroid axis.

Agouti-Related Protein↗

PubMed2002

Leptin secretion and hypothalamic neuropeptide and receptor gene expression in sheep.

Peripheral and hypothalamic mechanisms underlying the hyperphagia of lactation have been investigated in sheep. Sheep were fed ad libitum and killed at 6 and 18 days of lactation; ad libitum-fed nonlactating sheep were killed as controls. Despite increased food intake, lactating ewes were in negative energy balance. Lactation decreased plasma leptin and adipose tissue leptin mRNA concentrations. OB-Rb gene expression, determined by in situ hybridization, was increased in the hypothalamic arcuate nucleus (ARC) and ventromedial hypothalamic nucleus (VMH) at both stages of lactation. Neuropeptide Y (NPY) was increased by lactation in both the ARC and dorsomedial hypothalamus (DMH), although increased gene expression in the DMH was only apparent at day 18 of lactation. Gene expression was decreased for cocaine- and amphetamine-regulated transcript (CART) in the ARC and VMH and for proopiomelanocortin in ARC during lactation. Agouti-related peptide gene expression was increased in the ARC, and melanocortin receptor expression was unchanged in both the ARC and VMH with lactation. Thus the hypoleptinemia of lactation may activate NPY orexigenic pathways and attenuate anorexigenic melanocortin and CART pathways in the hypothalamus to promote the hyperphagia of lactation.

Animals↗

PubMed2002

Orexin receptor-1 (OX-R1) immunoreactivity in chemically identified neurons of the hypothalamus: focus on orexin targets involved in control of food and water intake.

The neuropeptides orexin-A and orexin-B are produced in neurons of the lateral hypothalamic area and have been implicated to be involved in the regulation of food/water intake and sleep-wake control. The orexins act at two different G-protein-coupled orexin receptors (OX-R1 and OX-R2) that are derived from separate genes and expressed differentially throughout the central nervous system. In the present study, we have used a polyclonal antipeptide antiserum to analyse in detail the distribution of OX-R1-immunoreactive neurons in the rat hypothalamus. In order to identify the chemical mediators of orexin action in the hypothalamus, the OX-R1-containing neurons were characterized with regard to the content of peptides shown previously to affect ingestive and drinking behaviour. Neurons containing OX-R1 immunoreactivity were widely distributed in the hypothalamus with cell bodies located in the suprachiasmatic, periventricular, paraventricular (both magno- and parvocellular division), supraoptic, arcuate, ventromedial, dorsomedial and tuberomammillary nuclei and the lateral hypothalamic area. In magnocellular neurons of the paraventricular and supraoptic nuclei, OX-R1 immunoreactivity was seen in both vasopressin- and oxytocin-containing neurons. OX-R1 immunoreactivity was demonstrated in vasopressin and vasoactive intestinal polypeptide (VIP) neurons of the suprachiasmatic nucleus, in somatostatin neurons of the periventricular nucleus and in corticotropin-releasing hormone (CRH) neurons of the parvocellular paraventricular nucleus. In the arcuate nucleus, OX-R1 immunoreactivity was present in neuropeptide Y (NPY) and agouti-related peptide (AGRP) neurons of the ventromedial part as well as in proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) neurons of the ventrolateral division. In the lateral hypothalamic area, OX-R1 immunoreactivity was demonstrated in melanin-concentrating hormone (MCH)- and orexin-containing neurons. In the hypothalamic tuberomammillary nucleus, OX-R1-immunoreactivity was shown in many histamine-containing neurons. The results support the idea that orexins have important actions on hypothalamic neurons that control food intake and fluid balance, but also that orexins may regulate other neuroendocrine systems.

Amino Acid Sequence↗

PubMed2002

Galanin/GALP and galanin receptors: role in central control of feeding, body weight/obesity and reproduction?

Scientific and commercial pharmacological interest in the role of galanin and galanin receptors in the regulation of food intake, energy balance, and obesity has waned recently, following initial enthusiasm during the 1980-1990s. It has been replaced by efforts to understand the role of newly discovered peptide systems such as the hypocretin/orexins, melanocortins and cocaine- and amphetamine-regulated transcript (CART) and their relationship to the important hormones, leptin and insulin. Thus, while numerous studies have revealed the ability of galanin to stimulate food intake via actions at sites within the hypothalamus, and shown reliable changes in hypothalamic galanin synthesis in response to food ingestion; findings including the lack of a 'body weight/obesity' phenotype in galanin transgenic mouse strains and a lack of agonists/antagonists for galanin receptor subtypes have probably served to reduce enthusiasm. However, as more is learnt about the general and galanin-related neurochemistry of brain pathways involved in feeding, metabolism and body weight control, the potential importance of galanin systems is again in focus. Studies of the newly discovered galanin family peptide, 'galanin-like peptide' (GALP), highlight the likely role of galanin peptides and receptors in the physiological coupling of body weight, adiposity and reproductive function. GALP is produced by a discrete population of neurons within the basomedial arcuate nucleus (and median eminence) that send projections to the anterior paraventricular nucleus and that make close contacts with leutinizing hormone-releasing hormone (LHRH) neurons in basal forebrain. Furthermore, GALP neurons express leptin receptors and respond to leptin treatment by increasing their expression of GALP mRNA. Centrally administered GALP activates LHRH-immunoreactive neurons and increases plasma LH levels. These findings suggest a direct stimulatory action of endogenous GALP on gonadotropin secretion via actions within the hypothalamus/basal forebrain, with leptin actions linking this system to body adipose levels.

