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PubMed1996

Characterization of the human cDNA and genomic DNA encoding CART: a cocaine- and amphetamine-regulated transcript.

PCR differential display screening has recently identified a rat mRNA termed CART (cocaine- and amphetamine-regulated transcript) which is transcriptionally regulated in the striatum following acute administration of psychomotor stimulants. The endogenous CART transcript is expressed in diverse rat brain structures, as well as endocrine tissues. The deduced CART protein contains a hydrophobic signal sequence, suggesting that it may be targeted for secretion. Thus, the CART protein may represent a novel neuroendocrine signaling molecule. The study described here represents a complete analysis of the human CART cDNA and gene. The complete nucleotide (nt) sequence of the approx. 900-nt human CART transcript is contained within three distinct exons, with the entire human CART gene localized to a segment of genomic DNA approx. 2 kb in length. The human CART cDNA sequence is 80% identical to the corresponding rat cDNA, with 92% homology observed within the deduced protein-coding region. Third-nt changes account for most of the latter differences, with CART exhibiting 95% identity between these two species at the amino-acid sequence level. PCR/Southern blot analysis of DNA isolated from human/rodent somatic cell hybrid panels localizes the CART gene to human chromosome 5. Lastly, Northern blot analysis reveals that the gross pattern of distribution of CART mRNA in human brain is similar to that previously observed in rat. These overall similarities suggest that CART plays a conserved role within the mammalian neuroendocrine system.

Amino Acid Sequence↗
PubMed1999

The hypothalamic satiety peptide CART is expressed in anorectic and non-anorectic pancreatic islet tumors and in the normal islet of Langerhans.

The hypothalamic satiety peptide CART (cocaine and amphetamine regulated transcript) is expressed at high levels in anorectic rat glucagonomas but not in hypoglycemic insulinomas. However, a non-anorectic metastasis derived from the glucagonoma retained high CART expression levels and produced circulating CART levels comparable to that of the anorectic tumors. Moreover, distinct glucagonoma lines derived by stable HES-1 transfection of the insulinoma caused severe anorexia but retained low circulating levels of CART comparable to that of insulinoma bearing or control rats. Islet tumor associated anorexia and circulating CART levels are thus not correlated, and in line with this peripheral administration of CART (5-50 mg/kg) produced no effect on feeding behavior. In the rat two alternatively spliced forms of CART mRNA exist and quantitative PCR revealed expression of both forms in the hypothalamus, in the different islet tumors, and in the islets of Langerhans. Immunocytochemistry as well as in situ hybridization localized CART expression to the somatostatin producing islet D cell. A potential endocrine/paracrine role of islet CART remains to be clarified.

Adenoma, Islet Cell↗
PubMed1999

Distinct physiologic and neuronal responses to decreased leptin and mild hyperleptinemia.

Leptin acts on specific populations of hypothalamic neurons to regulate feeding behavior, energy expenditure, and neuroendocrine function. It is not known, however, whether the same neural circuits mediate leptin action across its full biologic dose-response curve, which extends over a broad range, from low levels seen during starvation to high levels characteristic of obesity. Here, we show that the characteristic fall in leptin with fasting causes a rise in neuropeptide Y (NPY) messenger RNA (mRNA), as well as a fall in POMC and cocaine and amphetamine-regulated transcript (CART) mRNAs. Sc infusion of leptin sufficient to maintain plasma levels within the physiologic range during the fast prevents changes in the expression of these peptides, as well as changes in neuroendocrine function, demonstrating that multiple neural circuits are highly sensitive to small changes in leptin within its low physiologic range. In contrast, a modest elevation of plasma leptin above the normal fed range by constant sc infusion, which produced marked reduction in food intake and body weight, decreased NPY mRNA in the arcuate hypothalamic nucleus but did not affect the levels of mRNAs encoding the anorexigenic peptides alpha-MSH, CART or CRH. These results suggest that the dose response characteristics of leptin on hypothalamic target neurons at the level of mRNA expression are variable, with some neurons (e.g. NPY) responding across a broad dose range and others (e.g. POMC and CART) showing a limited response within the low range. These results further suggest that the central targets of leptin that mediate the transition from starvation to the fed state may be distinct from those that mediate the response to overfeeding and obesity.

