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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mouse mahogany gene encodes a protein that is involved in the suppression of diet-induced obesity. We studied the ability of its widely conserved C-terminal fragment to cross the blood-brain barrier (BBB) in mice. Multiple-time regression analysis showed that the entry rate (K(i)) of (125)I-mahogany (1377-1428) from blood-to-brain was 5.5 x 10(-4) ml/g. min. After coinjection of unlabeled mahogany (1377-1428), the K(i) was significantly decreased, showing the self-inhibition characteristic of a saturable transport mechanism. The excess mahogany (1377-1428) did not change the influx rate of (99m)Tcalbumin, the vascular control, indicating a lack of disruption of the BBB. Statistically significant cross-inhibition was not seen with agouti-related protein (83-132), melanin-concentrating hormone, epidermal growth factor, leptin, a melanocortin-4 receptor antagonist, or alpha-melanocyte-stimulating hormone. HPLC showed that most of the injected (125)I-mahogany (1377-1428) reached the brain intact, and capillary depletion with washout showed that most of it reached the parenchyma. There was no brain-to-blood efflux system for mahogany (1377-1428) but rather retention after i.c.v. administration, and the octanol/buffer partition coefficient showed low lipophilicity. Thus, the results show that the C-terminal peptide product encoded by the mahogany gene crosses the BBB by a transport mechanism that is saturable. The ability of this system to be regulated indicates the therapeutic potential of mahogany (1377-1428) in the treatment of obesity.
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PMID:Mahogany (1377-1428) enters brain by a saturable transport system. 1090 Feb 42

Obesity is a common problem in Western society and is associated with significant morbidity and mortality. Energy homeostasis is regulated by a complex system involving both peripheral signals such as leptin and a number of orexigenic and anorectic neuropeptides. Obesity can result from dysregulation of the peripheral and/or central signals. Melanin-concentrating hormone (MCH) is a hypothalamic peptide that is important in the regulation of feeding behavior, primarily via uncharacterized signaling pathways in the central nervous system. Leptin, expressed in adipose tissue, mediates some of its actions through several hypothalamic neuropeptides, notably agouti-related peptide, proopiomelanocortin, and neuropeptide Y. Expression of leptin is regulated by dietary status, insulin, and glucocorticoids. Furthermore, certain neuropeptides may act on adipocytes. However, the potential effect of MCH has not been investigated. We report that MCH stimulates leptin mRNA expression and leptin secretion. MCH stimulated a 2-fold increase in leptin secretion by isolated rat adipocytes after 4 h of treatment. This increase in secreted leptin was preceded by a rapid and transient increase in ob mRNA levels; MCH stimulated a 2.5-fold increase in ob mRNA within 1 h of treatment, followed by a decline to basal levels within 4 h. In addition, we demonstrate that the MCH receptor SLC-1 is expressed in adipocytes, suggesting that fat cells may be targets of MCH or an MCH-like peptide under physiological conditions. Finally, using a radioimmunoassay, MCH/MCH-like peptide was detected in rat plasma. This study establishes a novel in vitro mammalian system for examining MCH signaling pathways.
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PMID:Melanin-concentrating hormone regulates leptin synthesis and secretion in rat adipocytes. 1090 60

The neuropeptides, monoamines and many drugs involved with modulating food intake and fat stores have reciprocal effects on sympathetic activity and thermogenesis. Both serotonin, acting through 5HT1B/2C receptors, and norepinephrine acting through beta2 and/or beta3 receptors reduce food intake and augment sympathetic activity. Neuropeptide Y, beta-endorphin, orexin, galanin and melanin concentrating hormone all increase food intake and, where tested, reduce sympathetic activity. In contrast, a larger number of peptides including cholecystokinin, corticotrophin-releasing hormone/urocortin, enterostatin, leptin, CART and alpha-MSH reduce food intake and increase sympathetic activity. Nicotine, prostaglandin, dexfenfluramine and sibutramine also have this reciprocal effect on feeding and sympathetic nervous system (SNS) activity. Chronic administration of neuropeptide Y (NPY) can produce chronically increased food intake and obesity. This syndrome is similar to the ventromedial hypothalamus (VMH) syndrome and suggests that NPY must be acting as an inhibitory signal to stimulate a feeding system and inhibit sympathetic activity. The melanocortin receptor system may be particularly important in modulating food intake, because a transgenic mouse which does not express melanocortin-4 receptors is massively overweight. Adrenal glucocorticoids are important in obesity since adrenalectomy will reverse or prevent the development of all forms of obesity. The clinical importance of the sympathetic nervous system and food intake is emphasized by the inverse relation of sympathetic activity and body fat. The inhibition of food intake, lower body fat stores and higher energy expenditure in smokers also support this hypothesis. The reciprocal relationship between food intake and sympathetic activity is robust, suggesting that beta receptors in the periphery and brain may be involved in the control of feeding and a reduction in food intake in humans accounts for most of the weight loss with ephedrine and caffeine. We conclude that the inhibition of feeding by activating the SNS is an important satiety system which helps regulate body fat stores.
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PMID:Reciprocal relation of food intake and sympathetic activity: experimental observations and clinical implications. 1099

