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P J Larsen

Publications and source records attributed to P J Larsen.

At least 19 recordsLinked to original sources
PubMed2003

Cocaine- and amphetamine-regulated transcript is present in hypothalamic neuroendocrine neurones and is released to the hypothalamic-pituitary portal circuit.

Cocaine- and amphetamine-regulated transcript (CART) is present in a number of hypothalamic nuclei. Besides actions in circuits regulating feeding behaviour and stress responses, the hypothalamic functions of CART are largely unknown. We report that CART immunoreactivity is present in hypothalamic neuroendocrine neurones. Adult male rats received a systemic injection of the neuronal tracer Fluorogold (FG) 2 days before fixation, and subsequent double- and triple-labelling immunoflourescence analysis demonstrated that neuroendocrine CART-containing neurones were present in the anteroventral periventricular, supraoptic, paraventricular (PVN) and periventricular nuclei of the hypothalamus. In the PVN, CART-positive neuroendocrine neurones were found in all of cytoarchitectonically identified nuclei. In the periventricular nucleus, approximately one-third of somatostatin cells were also CART-immunoreactive. In the medial parvicellular subnucleus of the PVN, CART and FG coexisted with thyrotrophin-releasing hormone, whereas very few of the corticotrophin-releasing hormone containing cells were CART-immunoreactive. In the arcuate nucleus, CART was extensively colocalized with pro-opiomelanocortin in the ventrolateral part, but completely absent from neuroendocrine neurones of the dorsomedial part. To assess the possible role of CART as a hypothalamic-releasing factor, immunoreactive CART was measured in blood samples from the long portal vessels connecting the median eminence with the anterior pituitary gland. Adult male rats were anaesthetized and the infundibular stalk exposed via a transpharyngeal approach. The long portal vessels were transected and blood collected in 30-min periods (one prestimulatory and three poststimulatory periods). Compared to systemic venous plasma samples, baseline concentrations of immunoreactive CART were elevated in portal plasma. Exposure to sodium nitroprusside hypotension triggered a two-fold elevation of portal CART42-89 immunoreactivity throughout the 90-min stimulation period. In contrast, the concentration of portal plasma CART immunoreactivity dropped in the vehicle infused rats. The current study provides further evidence that CART is a neuroendocrine-releasing factor with a possible impact on anterior pituitary function during states of haemodynamic stress.

Animals↗
PubMed2002

Effects of leptin on arcuate pro-opiomelanocortin and cocaine-amphetamine-regulated transcript expression are independent of circulating levels of corticosterone.

In the hypothalamic arcuate nucleus, neurones that coexpress cocaine-amphetamine-regulated transcript (CART) and alpha-melanocyte-stimulating hormone [alpha-MSH; pro-opiomelanocortin (POMC) derived] peptides exert catabolic actions and are stimulated by leptin. However, leptin treatment also affects other circulating factors that influence hypothalamic gene expression. Notably, the hypercorticosteronaemia of ob/ob mice is lowered by leptin treatment. To examine the interaction between glucocorticoids and leptin on POMC/CART mRNA expression, an experiment combining leptin and adrenalectomy (ADX) in leptin deficient ob/ob mice was carried out. Obese ob/ob and lean littermate Ob/? mice were ADX or sham-operated. ADX mice received a pellet containing 25% corticosterone subcutaneously. Seven days postoperatively, mice were injected intraperitoneally for 5 days with either recombinant human leptin or vehicle. On the sixth day, the mice were decapitated and the brains removed and trunk blood was collected for corticosterone analysis. Plasma concentrations of corticosterone were elevated in all ob/ob groups compared to Ob/?. For both ob/ob and Ob/? groups, corticosterone concentrations exhibited a decline across groups: vehicle-sham>leptin-sham>ADX-vehicle>ADX-leptin. Leptin inhibited food intake and bodyweight in ob/ob-sham and ob/ob-ADX to a similar extent, whereas no effect of leptin was observed in Ob/? mice. Similarly, leptin caused an identical increase in arcuate POMC and CART mRNA expression in ob/ob-sham and ob/ob-ADX compared to vehicle. The present data support the view that leptin influences arcuate POMC and CART mRNA expression directly, and that the effect is not modulated by corticosterone across a wide range of circulating corticosterone concentrations.