Animals↗
PubMed2000

Cocaine- and amphetamine-regulated transcript-immunoreactivity in the rat sympatho-adrenal axis.

Distribution of cocaine- and amphetamine-regulated transcript-like immunoreactivity (CART-LI) was studied in the rat spinal cord, sympathetic ganglia and adrenal glands by immunohistochemical methods, utilizing a polyclonal antiserum raised against the CART peptide fragment 55-102. CART-LI was detected in nerve fibers and in basket-like terminals surrounding many postganglionic neurons of the superior cervical ganglion (SCG), stellate, paravertebral and prevertebral ganglia. Postganglionic neurons exhibited low or non-detectable levels of CART-LI. Surgical sectioning of the cervical sympathetic trunk for 6-7 days resulted in a nearly complete loss of CART-LI fibers and terminals in the SCG. In the adrenal gland, CART-LI nerve fibers formed a plexus underneath the capsule, some of which bifurcated and made a sharp turn toward the adrenal medulla, where clusters of chromaffin cells were intensely labeled. The detection of CART-LI in sympathetic ganglia and adrenal glands extends the previous observation of the presence of CART-LI in sympathetic preganglionic neurons and further supports the notion that CART peptide(s) may function as a signaling molecule in the sympatho-adrenal axis.

Amphetamine↗
PubMed2000

BDNF regulates eating behavior and locomotor activity in mice.

Brain-derived neurotrophic factor (BDNF) was studied initially for its role in sensory neuron development. Ablation of this gene in mice leads to death shortly after birth, and abnormalities have been found in both the peripheral and central nervous systems. BDNF and its tyrosine kinase receptor, TrkB, are expressed in hypothalamic nuclei associated with satiety and locomotor activity. In heterozygous mice, BDNF gene expression is reduced and we find that all heterozygous mice exhibit abnormalities in eating behavior or locomotor activity. We also observe this phenotype in independently derived inbred and hybrid BDNF mutant strains. Infusion with BDNF or NT4/5 can transiently reverse the eating behavior and obesity. Thus, we identify a novel non-neurotrophic function for neurotrophins and indicate a role in behavior that is remarkably sensitive to alterations in BDNF activity.

Adipocytes↗
PubMed2000

CART peptide immunoreactivity in the hypothalamus and pituitary in monkeys: analysis of ultrastructural features and synaptic connections in the paraventricular nucleus.

Cocaine and amphetamine regulated transcript (CART) has been identified as one of the most abundant mRNAs in the rat hypothalamus. The objective of the present study was to elucidate the distribution of CART peptide immunoreactive (CARTir) neurons in the monkey hypothalamus and characterize their ultrastructural features and synaptic connections in the paraventricular nucleus (PVN). CARTir neurons were particularly abundant in the PVN, supraoptic nucleus (SON), infundibular nucleus, and premammillary nucleus, whereas the anterior, lateral, and posterior hypothalamic areas as well as the posterior nucleus displayed moderate immunoreactivity. Dense bundles of CARTir fibers exited the PVN and SON and followed a trajectory to the infundibulum similar to that previously shown for vasopressin and oxytocin fibers. The posterior pituitary was densely packed with large CARTir varicosities which, in some cases, were apposed to labeled pituicytes. The external/palisade zone of the median eminence contained rich plexuses of small CARTir varicose fibers, and the internal/fibrous zone was enriched in large axon-like processes. Electron microscope analysis of the PVN revealed (1) that CART peptide immunoreactivity is found in neurosecretory and non-neurosecretory neurons contacted predominantly by unlabelled terminals forming asymmetric synapses, (2) that CARTir terminals resemble glutamatergic and/or noradrenergic boutons and form asymmetric synapses with non-neurosecretory dendrites, and (3) that neuropeptide Y (NPY)-containing terminals are apposed to CARTir neurons in the medial part of the nucleus. In conclusion, our findings demonstrate that CART peptide is abundant in neuronal perikarya and axon terminals throughout the monkey hypothalamus and along the hypothalamopituitary axis. This strengthens the idea that CART peptides may act as putative neurotansmitters/neuromodulators that mediate various neuroendocrine and autonomic functions in primates.