This review focuses on the expression, content, and release of neuropeptides and on their role in the development of obesity in animal models with single-gene mutations. The balance between neuropeptides that contribute to the control of feeding behavior is profoundly and variously altered in these models, supporting the concept of the existence of several types of obesity. The hypothalamic neuropeptide Y (NPY) and the pro-opiomelanocortin (POMC) systems are the networks most studied in relation to energy intake. Both receive information about the nutritional status and the level of energy storage through insulin and leptin signaling mediated by specific receptors located on POMC and NPY neurons present predominantly in the arcuate nucleus (ARC). When leptin signaling is defective, through a defect in either the receptor (Zucker fa/fa rat, cp/cp rat, and db/db mouse) or in the peptide itself (ob/ob mouse), the NPY system is upregulated as shown by mRNA overexpression and increased peptide release, whereas the content and/or release of some inhibitory peptides (neurotensin, cholecystokinin) are diminished. For the POMC system, there is a complex interaction between the tonic inhibition of food intake exerted by alpha-melanocyte-stimulating hormone (alpha-MSH) and the Agouti-related protein at the level of the type 4 melanocortin receptor. The latter peptide is coexpressed with NPY in the ARC. Corticotropin-releasing factor (CRF) is the link between food intake and environmental factors. It not only inhibits food intake and prevents weight gain, likely through hypothalamic effects, but also activates the hypothalamo-pituitary axis and therefore contributes to energy storage in adipose tissue. The factors that prod the CRF system toward the hypothalamic or hypothalamo-pituitary axis system remain to be more clearly defined (comodulators, connections between limbic system and ARC, cellular location, and type of receptors, etc. ). The pathways used by all of these neuromodulators include numerous brain areas, but some interest has returned to the classic ones such as the ventromedial and lateral hypothalamic areas because of the recent discovery of some peptides (orexins and melanin-concentrating hormone for the lateral hypothalamus) and receptors (CRF type 2 in the ventromedial hypothalamus). All of these pathways are redundant and function in a coordinated manner and sometimes by the novel expression of a peptide in an unusual area. The importance of such a phenomenon in obesity remains to be determined. Even if single-gene mutations are exceptions in human obesity, the study of genetic animal models of obesity has greatly contributed to the understanding of the regulation of feeding behavior and will allow researchers to develop new drug treatments for obesity that have to be associated with drastic changes in lifestyle (feeding, work habits, and physical activity) for a complete efficiency.
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PMID:Neuropeptides and obesity. 1105 97

Several lines of investigation suggest that the hypothalamic neuropeptide melanin-concentrating hormone (MCH) regulates body weight in mammals. Obese mice lacking functional leptin overexpress the MCH message in the fed or fasted state. Acute intracerebroventricular injection of MCH increases energy intake in rats. Mice lacking the MCH gene are lean. To test the hypothesis that chronic overexpression of MCH in mice causes obesity, we produced transgenic mice that overexpress MCH (MCH-OE) in the lateral hypothalamus at approximately twofold higher levels than normal mice. On the FVB genetic background, homozygous transgenic animals fed a high-fat diet ate 10% more and were 12% heavier at 13 weeks of age than wild-type animals, and they had higher systemic leptin levels. Blood glucose levels were higher both preprandially and after an intraperitoneal glucose injection. MCH-OE animals were insulin-resistant, as demonstrated by markedly higher plasma insulin levels and a blunted response to insulin; MCH-OE animals had only a 5% decrease in blood glucose after insulin administration, compared with a 31% decrease in wild-type animals. MCH-OE animals also exhibited a twofold increase in islet size. To evaluate the contribution of genetic background to the predisposition to obesity seen in MCH-OE mice, the transgene was bred onto the C57BL/6J background. Heterozygote C57BL/6J mice expressing the transgene showed increased body weight on a standard diet, confirming that MCH overexpression can lead to obesity.
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PMID:Melanin-concentrating hormone overexpression in transgenic mice leads to obesity and insulin resistance. 1116 Jan 62