Amino Acid Sequence↗

PubMed2001

Leptin and the regulation of food intake, energy homeostasis and immunity with special focus on periparturient ruminants.

The biology of leptin has been studied most extensively in rodents and in humans. Leptin is involved in the regulation of food intake, energy homeostasis and immunity. Leptin is primarily produced in white adipose tissue and acts via a family of membrane bound receptors, including an isoform with a long intracellular domain (OB-Rb), and many isoforms with short intracellular domains (Ob-Rs). OB-Rb is predominantly expressed in the hypothalamic regions involved in the regulation of food intake and energy homeostasis. The other isoforms are distributed ubiquitously and are found in most peripheral tissues in far greater abundance than OB-Rb. The effects of leptin on food intake and energy homeostasis are central and are mediated via a network of orexigenic neuropeptides (neuropeptide Y, galanin, galanin-like peptide, melanin-concentrating hormone, orexins, agouti-related peptide) and anorexigenic neuropeptides (corticotropin-releasing hormone, pro-opiomelanocortin, alpha-melanocyte stimulating hormone and cocaine- and amphetamine-regulated transcript). In addition, leptin acts directly on immune cells to stimulate hematopoesis, T-cell immunity, phagocytosis, cytokine production, and to attenuate susceptibility to infectious insults. Emerging data in ruminants suggest that leptin is dynamically regulated by many factors and physiological states. Thus, leptin is secreted in a pulsatile fashion, but without a marked diurnal rhythm. A positive relationship between adiposity and plasma leptin concentration exists in growing and lactating ruminants. The concentration of plasma leptin increases during pregnancy, starts to decline 1--2 wk before parturition, and reaches a nadir in early lactation. The reduction of plasma leptin at parturition is likely to promote centrally mediated adaptations required in periods of energy deficit, but could have negative effects on immune cell function. Future research is needed in ruminants to address the roles played by leptin and the central nervous system in orchestrating metabolism during the periparturient period and during infectious diseases.

Adipose Tissue↗

PubMedDate not supplied

Leptin and the hypothalamic-pituitary regulation of the gonadotropin-gonadal axis.

Leptin is an adipocyte-derived protein hormone which not only conveys a signal of the amount of energy stores to the central nervous system but also plays an important role in regulating neuroendocrine function. The importance of leptin in the reproductive system has been suggested by the reproductive dysfunction associated with leptin deficiency and resistance in both animal models and humans as well as the ability of leptin to accelerate the onset of reproductive function in normal mice. Transgenic mice overexpressing leptin also have accelerated puberty, and leptin administration reverses the fasting-induced suppression of sexual maturation in rodents, indicating that leptin may serve as the critical link between sufficient energy stores and proper functioning of the reproductive system. Normal women have a pulsatile release pattern of leptin that is significantly associated with the variations in luteinizing hormone (LH) and estradiol levels. In various animal models, leptin administration restores the LH pulsatility pattern which is suppressed during fasting, indicating a hypothalamic site of action since LH pulsatility is under the control of gonadotropin-releasing hormone (GnRH). In humans, leptin has been administered to a 9-year-old leptin-deficient girl, resulting in a gonadotropin secretory pattern consistent with early puberty. While in vitro experiments with hypothalamic explants and a GnRH-secreting neuronal cell line have shown that leptin can directly stimulate GnRH secretion, the lack of leptin receptors on GnRH neurons suggests that leptin may act through other hypothalamic neuropeptides. Several neuropeptides which act as downstream effectors of leptin have been investigated, and recent studies indicate that cocaine and amphetamine-regulated transcript may be such a mediator of leptin's effect on GnRH. Leptin receptors have also been identified in human pituitaries, and leptin may influence LH release from the pituitary. However, the current evidence is conflicting, and further studies are needed in order to clarify leptin's role at the level of the pituitary. Thus, accumulating evidence suggests that leptin can regulate gonadotropin levels, and its secretion may, in turn, be influenced by GnRH or gonadal steroids but appears to be independent of LH control.

Animals↗