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 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this paper a new immunological model of anorexia and bulimia nervosa will be presented in which the inflammatory cytokines are conceived as the fundamental regulators of body metabolism. This conception differs from the conventional view in which the inflammatory cytokines are perceived primarily as peptide molecules utilized by the immune system to control infection, inflammation and tissue or neuronal damage. Given that the inflammatory cytokines are also fundamental regulators of body metabolism, when they become dysregulated they create physiological chaos which results in the development of a number of autoimmune, metabolic and psychiatric disorders. In this proposed immunological model of anorexia and bulimia nervosa, elevated tumor necrosis factor-alpha features as the primary cause of these conditions. Pathophysiological parallels are drawn between anorexia nervosa and cancer cachexia in terms of the causal role the cytokines, neuropeptides and neurotransmitters play in the manifestation of shared symptoms. These shared symptoms include elevated tumour necrosis factor-alpha, down-regulated interleukin-2 and interleukin-4 and depletion of lean body mass. Furthermore, the following neuropeptides are dysregulated in both anorexia nervosa and cancer cachexia: vasoactive intestinal peptide, cholecystokinin, corticotropin-releasing factor, neuropeptide Y, peptide YY and beta-endorphin. In addition, in anorexia and bulimia nervosa, secretion of the neurotransmitter serotonin is inhibited while norepinephrine is enhanced. It will be argued that the causal interplay between the cytokines, neuropeptides and neurotransmitters initiates a cascade of biochemical events which may result in either anorexia or bulimia nervosa, or cancer cachexia. The extent to which these inflammatory cytokines, neuropeptides and neurotransmitters are causally efficacious in the pathogenesis of other autoimmune disorders, such as diabetes mellitus and rheumatoid arthritis, will also be addressed.
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PMID:The role of tumor necrosis factor-alpha in the pathogenesis of anorexia and bulimia nervosa, cancer cachexia and obesity. 896 Dec 38

We previously reported that the human melanoma cell line, SEKI, induces severe weight loss in nude mice. In the present study, we examined the expression of weight-regulating neuropeptide mRNAs in the hypothalamus of this cancer cachectic model by using a sensitive quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) method and in situ hybridization. mRNA levels of neuropeptide Y (NPY) and corticotropin-releasing hormone (CRH) in the whole hypothalamus were elevated significantly in the SEKI mice as compared with control mice. In situ hybridization showed that NPY and CRH mRNA were upregulated in the arcuate nucleus and the paraventricular nucleus, respectively. There were no significant differences in melanin-concentrating hormone (MCH), orexin (OX), and cholecystokinin mRNA levels between the SEKI and control mice. These results suggest that the NPYergic system is functioning in the rodent model of cancer cachexia; however, the role of the CRHergic system in energy homeostasis remains to be elucidated. This is the first report of the hypothalamic neuropeptide response to cachexia-inducing human cells.
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PMID:Hypothalamic appetite-regulating neuropeptide mRNA levels in cachectic nude mice bearing human tumor cells. 1158 96

Infection with the human immunodeficiency virus (HIV) results in a chronic systemic illness with multi-organ involvement, severe immunosuppression and profound cachexia. It has had a major impact on women's health. Endocrine abnormalities may contribute to the clinical presentation and therefore appropriate treatment would theoretically improve the patient's condition. This pilot study was undertaken to assess the endocrine status in a group of HIV seropositive women with the view to developing recommendations for future investigations. Thirteen women were recruited from a clinic for HIV-infected patients. All women had a comprehensive general and gynecological examination. Basal endocrine status was assessed and combined pituitary testing with gonadotropin-releasing hormone, thyrotropin-releasing hormone, growth hormone-releasing hormone and corticotropin-releasing hormone was performed. None of the participating women presented with gynecological complaints or had symptoms suggestive of an endocrinopathy. On questioning, seven women complained of menstrual abnormalities. Three had a body mass index of less than 20 kg/m2. Genital tract infections were common. Endocrine assessment demonstrated abnormalities of the pituitary-adrenal, pituitary-thyroid and pituitary-ovarian axes in seven women. One woman had panhypopituitarism. In six of the seven affected women CD4 counts were below 200 cells/mm3. Alterations in endocrine function were observed in seven of the women tested. While routine endocrine testing may not be indicated in all HIV-seropositive women, we should be aware of possible subtle presentations of endocrine abnormalities which may require treatment, especially in stress situations.
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PMID:Endocrine function in HIV-infected women. 1191 79