Obesity is a common problem in western society that is directly linked to several disease processes and is associated with significant morbidity and mortality. Adipocytes--the primary site for energy storage (as triglycerides) and release--were long suspected to have an active role in regulating body weight homeostasis and energy balance. As a result, many studies have focused on finding abnormalities in adipocyte physiology and metabolism. An ever-increasing body of evidence indicates that, in addition to serving as a repository for energy reserves, adipocytes secrete a myriad of factors that comprise a complex network of endocrine, autocrine, and paracrine signals. Very little is known regarding the molecular mechanisms utilized by the adipocyte in regulating the biosynthesis and exocytosis of these secreted products. In order to gain a better understanding of these processes, we have examined the two classical secretory pathways: regulated and constitutive. Using leptin as a model adipocyte-secretory protein, this review focuses primarily on the latter pathway. This includes regulation of leptin synthesis and secretion by insulin and glucocorticoids and, more recently, the finding that the orexigenic neuropeptide, melanin-concentrating hormone (MCH), can stimulate leptin synthesis and secretion. This chapter also incorporates new data describing the partial purification and effect of insulin on leptin-containing vesicles in rat adipocytes. These data indicate that the majority of leptin trafficking occurs via a constitutive secretory pathway and that the primary acute insulin effect on leptin secretion is to increase leptin protein content. In addition, we describe the identification and characterization of the vesicle-associated protein, pantophysin, which may play a multifunctional role in vesicle biogenesis and transport.
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PMID:The adipocyte as a secretory organ: mechanisms of vesicle transport and secretory pathways. 1123 20

Feeding behavior results from complex interactions arising between numerous neuromediators, including classical neurotransmitters and neuropeptides present in hypothalamic networks. One way to unravel these complex mechanisms is to examine animal models with a deletion of genes coding for the different neuropeptides involved in the regulation of feeding. The aim of this review is to focus on feeding and body weight regulation in mice lacking neuropeptide Y (NPY), melanocortins (POMC), corticotropin-releasing hormone, melanin-concentrating hormone, or bombesin-like peptides respectively. The phenotypes, which relate to the deletion of gene coding for the peptides, rarely include changes in body weight and food intake, indicating therefore the existence of redundant mechanisms to compensate for the loss of the peptide. The phenotype is much more marked when the gene deletion is targeted towards the functioning of the peptidergic machinery, e.g. the receptors and especially the POMC and NPY receptors, as well as one subtype of bombesin receptor (BRS-3). These knockout models are also interesting when examining the role of environmental and social factors in the determination of feeding behavior. They have granted us better knowledge of all these integrated and complex mechanisms. Moreover, they are also valuable tools for pharmacological studies when specific antagonists are lacking. From the information obtained by the study of knockouts, it is possible to determine certain targets for selective drugs that could be efficient for the pharmacological treatment of obesity. However, at the present state of our knowledge, it seems necessary to target several peptides in order to get good results with weight loss. It will also be imperative to associate these multitherapies with changes in eating and behavioral habits, in order to obtain complete effectiveness and long-lasting results.
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PMID:KO's and organisation of peptidergic feeding behavior mechanisms. 1132 79