Animals↗
PubMed1999

Hypothalamic cocaine- and amphetamine-regulated transcript (CART) neurons: histochemical relationship to thyrotropin-releasing hormone, melanin-concentrating hormone, orexin/hypocretin and neuropeptide Y.

Recent demonstrations of the feeding-inhibitory properties of putative peptides derived from cocaine- and amphetamine-regulated transcript (CART) raise the question of interactions between CART peptides and other messenger molecules implicated in the control of food intake. The present study investigated the histochemical relationship of CART to the neuropeptides thyrotropin-releasing hormone (TRH), melanin-concentrating hormone (MCH), orexin/hypocretin and neuropeptide Y (NPY) in the hypothalamus. Double-label in situ hybridization showed that CART to a great extent is co-expressed with TRH in hypothalamic paraventricular nucleus neurons. This technique was also used to demonstrate that MCH, but not orexin/hypocretin, mRNA colocalized with CART in neurons of the dorsomedial hypothalamic nucleus/lateral hypothalamic area. CART-peptide immunoreactive cell bodies in this region, as well as in the arcuate nucleus and the medial posterodorsal nucleus of the amygdala, were all seen to have close appositions formed by NPY-immunoreactive nerve terminals. Lastly, in a study of mice treated with the neurotoxin, monosodium glutamate, which targets the arcuate nucleus, a near-total ablation of CART peptide immunoreactive cell bodies in this nucleus was accompanied by decreased terminal staining for CART peptide in the paraventricular hypothalamic nucleus, the arcuate nucleus itself and in the dorsomedial hypothalamic nucleus. These findings further define the position of hypothalamic CART neurons within the hierarchy of brain circuitries regulating energy balance, demonstrating the presence of CART peptide in several cell populations that form putative down-stream targets of NPY terminals, including hypophysiotropic TRH neurons and lateral hypothalamic MCH neurons.

Animals↗
PubMed1998

CART peptides in the central control of feeding and interactions with neuropeptide Y.

While CART peptides have been implicated as novel, putative peptide neurotransmitters/cotransmitters, behavioral effects of these peptides have not yet been demonstrated. In this study, we show the first behavioral effect of CART peptides. I.c.v. administration of CART peptide fragments inhibits feeding in rats. Moreover, injection of an antibody to CART peptide 82-103 stimulates feeding, suggesting that endogenous CART peptides exert an inhibitory tone on feeding. Injection of CART peptide 82-103 five min before NPY reduces the increase in feeding caused by injection of NPY alone. Also, in light microscopic immunohistochemical studies, NPY-positive varicosities were observed around CART peptide-positive cell bodies in the paraventricular nucleus of the hypothalamus. These data suggest functional interactions between CART peptides and NPY. These results indicate that CART peptides play a role in the control of food intake by the brain.

Amino Acid Sequence↗
PubMed1997

Immunohistochemical localization of novel CART peptides in rat hypothalamus, pituitary and adrenal gland.

CART peptide specific polyclonal antisera were raised in rabbits. The antisera were raised to CART peptide fragments that span most of the predicted CART protein. The specificity of each antisera was demonstrated by blockade of immunostaining by the immunizing peptide but not by the other CART peptide fragments. In the hypothalamus and pituitary of colchicine and noncolchicine treated rats, immunostaining was observed in cell bodies, fibers and varicosities. Clusters of cells were also stained in the adrenal medulla. It is noteworthy that cellular immunostaining was only found in areas previously shown to express CART mRNA. These findings indicate the presence of CART peptide(s) in the hypothalamus, pituitary, and adrenal gland. Furthermore, we also present evidence for the possible processing of the CART pro-peptide into smaller peptide fragments. These neuroanatomical findings suggest a role of CART peptides in hypothalamic, pituitary and adrenal function.

Adrenal Glands↗
PubMed1999

Comparing the hypothalamic and extrahypothalamic actions of endogenous hyperleptinemia.