Animals↗
PubMed2001

Identification of NPY-induced c-Fos expression in hypothalamic neurones projecting to the dorsal vagal complex and the lower thoracic spinal cord.

Neuropeptide Y exerts profound effects on body weight and glucose homeostasis. We have investigated the effect of centrally administered neuropeptide Y on the activity of descending neurones of the hypothalamic paraventricular nucleus by combining retrograde tract tracing with c-Fos immunocytochemistry. Male rats were injected with True Blue into the dorsal vagal complex and with FluoroGold into the intermediolateral column of the lower thoracic spinal cord. One week after the last surgical procedure, animals were injected centrally with an orexigenic dose of neuropeptide Y (5 microg) and sacrificed 60 to 240 minutes following this injection. Temporal analysis of NPY-induced c-Fos expression showed a peak at 90 minutes, which was nearly returned to basal levels between 120 and 240 minutes. Expression of c-Fos was prominent in several of the subnuclei of the paraventricular nucleus and in the adjacent perifornical nucleus. Neurones projecting to the spinal cord were prominent in the dorsal, lateral, and ventral portion of the medial parvicellular subnuclei of the PVN. About 15% of IML projecting neurones of the medial parvicellular subnucleus were Fos-positive, whereas less than 5% of IML projecting neurones from other subnuclei were Fos-positive. Hardly any PVN neurones projecting to the dorsal vagal complex were concomitantly Fos-positive. A considerably larger (>10%) proportion of perifornical neurones projecting to the nucleus of the solitary tract were c-Fos-immunopositive. In conclusion, NPY induces c-Fos in paraventricular neurones projecting to intermediolateral column of the spinal cord and in neurones of the perifornical nucleus projecting to the dorsal vagal complex.

Animals↗
PubMed2001

[Glucagon-like peptide 2, a neurotransmitter with a newly discovered role in the regulation of food ingestion].

We report here that glucagon-like peptide 2(GLP-2) and its receptor constitute a distinct projection system connecting the nucleus of the solitary tract with the dorsomedial hypothalamic nucleus (DMH). The DMH contains a dense plexus of GLP-2 immunoreactive fibres and is the only hypothalamic nucleus expressing GLP-2 receptor mRNA. Consistent with this, central application of GLP-2 activates the expression of neurones solely in the DMH. Furthermore, central administration of GLP-2 causes a dose-related, a pharmacologically and behaviourally specific inhibition of food intake in rats. Surprisingly, the alleged GLP-1 receptor antagonist, Exending (9-39), proved a functional antagonist of centrally applied GLP-2. These data implicate GLP-2 as an important neurotransmitter in the regulation of food intake and likely bodyweight. Our data therefore point to the DMH as a crossroad for endocrine and visceral information affecting feeding behaviour.

Animals↗
PubMed2001

Glucagon-like peptide containing pathways in the regulation of feeding behaviour.

The pre-proglucagon derived peptides, glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are both involved in a wide variety of peripheral functions, such as glucose homeostasis, gastric emptying, intestinal growth, insulin secretion as well as the regulation of food intake. Pre-proglucagon is also found in the brainstem in a small population of nerve cells in the nucleus of the solitary tract (NTS) that process the pre-propeptide as in the gut to yield GLP-1 and GLP-2. GLP-1 containing nerve fibres and the GLP-1 receptor are found predominantly in hypothalamic midline nuclei. GLP-1 given centrally to naive rats results in a marked induction of c-Fos protein in the supraoptic nucleus, paraventricular nucleus of the hypothalamus (PVN) and central nucleus of the amygdala, but only a moderate increase in the arcuate nucleus. The pattern of c-Fos activation is compatible with the appetite suppressing effects of GLP-1. This anorectic effect of GLP-1 appears to be mediated by the PVN, as direct injections of GLP-1 into this nucleus cause anorexia without concomitant taste aversion, suggesting a specific action upon neuronal circuits involved in the regulation of feeding. Recent experiments have also shown that GLP-1 is implicated in mediating signals from the gastrointestinal tract pertaining to discomfort and malaise. The distribution of the co-localised peptide, GLP-2, displays a perfect overlap with GLP-1 in the CNS with the highest concentration in the diffuse ventral part of the dorsomedial nucleus (DMHv). In contrast to the widely distributed GLP-1 receptor mRNA, GLP-2 receptor mRNA is exclusively expressed in the compact part of the DMH (DMHc). Interestingly, the DMHc is also the only nucleus responding to central administration of GLP-2 with a significant increase in the number of c-Fos positive cells. When injected into the lateral ventricle, GLP-2 has a marked inhibitory effect on feeding. The effect of GLP-2 on feeding is both behaviourally and pharmacologically specific. Future experiments will elucidate whether or not GLP-1 and GLP-2 are involved in the long-term or short-term regulation of feeding behaviour and hence have an impact on bodyweight.