Melanin-concentrating hormone (MCH), a neuropeptide expressed in central and peripheral nervous systems, plays an important role in the control of feeding behaviors and energy metabolism. An orphan G protein-coupled receptor (SLC-1/GPR24) has recently been identified as a receptor for MCH (MCHR1). We report here the identification and characterization of a G protein-coupled receptor as the MCH receptor subtype 2 (MCHR2). MCHR2 has higher protein sequence homology to MCHR1 than any other G protein-coupled receptor. The expression of MCHR2 has been detected in many regions of the brain. In contrast to MCHR1, which is intronless in the coding region and is located at the chromosomal locus 22q13.3, the MCHR2 gene has multiple exons and is mapped to locus 6q21. MCHR2 is specifically activated by nanomolar concentrations of MCH, binds to MCH with high affinity, and signals through Gq protein. This discovery is important for a full understanding of MCH biology and the development of potential therapeutics for diseases involving MCH, including obesity.
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PMID:Identification and characterization of a melanin-concentrating hormone receptor. 1141 25

Obesity may be a low-grade systemic inflammatory disease. Overweight and obese children and adults have elevated serum levels of C-reactive protein, interleukin-6, tumor necrosis factor-alpha, and leptin, which are known markers of inflammation and closely associated with cardiovascular risk factors and cardiovascular and non-cardiovascular causes of death. This may explain the increased risk of diabetes, heart disease, and many other chronic diseases in the obese. The complex interaction between several neurotransmitters such as dopamine, serotonin, neuropeptide Y, leptin, acetylcholine, melanin-concentrating hormone, ghrelin, nitric oxide, and cytokines and insulin and insulin receptors in the brain ultimately determines and regulates food intake. Breast-feeding of more than 12 mo is associated with decreased incidence of obesity. Breast milk is a rich source of long-chain polyunsaturated fatty acids (LCPUFAs) and brain is especially rich in these fatty acids. LCPUFAs inhibit the production of proinflammatory cytokines and enhance the number of insulin receptors in various tissues and the actions of insulin and several neurotransmitters. LCPUFAs may enhance the production of bone morphogenetic proteins, which participate in neurogenesis, so these fatty acids might play an important role in brain development and function. It is proposed that obesity is a result of inadequate breast feeding, which results in marginal deficiency of LCPUFAs during the critical stages of brain development. This results in an imbalance in the structure, function, and feedback loops among various neurotransmitters and their receptors, which ultimately leads to a decrease in the number of dopamine and insulin receptors in the brain. Hence, promoting prolonged breast feeding may decrease the prevalence of obesity. Exercise enhances parasympathetic tone, promotes antiinflammation, and augments brain acetylcholine and dopamine levels, events that suppress appetite. Acetylcholine and insulin inhibit the production of proinflammatory cytokines and provide a negative feedback loop for postprandial inhibition of food intake, in part, by regulating leptin action. Statins, peroxisome proliferator-activated receptor-gamma binding agents, non-steroidal antiinflammatory drugs, and infant formulas supplemented with LCPUFAs, and LCPUFAs themselves, which suppress inflammation, may be beneficial in obesity.
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PMID:Is obesity an inflammatory condition? 1174 55

The fatty acid synthase inhibitor, C75, acts centrally to reduce food intake and body weight in mice. Here we report the effects of C75 on the expression of key orexigenic [neuropeptide Y (NPY), agouti-related protein (AgRP), and melanin-concentrating hormone] and anorexigenic [pro-opiomelanocortin (POMC) and cocaine-amphetamine-related transcript (CART)] neuropeptide messages in the hypothalami of lean and obese (ob/ob) mice. In lean mice, C75 rapidly and almost completely blocked food intake and prevented fasting-induced up-regulation of hypothalamic AgRP and NPY mRNAs, as well as down-regulation of CART and POMC mRNAs. Thus, in lean mice C75 seems to interrupt the fasting-induced signals that activate expression of NPY and AgRP and suppression of POMC and CART. In obese mice, C75 rapidly suppressed food intake, reduced body weight, and normalized obesity-associated hyperglycemia and hyperinsulinemia. Like its effect in lean mice, C75 prevented the fasting-induced increase of hypothalamic NPY and AgRP mRNAs in obese mice, but had no effect on the expression of POMC and CART mRNAs. The suppressive effect of C75 on food intake in lean mice seems to be mediated both by NPY/AgRP and POMC/CART neurons, whereas in obese mice the effect seems to be mediated primarily by NPY/AgRP neurons. In both lean and obese mice, C75 markedly increased expression of melanin-concentrating hormone and its receptor in the hypothalamus.
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PMID:Effect of a fatty acid synthase inhibitor on food intake and expression of hypothalamic neuropeptides. 1175 83


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