Melanocortin receptors (MC-R) activated by one of several peptides derived from the pro-opiomelanocortin (POMC) precursor have become leading contenders for a pivotal role in controlling food intake. Evidence has emerged over the last decade to implicate primarily the MC4-R and, to a lesser extent, MC3-R as the key sub-types involved and both are strategically located in those regions within the hypothalamus known to be associated with feeding. The receptors are within class A of the GPCR superfamily and the key electrostatic interaction with the positively charged peptide (Arg) has been mapped to one or more Asp or Glu residues located on helices II and III of the seven helical bundle characteristic of this class of receptor. Sites for secondary interactions from which sub-type selectivity may be derived have also been located in the extracellular and helical domains. Unique amongst GPCRs is the presence of endogenous antagonist peptides, Agouti and Agouti-related peptide (AGRP), which confer an extra level of control on the system. Recently, several reports of potent and selective non-peptide ligands have been published and these are seen as prototypic molecules from which drugs may emerge to treat obesity (agonists) and cachexia (antagonists). The role played by the melanocortin system is the subject of this review and advances in our understanding of the structure of the endogenous ligand(s), non-peptide, small molecule ligands and the receptors at which they interact will be discussed.
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PMID:The melanocortin system and its role in obesity and cachexia. 1267 37

Resistive breathing is an "immune challenge" for the body, initiating an inflammatory response consisting of an elevation of plasma cytokines, and the recruitment and activation of lymphocyte subpopulations. These cytokines do not originate from monocytes, but are, instead, produced within the diaphragm, secondary to the increased muscle activation. Oxidative stress is a major stimulus for the cytokine induction, secondary to resistive breathing. The production of cytokines within the diaphragm may be mediating the diaphragm muscle fibre injury that occurs with strenuous contractions, or contributing towards the expected repair process. These cytokines may also compromise diaphragmatic contractility or contribute towards the development of muscle cachexia. They may also have systemic effects, mobilising glucose from the liver and free fatty acid from the adipose tissue to the strenuously working respiratory muscles. At the same time, they stimulate the hypothalamic-pituitary-adrenal axis, leading to production of adrenocorticotropin and beta-endorphins. The adrenocorticotropin response may represent an attempt of the organism to reduce the injury occurring in the respiratory muscles via the production of glucocorticoids and the induction of the acute phase-response proteins. The beta-endorphin response would decrease the activation of the respiratory muscles and change the pattern of breathing, which becomes more rapid and shallow, possibly in an attempt to reduce and/or prevent further injury to the respiratory muscles.
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PMID:The immune response to resistive breathing. 1592 72

Recent studies have demonstrated that melanocortin-4 receptor (MC4R) antagonists can prevent weight loss in tumor-bearing mice, which indicates clinical usage for the treatment of cachexia. In our efforts to develop potent and selective antagonists of the human MC4R, we designed piperazinebenzylamines bearing a 2,4-dichlorophenylalanine, by utilizing information derived from structure--activity relationships of MC4R agonists and mutagenesis results of the MC4R and peptide ligands. On the basis of known MC4R agonists such 6, we successfully synthesized potent MC4R antagonists exemplified by 10, which possesses a K(i) value of 1.8 nM in binding affinity. 10 does not stimulate cAMP release in HEK 293 cells expressing the human MC4 receptor at 10 microM concentration. It was demonstrated by Schild analysis that 10 was a competitive functional antagonist with a pA(2) value of 7.9 in the inhibition of alpha-MSH-stimulated cAMP accumulation. 10 also penetrated into the brain when dosed intravenously in rats.
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PMID:4-{(2R)-[3-Aminopropionylamido]-3-(2,4-dichlorophenyl)propionyl}-1-{2-[(2-thienyl)ethylaminomethyl]phenyl}piperazine as a potent and selective melanocortin-4 receptor antagonist--design, synthesis, and characterization. 1561 31