Angiotensin II↗
PubMed2001

Insulin and glucose administration stimulates Fos expression in neurones of the paraventricular nucleus that project to autonomic preganglionic structures.

Insulin and glucose play a key role in the control of body energy homeostasis. However, the anatomical organization of the network of central insulin and glucose sensitive areas is still unclear. In the present study, we used a multiple-labelling technique combining retrograde tracing and Fos-like immunohistochemistry, to analyse the anatomical projections from hypothalamic neurones activated by the combined stimulus of insulin and glucose. After intraperitoneal injections of a bolus of insulin plus glucose, Fos-like immunoreactive neurones were observed in the paraventricular nucleus (PVN), ventromedial and arcuate nuclei, as well as the lateral hypothalamic area. In addition, neurones projecting to the autonomic preganglionic levels in the brainstem and spinal cord potentially involved in the control of glucose metabolism were identified by injections of fluorochrome tracers. Thus, Fluorogold was injected into the intermediolateral cell column of the lower spinal cord and Fast Blue was injected into the dorsal motor nucleus of the vagus. Perikarya of descending neurones were detected chiefly in the dorsal, medial and lateral parvocellular subnuclei and also in the posterior magnocellular subnucleus of the PVN. In contrast, insulin-glucose activated neurones in the PVN were observed mainly in the medial parvocellular and posterior magnocellular subnuclei. Fluorogold/Fos double-labelled neurones were only observed in the ventral zone of the medial parvocellular subnucleus. These data indicate that, within the PVN, there could be neurones responding to insulin-glucose administration, which are involved in the sympathetic control of the classical regulatory structures of body energy homeostasis, such as the liver and pancreas, and which could play a role in the output of the neuronal circuitry controlling food intake.

Amidines↗
PubMed2001

Leptin receptor immunoreactivity is present in ascending serotonergic and catecholaminergic neurons of the rat.

Using double-labelling immunohistochemistry we have studied the localisation of leptin receptor proteins including both long and short forms and their possible presence in serotonergic (5-HT) and catecholaminergic neurons in the rat brain. Leptin receptor immunoreactivity was found to be widely distributed in the central nervous system including cortical areas, amygdala, several hypothalamic and thalamic nuclei, the raphe system, pontine nuclei, locus coeruleus, parabrachial nucleus, tractus solitarus and the medullary reticular formation. Serotonergic cell groups were identified by 5-HT immunocytochemistry and classified according to standard nomenclature. High degrees of co-existence of leptin receptor immunoreactivity with serotonin in the raphe system were observed in B1, B5, B6, B7, B8 and B9. In B3 and B2 less than 50% of the 5-HT cells colocalised leptin receptor immunoreactivity. Brainstem and diencephalic (catecholaminergic) neurons were identified by tyrosine hydroxylase immunocytochemistry and classified according to standard nomenclature. Within the periventricular hypothalamic dopaminergic nuclei A14 and A12, the metencephalic noradrenergic A6, A7, A2, A1, and the adrenergic C3, C2 and C1 cell groups, nearly all tyrosine hydroxylase-positive cells colocalised with leptin receptor immunoreactivity. In contrast, co-existence of tyrosine hydroxylase and leptin receptor immunoreactivities in the dopaminergic A13, A11, A10, A9 and A8 cell was practically non-existent. Thus leptin, the adipose tissue-derived ligand of the leptin receptor, may in some brain areas directly influence serotonergic, dopaminergic, adrenergic and noradrenergic inputs to the periventricular and medial hypothalamic nuclei.

