Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cocaine and amphetamine regulated transcript peptide (CART), is a recently discovered hypothalamic peptide with a potent appetite suppressing activity. In the rat the CART gene encodes a peptide of either 129 or 116 amino acid residues whereas only the short form exists in humans. The predicted signal sequence is 27 amino acid residues resulting in a prohormone of 102 or 89 residues. The C-terminal end of CART, consisting of 48 amino acid residues and 3 disulphide bonds, is thought to constitute a biologically active part of the molecule. In the central nervous system CART is highly expressed in many hypothalamic nuclei, some of which are involved in regulating feeding behaviour. The CART mRNA is regulated by leptin, and the expressed CART is a potent inhibitor of feeding that even overrides the feeding response induced by neuropeptide Y. The putative CART receptor is therefore a potential therapeutic target for an anti-obesity drug.
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PMID:CART, a new anorectic peptide. 992 97

Cocaine- and amphetamine-regulated transcript (CART) is a hypothalamic peptide that may be involved in the regulation of food intake. We screened the human CART gene and identified a novel C-->G substitution in the 3'-untranslated region of exon 3. This polymorphism was genotyped in a total of 68 Pima Indians with extremes of BMI. The frequencies for alleles C and G were 0.76 and 0.24, respectively. There was no evidence of an association between the genotype frequency at this variant and extremes of BMI in this group of Pima Indians. The results of this study do not suggest a significant role for this variant in exon 3 of CART as a determinant of obesity in Pima Indians.
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PMID:A polymorphism in the gene encoding CART is not associated with obesity in Pima Indians. 1080 12

The pathophysiology of obesity is complex with many different pathways involved. A better understanding of these weight-regulating mechanisms has lead to the identification of new targets for anti-obesity agents. Most attention has been given to the centrally acting neuropeptides regulating food intake. Leptin, playing a key-role, exerts its action through several neuropeptides such as neuropeptide Y, alpha-melanocyte stimulating hormone and agouti related protein. Cocaine- and amphetamine-regulated transcript peptide and the orexins are the latest discovered peptides acting at the level of the hypothalamus. Targets for new drugs acting on peptides secreted from the periphery are cholecystokinin and glucagon-like peptide 1. Another potential target in the treatment of obesity is increasing energy expenditure via beta3 adrenoceptors or uncoupling proteins. These new pharmacological agents in development could be valuable adjuncts to more traditional treatment strategies such as dietary treatment, behavioural/psychological counselling and physical activity.
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PMID:Promising new approaches to the management of obesity. 1092 26

Cocaine- and amphetamine-regulated transcript (CART) is expressed in the hypothalamus, and putative peptides encoded by CART potently inhibit feeding when administered centrally. CART is strongly down-regulated in the lateral hypothalamic area and the arcuate nucleus in animal models of obesity with disrupted leptin signaling. Here we have used in situ hybridization and immunohistochemistry to study CART expression in mice homozygous for the anorexia (anx) mutation which are characterized by a much reduced food intake and premature death. anx/anx mice had significantly decreased levels of CART mRNA label and peptide-immunoreactive cell bodies and fibers in the arcuate nucleus and a lower number of detectable CART-expressing cells in the dorsomedial hypothalamic nucleus/lateral hypothalamic area. Moreover, serum leptin levels were significantly lower in anx/anx mice compared to normal littermates, most likely due to the prominent depletion of body fat in these animals. The decrease in the anorexigenic agents leptin and CART, may reflect a compensatory down-regulation in response to the energy-deprived state of anx/anx mice. Alternatively, the reduced arcuate CART expression may be a consequence of a molecular defect in the arcuate nucleus of these animals.
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PMID:Hypothalamic CART and serum leptin levels are reduced in the anorectic (anx/anx) mouse. 1111 36