Malnutrition is defined as abnormalities caused by an inadequate diet, but this term is often used inappropriately to describe the syndrome of loss of body weight with muscle mass being replaced by fatty tissue and declining serum proteins present in adults and children with chronic kidney disease (CKD). This syndrome is more accurately described as cachexia, and manifests as growth failure in children with CKD. Cachexia is common and is an important risk factor for poor quality of life and increased mortality and morbidity in both adults and children with CKD. Anorexia, acidosis and inflammation are important causes of cachexia, but the underlying molecular mechanism is not well understood. Dietary intake is often poor and resting metabolic rate is increased in CKD. The energy cost of growth is increased in experimental CKD. Circulating concentrations of cytokines, such as leptin, tumor necrosis factor-alpha and interleukins 1 and 6 are increased in patients with CKD and correlate with the degree of cachexia in these individuals. We hypothesize that cytokines signal through orexigenic neuropetides such as agouti-related peptide and neuropeptide Y (NPY), and anorexigenic neuropetides such as proopiomelanocortin and alpha-melanocyte-stimulating hormone in the arcuate nucleus in the hypothalamus. This signaling system also involves the NPY receptor and the melanocortin receptors and controls appetite and metabolic rate in health and disease. Furthermore, the first order neurons of this system are located outside the blood-brain barrier and can therefore sense the circulating levels of cytokines, as well as long-term satiety hormones such as leptin and insulin and short-term satiety hormones such as ghrelin and peptide (P) YY. There is experimental evidence that this hypothalamic neuropeptide signaling system may have an important role in the pathogenesis of cachexia in CKD. Understanding the molecular mechanism of cachexia in CKD may lead to novel therapeutic strategies.
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PMID:Orexigenic and anorexigenic mechanisms in the control of nutrition in chronic kidney disease. 1566 37

The melanocortins, a family of peptides produced from the post-translational processing of pro-opiomelanocortin (POMC), regulate ingestive behavior and energy expenditure. Loss of function mutations of genes encoding POMC, or of either of two melanocortin receptors expressed in the central nervous system (MC3R, MC4R), are associated with obesity. The analyses of MC4R knockout mice indicate that activation of this receptor is involved in the regulation of appetite, the adaptive metabolic response to excess caloric consumption, and negative energy balance associated with cachexia induced by cytokines. In contrast, MC3R knockout mice exhibit a normal, or even exaggerated, response to signals that induce a state of negative energy balance. However, loss of the MC3R also results in an increase in adiposity. This article discusses the regulation of energy balance by the melanocortins. Published and newly presented data from studies analyzing of energy balance of MC3R and MC4R knockout mice indicate that increased adiposity observed in both models involves an imbalance in fat intake and oxidation.
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PMID:The melanocortin system and energy balance. 1643 23

Cachexia affects many different chronically ill patient populations, including those with cancer. It results in loss of body weight, particularly of lean body mass (LBM), and is estimated to be responsible for over 20% of all cancer-related deaths. Currently, available drugs are ineffective, and new therapies are urgently needed. Melanocortin 4-receptor (MC4-R) blockade has been shown recently to be effective in preventing cancer cachexia in rodent models. In the present study, we have tested a MC4-R blocker, ML00253764 [2-{2-[2-(5-bromo-2-methoxyphenyl)-ethyl]-3-fluorophenyl}-4,5-dihydro-1H-imidazolium hydrochloride] (Vos et al., 2004), in vitro and in vivo. In membranes of human embryonic kidney 293 cells expressing human MC4-R, ML00253764 displaced [Nle(4), d-Phe(7)]-alpha-melanocyte-stimulating hormone binding with an IC(50) of 0.32 microM. At concentrations above 1 microM, ML00253764 decreased cAMP accumulation (maximal reduction of -20%) indicative of inverse agonist activity. ML00253764 was administered twice daily (15 mg/kg s.c.) for 13 days to C57BL6 mice bearing s.c. Lewis lung carcinoma tumors. Food intake and body weight were measured, and body composition was assessed using magnetic resonance relaxometry. ML00253764 stimulated light-phase food intake relative to vehicle-treated controls (p < 0.05), although no effect was observed on 24-h food intake. During the 21 days of the experiment, the LBM of tumor vehicle-treated mice decreased (p < 0.05). In contrast, the tumor-bearing mice treated with ML00253764 maintained their LBM. These data support the view that MC4-R blockade may be a suitable approach for the treatment of cancer cachexia and that MC4-R inverse agonists may have potential as drug candidates.
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PMID:Peripheral administration of a melanocortin 4-receptor inverse agonist prevents loss of lean body mass in tumor-bearing mice. 1643 98

It is well established that disruptions in melanocortin signaling in the CNS result in morbid obesity, but only recently has evidence linked the activation of this system with the production of cachexia, also known as disease-associated wasting. Pro-opiomelanocortin-producing neurons, which express cytokine receptors, show increased activation in the presence of several cytokines that are increased in diseases that are associated with cachexia. Recent experiments show that blockade of melanocortin signaling using antagonists to the melanocortin MC(4) receptor attenuates disease-associated anorexia and wasting in rodent models of cancer and renal failure. This successful inhibition of cachexia is important because loss of appetite and lean body mass worsen the prognosis of many the diseases with which cachexia is associated.
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PMID:Cachexia: lessons from melanocortin antagonism. 1675 Jun 33


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