Animals↗
PubMed2001

Systemic administration of the long-acting GLP-1 derivative NN2211 induces lasting and reversible weight loss in both normal and obese rats.

Postprandial release of the incretin glucagon-like peptide-1 (GLP-1) has been suggested to act as an endogenous satiety factor in humans. In rats, however, the evidence for this is equivocal probably because of very high endogenous activity of the GLP-1 degrading enzyme dipeptidyl peptidase-IV. In the present study, we show that intravenously administered GLP-1 (100 and 500 microg/kg) decreases food intake for 60 min in hungry rats. This effect is pharmacologically specific as it is inhibited by previous administration of 100 microg/kg exendin(9-39), and biologically inactive GLP-1(1-37) had no effect on food intake when administered alone (500 microg/kg). Acute intravenous administration of GLP-1 also caused dose-dependent inhibition of water intake, and this effect was equally well abolished by previous administration of exendin(9-39). A profound increase in diuresis was observed after intravenous administration of both 100 and 500 microg/kg GLP-1. Using a novel long-acting injectable GLP-1 derivative, NN2211, the acute and subchronic anorectic potentials of GLP-1 and derivatives were studied in both normal rats and rats made obese by neonatal monosodium glutamate treatment (MSG). We showed previously that MSG-treated animals are insensitive to the anorectic effects of centrally administered GLP-1(7-37). Both normal and MSG-lesioned rats were randomly assigned to groups to receive NN2211 or vehicle. A single bolus injection of NN2211 caused profound dose-dependent inhibition of overnight food and water intake and increased diuresis in both normal and MSG-treated rats. Subchronic multiple dosing of NN2211 (200 microg/kg) twice daily for 10 days to normal and MSG-treated rats caused profound inhibition of food intake. The marked decrease in food intake was accompanied by reduced body weight in both groups, which at its lowest stabilized at approximately 85% of initial body weight. Initial excursions in water intake and diuresis were transient as they were normalized within a few days of treatment. Lowered plasma levels of triglycerides and leptin were observed during NN2211 treatment in both normal and MSG-treated obese rats. In a subsequent study, a 7-day NN2211 treatment period of normal rats ended with measurement of energy expenditure (EE) and body composition determined by indirect calorimetry and dual energy X-ray absorptiometry, respectively. Compared with vehicle-treated rats, NN2211 and pair-fed rats decreased their total EE corresponding to the observed weight loss, such that EE per weight unit of lean body mass was unaffected. Despite its initial impact on body fluid balance, NN2211 had no debilitating effects on body water homeostasis as confirmed by analysis of body composition, plasma electrolytes, and hematocrit. This is in contrast to pair-fed animals, which displayed hemoconcentration and tendency toward increased percentage of fat mass. The present series of experiments show that GLP-1 is fully capable of inhibiting food intake in rats via a peripherally accessible site. The loss in body weight is accompanied by decreased levels of circulating leptin indicative of loss of body fat. The profound weight loss caused by NN2211 treatment was without detrimental effects on body water homeostasis. Thus, long-acting GLP-1 derivatives may prove efficient as weight-reducing therapeutic agents for overweight patients with type 2 diabetes.

Animals↗
PubMed2000

The proglucagon-derived peptide, glucagon-like peptide-2, is a neurotransmitter involved in the regulation of food intake.

The dorsomedial hypothalamic nucleus harbors leptin sensitive neurons and is intrinsically connected to hypothalamic nuclei involved in feeding behavior. However, it also receives ascending input from the visceroceptive neurons of the brainstem. We have identified a unique glucagon-like-peptide-2 containing neuronal pathway connecting the nucleus of the solitary tract with the dorsomedial hypothalamic nucleus. A glucagon-like-peptide-2 fiber plexus targets neurons expressing its receptor within the dorsomedial hypothalamic nucleus. Pharmacological and behavioral studies confirmed that glucagon-like-peptide-2 signaling is a specific transmitter inhibiting rodent feeding behavior and with potential long-term effects on body weight homeostasis. The glucagon-like-peptide-1 receptor antagonist, Exendin (9-39) is also a functional antagonist of centrally applied glucagon-like-peptide-2.