Cocaine- and amphetamine-regulated transcript (CART) inhibits feeding and induces the expression of c-Fos in hypothalamic areas implicated in appetite regulation. Furthermore, the CART peptide is found in neurons regulating sympathetic outflow, which in turn play an integral role in regulating body temperature and energy expenditure. The CART gene was screened by single-strand conformation polymorphism and automatic sequencing in 130 (72 girls) unrelated obese Italian children and adolescents. Their Z-scores (mean +/- SD) of relative to BMI percentiles was 3.9 +/- 1.8, and the average age at obesity onset was 4.7 +/- 2.6 years. Two previously described silent polymorphisms were found in the 3' untranslated region: an adenine deletion at position 1457 in 9 patients (allele frequency 0.035) and an A/G substitution at position 1475 in 11 patients (allele frequency 0.042). We found no difference between the obese patients heterozygous for one of these polymorphisms and those patients homozygous for the wild allele with respect to their age of obesity onset, BMI Z-scores, and leptin levels. A missense mutation of G729C resulting in the substitution of Leu with Phe at codon 34, within the NH2-terminal CART region, has been detected in the heterozygous state in a 10-year-old obese boy who has been obese since the age of 2 years. The patient belongs to a large family of obese subjects. The mutation cosegregated with the severe obesity phenotype over three generations and was not found in the control population. Resting metabolic rates were lower than expected in the propositus (-14%) and his mother (-16%), who carried the mutation. Leucine at codon 34, conserved in this position in the human and in the rat sequences, immediately precedes a couple of lysine residues that may well represent a dibasic processing site. The Leu34Phe mutation might alter the susceptibility to proteolysis of this potential processing site, likely altering the CART effect on thermogenesis and energy expenditure.
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PMID:Mutational screening of the CART gene in obese children: identifying a mutation (Leu34Phe) associated with reduced resting energy expenditure and cosegregating with obesity phenotype in a large family. 1152 84

Cocaine and amphetamine-regulated transcript (CART) mRNA and immunoreactivity are expressed abundantly in the hypothalamus. Central administration of various fragments of this neuropeptide decreases food intake in rodents. To find out whether CART might play a role in the physiological regulation of energy balance, we used in situ hybridization to investigate whether CART mRNA abundance changed in two chronic obese/fat versus lean states and after acute dietary restriction. In the first study, mice were treated with goldthioglucose to destroy glucose-responsive neurones in the ventromedial hypothalamus. This produced hyperphagia and obesity: 7 weeks after treatment, those receiving goldthioglucose weighed 70% more than the controls. CART mRNA abundance in the arcuate nucleus of goldthioglucose-treated mice was decreased by 71% compared to levels in the control mice, but CART expression was unaffected in the dorsolateral hypothalamus. In the second study, male Siberian hamsters were exposed to short days to induce a physiological winter response in which body weight decreases as fat reserves are catabolized, and food intake correspondingly declines. After 8 weeks in short days, body weight had declined by 18% relative to controls maintained in long days in a summer fat state. CART mRNA levels did not differ significantly between the two groups in any hypothalamic areas. In the third study, male Siberian hamsters, either in long days or after 12 weeks exposure to short days to induce weight loss, were subject to a 48-h period of fasting. Although photoperiod per se did not affect CART expression, fasting produced a significant decrease in CART mRNA in the arcuate nucleus of hamsters in both the long- and short-day state. We conclude that CART-producing cells are involved in energy homeostasis: the marked decrease in CART expression in the arcuate nucleus in goldthioglucose-lesioned mice may contribute to the development of obesity, and the decrease following acute dietary restriction in hamsters may reflect a compensatory mechanism to reduce caloric expenditure, but our results do not indicate that CART is involved in long-term seasonal regulation of body weight.
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PMID:Cocaine and amphetamine-regulated transcript mRNA regulation in the hypothalamus in lean and obese rodents. 1221 31

Cocaine- and amphetamine-regulated transcript (CART) and CART-derived peptides are widely expressed in the hypothalamus. CART is involved in food intake control and is regulated by circulating leptin, a hormone implicated in a variety of endocrine functions. Lack of leptin (ob/ob mice) is associated with obesity, hypogonadism and infertility. In the arcuate nucleus, dorsomedial nucleus of the hypothalamus, and ventral premammillary nucleus, CART neurons also express leptin receptor long-form splice-variant. Recent studies have suggested that the facilitatory effect of leptin on gonadotropin-releasing hormone (GnRH) secretion is mediated by CART. In the present study, using dual- and triple-label immunohistochemistry, we identified CART fibers in close apposition with GnRH neurons expressing Fos in the afternoon of the proestrous day, as well as with GnRH neurons in male rats. In order to investigate the origin of these fibers, we injected the retrograde tracer Fluorogold into areas containing GnRH cell bodies. In male and female rats, the tracer was injected around the vascular organ of lamina terminalis, median preoptic nucleus and medial preoptic nucleus, as well as in the anteroventral periventricular nucleus. We observed retrogradely labeled neurons in various hypothalamic nuclei, including the arcuate, dorsomedial and ventral premammillary. In these areas, dual-label immunohistochemistry/in situ hybridization revealed that part of the retrogradely labeled neurons also express CART mRNA. As a control, we injected the anterograde tracer biotinylated dextran amine into the ventral premammillary nucleus of both males and females. Most projections targeted brain areas related to reproductive behavior and few fibers were closely associated with GnRH neurons. Our findings indicate that ventral premammillary nucleus CART neurons intermingle with brain circuitry involved in reproduction. Therefore, these neurons are well positioned to mediate leptin effect on reproductive control.
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PMID:Hypothalamic cocaine- and amphetamine-regulated transcript neurons project to areas expressing gonadotropin releasing hormone immunoreactivity and to the anteroventral periventricular nucleus in male and female rats. 1509 87