To determine whether the depletion of body fat caused by adenovirus-induced hyperleptinemia is mediated via the hypothalamus, we used as a "bioassay" for hypothalamic leptin activity the hypothalamic expression of a leptin-regulated peptide, cocaine- and amphetamine-regulated transcript (CART). The validation of this strategy was supported by the demonstration that CART mRNA was profoundly reduced in obese rats with impaired leptin action, whether because of ablation of the ventromedial hypothalamus (VMH) or a loss-of-function mutation in the leptin receptor, as in Zucker diabetic fatty rats. We compared leptin activity in normal rats made hyperleptinemic by adenovirus-leptin treatment (43 +/- 9 ng/ml, cerebrospinal fluid leptin 100 pg/ml) with normal rats made hyperleptinemic by a 60% fat intake (19 +/- 4 ng/ml, cerebrospinal fluid leptin 69 +/- 22 pg/ml). CART was increased 5-fold in the former and 2-fold in the latter, yet in adenovirus-induced hyperleptinemia, body fat had disappeared, whereas in high-fat-fed rats, body fat was abundant. Treatment of the high-fat-fed rats with adenovirus-leptin further increased their hyperleptinemia to 56 +/- 6 ng/ml without changing CART mRNA or food intake, indicating that leptin action on hypothalamus had not been increased. Nevertheless, their body fat declined 36%, suggesting that an extrahypothalamic mechanism was responsible. We conclude that in diet-induced obesity body-fat depletion by leptin requires supraphysiologic plasma concentrations that exceed the leptin-transport capacity across the blood-brain barrier.

Adipose Tissue↗
PubMed2000

Anorexigenic cocaine- and amphetamine-regulated transcript peptide intensifies fear reactions in rats.

An increasing number of appetite-regulating peptides are being discovered. The list of regulators inhibiting food intake is considerably longer than that of appetite stimulators. In many cases, the peptides inhibiting food intake facilitate fear reactions, whereas the majority of the agents reducing anxiety responses stimulate appetite. Cocaine- and amphetamine-regulated transcript (CART) cDNA was isolated from hypothalamic libraries and CART was reported to inhibit food intake and to mediate the anorectic effects of leptin. Here, we show that the active core fragment of CART (CART(89-103), 0.04-5.0 nmol) injected into lateral cerebral ventricle not only inhibits food intake, but also causes a dose-dependent increase in anxiety-like reactions in elevated plus-maze test. Intracerebroventricular administration of CART(82-103) (0.04-5.0 nmol) did not inhibit water intake and did not affect spontaneous locomotor activity in the open field test ruling out unspecific effects of the peptide. Our results suggest that CART could be an endogenous factor in the brain mediating the effects of stress on appetite.

Animals↗
PubMed1997

Ultrastructural localization of CART (cocaine- and amphetamine-regulated transcript) peptides in the nucleus accumbens of monkeys.

CART (cocaine- and amphetamine-regulated transcript) peptides are proposed to play a role in the action of psychostimulants as neurotransmitters/neuromodulators. In the present study, we demonstrate that the shell of the nucleus accumbens, a brain structure involved in drug reinforcement, is densely innervated by a dense plexus of CART peptide-immunoreactive varicose fibers in register with immunoreactive perikarya in monkeys. At the electron microscopic level, varicosities appeared as immunoreactive axon terminals packed with round electron-lucent vesicles and a variable number of darkly stained dense-core vesicles that formed symmetric synapses with dendrites. These findings suggest that CART peptides may be a cotransmitter with gamma aminobutyric acid (GABA) in intrinsic axon collaterals of striatal projection neurons or interneurons in the primate nucleus accumbens.

Animals↗
PubMed1999

Entry of CART into brain is rapid but not inhibited by excess CART or leptin.

Cocaine- and amphetamine-regulated transcript (CART) is a new anorectic peptide found in the brain and periphery. It is closely associated with leptin, an anorectic agent saturably transported across the blood-brain barrier (BBB). Using multiple time-regression analysis, we found that CART has a rapid rate of entry into brain from blood. However, there was no self-inhibition with CART, even when perfused in blood-free buffer or in fasted mice, showing a lack of saturation. HPLC showed that at least 58% of the injected CART reached brain tissue in intact form, and capillary depletion with and without washout showed that the CART was not bound to endothelial cells or adherent to vascular components. There was no evidence for an efflux system out of the brain for CART. Thus CART can cross the BBB from blood to brain, but its rapid rate of entry is not inhibited by excess CART or leptin.

Albumins↗
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↗
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↗
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↗
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↗