Animals↗
PubMed2000

Chronic intracerebroventricular administration of recombinant CART(42-89) peptide inhibits and causes weight loss in lean and obese Zucker (fa/fa) rats.

OBJECTIVE: Hypothalamic neuropeptide CART (cocaine-amphetamine-regulated transcript) is a leptin-dependent endogenous satiety factor in the rat, and single central injections of recombinant CART(42-89) lowers food intake in rats and mice. To assess the potential role of CART as a long-term regulator of food intake, we investigated the effects of continuous infusion of recombinant CART(42-89) on food consumption and body weight. RESEARCH METHODS AND PROCEDURES: Two doses of CART(42-89) were tested: 12 or 4.8 microg/d. Adult male, both lean (+/?) and Zucker (fa/fa) obese, rats were equipped with intracerebroventricular cannulae in the right lateral ventricle. The cannulae were connected to subcutaneously placed osmotic mini-pumps. Pumps were filled with either CART(42-89) or vehicle (50 mM phosphate-buffered saline, pH 7.4). The pumps delivered a continuous infusion of CART(42-89) or vehicle, and food intake and body weight were followed for 10 days (12 microg/d) or 7 days (4.8 microg/d). Animals given the low dose had the pump removed on Day 7, and from half of the group, trunk blood was collected after decapitation, whereas the other half of the group had their mini-pumps removed and were followed for another 7 days before being decapitated. RESULTS: Animals receiving the high doses displayed overt motor disturbances, whereas the low dose was devoid of such behavioral side effects. Both doses significantly lowered food intake with maximal effect on days 3 to 5 of the infusion period. The high dose of CART decreased body weight of normal animals to 85% of initial weight at days 3 to 5, whereas the weight of Zucker (fa/fa) obese rats dropped to 95% of the initial weight. In animals receiving 4.8 microg/d, moderate effects on body weight were seen between days 4 and 6 of the treatment period, but soon after termination of the treatment animals regained lost weight. To assess the biological activity of the contents of the osmotic mini-pumps, the pumps were removed from the subcutaneous implantation site, and 5 microL of their contents were injected intracerebroventricularly to naive animals kept on a restricted feeding schedule. The content of pumps from animals receiving 4.8 microg/d of CART(42-89) potently inhibited food intake, confirming full biological activity despite being kept for 7 days at body temperature. DISCUSSION: Due to obvious effects on motor behavior, it is impossible with certainty to conclude that the observed effects on feeding and body weight are primary interference with satiety centers or secondary to effects on locomotor pathways. Also, the present experiments suggest that hypothalamic appetite-regulating neurons are subject to pharmacological desensitization upon prolonged exposure to CART peptide. The underlying mechanism of such desensitization is as yet unknown.

Animals↗
PubMed2000

Central administration of cocaine-amphetamine-regulated transcript activates hypothalamic neuroendocrine neurons in the rat.