Obesity is an escalating problem in Western societies. Susceptibility to weight gain within an obesogenic environment is variable. It remains unclear how the range of weight gain responses are generated. It is possible that an individual's immediate and/or sustained appetite for apparently palatable foods, or metabolic adaptations to a new diet could be important. The present study therefore examined the short- to medium-term effects of a high-energy (HE) diet on bodyweight, food intake, and energy balance-related signalling systems. Sprague-Dawley rats were fed either chow or an HE diet for 12 h, 24 h, 48 h or 14 days. Blood hormones and metabolites were assayed, and expression of uncoupling protein-1 (UCP-1) and hypothalamic energy-balance related genes were determined by Northern blotting or in situ hybridisation, respectively. Short-term exposure (12 h, 24 h, 48 h) to the HE diet had no effect on grams of food consumed, but caloric intake was increased. Exposure to HE diet for 14 days (medium term) established a bodyweight differential of 7.7 g, and animals exhibited a transient increase in caloric intake of 5 days duration. Terminal levels of leptin, insulin, glucose and non-esterified fatty acids (NEFAs) were all increased in HE-fed animals. UCP-1 mRNA was elevated in interscapular brown adipose tissue from HE-fed rats only at 12 h. Cocaine and amphetamine-regulated transcript (CART) and Mc4R gene expression in the hypothalamus were increased after 12 h and 24 h on an HE diet, respectively. The rats appear to passively over-consume calories as a result of consuming a similar weight of a more energy dense food. This evokes physiological responses, which adjust caloric intake over several days. Circulating NEFA and insulin concentrations, UCP-1, Mc4R and CART gene expression are increased as an immediate consequence of consuming HE diet, and may be involved in countering hypercaloric intake. Circulating leptin is increased in the HE-fed animals after 48 h, reflecting their increasing adiposity.
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PMID:Introduction of a high-energy diet acutely up-regulates hypothalamic cocaine and amphetamine-regulated transcript, Mc4R and brown adipose tissue uncoupling protein-1 gene expression in male Sprague-Dawley rats. 1572 Apr 70

Obesity, a condition already at epidemic proportions in the developed world, is largely attributable to an indulgent lifestyle. Biologically we feel hunger more acutely than feeling "full-up" (satiety). The discovery over a decade ago of leptin, an adiposity signal, revolutionised our understanding of hypothalamic mechanisms underpinning the central control of ingestive behaviour. The structure and function of many hypothalamic peptides (Neuropeptide Y (NPY), Melanocortins, Agouti related peptide (AGRP), Cocaine and amphetamine regulated transcript (CART), Melanin concentrating hormone (MCH), Orexins and endocannabinoids) have been characterised in rodent models. The pharmacological potential of several endogenous peripheral peptides released prior to, during and/or after feeding are being explored. Short-term signal hormones including Cholecystokinin (CCK), Ghrelin, Peptide YY (PYY(3-36)) and Glucagon-like peptide 1 (GLP-1) control meal size via pathways converging on the hypothalamus. Long-term regulation is provided by the main circulating hormones leptin and insulin. These systems among others, implicated in hypothalamic appetite regulation all provide potential "drugable" targets by which to treat obesity.
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PMID:The hypothalamus and obesity. 1577 92

Cocaine- and amphetamine-regulated transcript (CART) is an anorexigenic neuropeptide synthesized in the hypothalamus. A Leu34Phe missense mutation in proCART has been found in an obese family in humans. Here we show that humans bearing the Leu34Phe mutation in proCART have severely diminished levels of bioactive CART, but elevated amounts of partially processed proCART in their serum. Expression of wild-type proCART in AtT-20 cells showed that it was sorted to the regulated secretory pathway, a necessity for proper processing to bioactive CART. However, expressed Leu34Phe proCART was missorted, poorly processed, and secreted constitutively. The defective intracellular sorting of Leu34Phe proCART would account for the reduced levels of bioactive CART in affected humans. These results suggest that the obesity observed in humans bearing the Leu34Phe mutation could be due to a putative deficiency in hypothalamic bioactive CART.
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PMID:The Leu34Phe ProCART mutation leads to cocaine- and amphetamine-regulated transcript (CART) deficiency: a possible cause for obesity in humans. 1621 Mar 70


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