We have recently shown that intracerebroventricular (i.c.v.) administration of the hypothalamic neuropeptide cocaine-amphetamine-regulated transcript (CART) inhibits food intake and induces the expression of c-fos in several nuclei involved in the regulation of food intake. A high number of CART-induced c-Fos-positive nuclei in the paraventricular nucleus of the hypothalamus prompted us to examine the effect of i.c.v. recombinant CART-(42-89) on activation of CRH-, oxytocin-, and vasopressin-synthesizing neuroendocrine cells in the paraventricular nucleus (PVN). In addition, plasma levels of glucose were examined after central administration of CART-(42-89). Seventy-six male Wistar rats were fitted with i.c.v. cannulas and singly housed under 12-h light, 12-h dark conditions. One week postsurgery the animals were injected i.c.v. in the morning with 0.5 microg recombinant CART-(42-89) or saline. Trunk blood was collected by decapitation at 0 (baseline), 10, 20, 40, 60, 120, or 240 min. CART caused a strong increase in circulating corticosterone that was significantly different from saline at 20, 40, 60, and 120 min postinjection (P<0.05). Furthermore, CART caused a transient rise in plasma oxytocin levels (P<0.05 at 10 and 20 min postinjection), whereas plasma vasopressin levels were unaffected by i.c.v. CART. Animals injected i.c.v. with CART showed a rise in blood glucose levels 10 min postinjection (P<0.05). To examine whether the stimulatory effect of i.c.v. CART on corticosterone and oxytocin secretion is caused by activation of paraventricular nucleus/supraoptic nucleus (PVN/SON) neuroendocrine neurons, we used c-Fos as a marker of neuronal activity. Animals injected with CART showed a strong increase in c-Fos-immunoreactive nuclei in the PVN. Double immunohistochemistry revealed that a high (89+/-0.4%) number of CRH-immunoreactive neurons in the PVN contained c-Fos after CART i.c.v.. c-Fos expression was also observed in oxytocinergic cells (in both magnocellular and parvicellular PVN neurons as well as in the supraoptic nuclei) 120 min after CART administration, whereas none of the vasopressinergic neurons contained c-Fos. Triple immunofluorescence microscopy revealed that CART-immunoreactive fibers closely apposed c-Fos-positive CRH neurons, suggestive of a direct action of CART on PVN CRH neurons. In summary, i.c.v. CART activates central CRH neurons as well as both magnocellular (presumably neurohypophysial) and parvicellular (presumably descending) oxytocinergic neurons of the PVN. The effect of CART on CRH neurons most likely leads to corticosterone secretion from the adrenal gland, which may contribute to the inhibitory effects of CART on feeding behavior.

Animals↗
PubMed2000

Substance P is involved in terminating the hypothalamo- pituitary-adrenal axis response to acute stress through centrally located neurokinin-1 receptors.

The neurokinin substance P (SP) has been previously shown to inhibit basal hypothalamo-pituitary-adrenal (HPA) axis activity. This study was designed to investigate the effects of central injection of the specific neurokinin-1 receptor antagonist RP67580 on the HPA axis response to acute restraint stress. In non-restrained rats injected with RP67580, plasma ACTH and corticosterone levels were elevated at 30 and 60 min compared to rats injected with vehicle, but there were no differences between vehicle and RP67580 groups at 4h. In restrained rats injected with vehicle, plasma ACTH and corticosterone levels were significantly elevated at 30 min and 60 min following initiation of the stress but had returned to basal levels at 4h. In restrained rats injected icv with RP67580, plasma corticosterone and ACTH levels were significantly elevated at 30 min and 60 min, with no significant differences compared to the restraint stressed vehicle-injected group. However, in the RP67580-injected group, corticosterone and ACTH levels remained significantly elevated at 4h following onset of restraint compared to those in the restraint stressed vehicle-injected group. Corticotrophin-releasing factor mRNA levels in the parvocellular subdivision of the paraventricular nucleus of the hypothalamus and POMC mRNA levels in the anterior pituitary were significantly increased in the stressed group 4h following injection with RP67580 compared to the stressed group injected with vehicle alone. These data show that endogenous SP does not inhibit the initial magnitude of the HPA axis response to restraint stress, but does act through neurokinin-1 receptors at a central level to reduce the duration of the response to stress. This suggests that SP may be an important central agent controlling the transition between acute and chronic stress.

Adrenocorticotropic Hormone↗
PubMed1999

Effects of stress on susceptibility and severity of inflammation in adjuvant-induced arthritis.

We have utilized the open field and learned helplessness (LH) models of psychological stress to determine whether a differential response to stress can affect the severity of adjuvant-induced arthritis (AA) within a single rat strain. In response to open field stress, the corticosterone response of the low emotivity rats was significantly lower than that of the high emotivity rats. In spite of the differential corticosterone response to stress, no significant difference was found in paw volumes between the AA high and low emotivity groups. In another study, rats were subjected to a learned LH paradigm and separated into two groups based on failed (LH+) or successful (LH-) avoidance. Plasma corticosterone levels in response to avoidable foot shock in the LH- rats were significantly greater than in the LH+ group. Following injection with adjuvant, paw inflammation occurred earlier and was more severe in the LH- rats compared to the LH+ group. These data show that rats with a greater tendency to avoid foot shock have more severe inflammation, despite having a greater corticosterone response to stress. We conclude that an increased corticosterone response to stress does not affect susceptibility to or severity of inflammation in AA. Indeed, in the LH model a more robust response to stress is associated with increased inflammation and earlier onset of the disease.

Animals↗
PubMed1999

Neurochemical characterization of hypothalamic cocaine- amphetamine-regulated transcript neurons.

The novel neuropeptide cocaine-amphetamine-regulated transcript (CART) is expressed in several hypothalamic regions and has recently been shown to be involved in the central control of food intake. To characterize the hypothalamic CART neurons and understand the physiological functions they might serve, we undertook an in situ hybridization and immunohistochemical study to examine distribution and neurochemical phenotype of these neurons. In situ hybridization studies showed abundant CART mRNA in the periventricular nucleus (PeV), the paraventricular nucleus of the hypothalamus (PVN), the supraoptic nucleus (SON), the arcuate nucleus (Arc), the zona incerta, and the lateral hypothalamic area. The distribution of CART-immunoreactive neurons as revealed by a monoclonal antibody raised against CART(41-89) displayed complete overlap with CART mRNA. Double immunohistochemistry showed co-existence of CART immunoreactivity (CART-IR) and somatostatin in some neurons of the PeV. In the magnocellular division of the PVN as well as the SON, CART-IR was demonstrated in both oxytocinergic and vasopressinergic perikarya. In the medial parvicellular region of the PVN a few CART-IR neurons co-localized galanin, but none was found to co-localize corticotropin-releasing hormone. In the Arc, almost all pro-opiomelanocortinergic neurons were shown to contain CART, whereas no co-localization of CART with NPY was found. In the lateral hypothalamic area nearly all CART neurons were found to contain melanin-concentrating hormone. The present data support a role for CART in neuroendocrine regulation. Most interestingly, CART is co-stored with neurotransmitters having both positive (melanin-concentrating hormone) as well as a negative (pro-opiomelanocortin) effect on food intake and energy balance.

Animals↗
PubMed1999

Recombinant CART peptide induces c-Fos expression in central areas involved in control of feeding behaviour.

We have recently shown that the hypothalamic neuropeptide CART (cocaine-amphetamine-regulated-transcript) is a leptin dependent endogenous satiety factor in the rat. In the present study we confirm and extend our previous observations by showing that intracerebroventricular (i.c.v.) administered CART(42-89) dose-dependently inhibits 3-h food intake in food restricted rats with a lowest effective dose of 0.5 microgram. CART also potently inhibits NPY-induced food intake in satiated rats as well as nighttime food intake in free feeding animals. To identify brain areas potentially involved in mediating the anorectic effects of CART, the temporal expression pattern of the immediate early gene c-fos was examined in the central nervous system by immunohistochemistry in rats receiving recombinant CART. Compared to vehicle, CART induced c-Fos expression in several hypothalamic and brainstem structures implicated in the central control of food intake. In the hypothalamus, high numbers of c-Fos immunoreactive (-ir) cells were observed in the medial parvocellular part of the paraventricular nucleus and in the posterior part of the dorsomedial nucleus. Lower numbers of c-Fos positive nuclei were found in the supraoptic and arcuate nuclei. A relatively high number of c-Fos-ir cells was found in the central nucleus of the amygdala. In the brainstem, c-Fos-positive nuclei were found in the parabrachial nucleus, and in the nucleus of the solitary tract. Notably both the area postrema and the dorsal motor nucleus of the vagus were virtually devoid of c-Fos-ir cells. The present experiments suggest that CART peptide exerts its inhibitory effects on appetite by activating hypothalamic and brainstem neurones implicated in the central control of feeding behaviour and metabolism.

Amphetamine↗