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)

Obese patients have an increased incidence of systemic infections and higher morbidity and mortality rates than normal weight subjects. Ghrelin is a potent orexigenic signal from the stomach and seems to play a role in the generation and control of immune interactions. To examine a possible benefit of a single ghrelin application on acute endotoxemia, chronic intravenous (i.v.) cannulated lean and diet-induced obese male LEW rats were treated with a bolus injection of either ghrelin (10 nmol/kg) or vehicle, 10 min prior to a challenge with a sublethal bolus of endotoxin (100 microg/kg) or vehicle. Multiple blood samples were taken within a period from 24 h before the experiment up to 24 h after the endotoxin challenge to measure ghrelin and cytokine levels. Additionally, food consumption was recorded and ghrelin expression in fore- and glandular stomach was evaluated immunohistochemically. Despite higher serum ghrelin levels, the food consumption was significantly decreased in obese endotoxemic rats compared to lean littermates after ghrelin treatment. Furthermore we could show an increase of anti-inflammatory IL-10 serum levels after ghrelin treatment of normal weight endotoxemic and an opposite effect in obese animals. As the therapy of disease-associated cachexia and various immunological problems in endotoxemia is still insufficient, peptides such as ghrelin with their modulating abilities for the endocrine and the immune system are of special interest. However, the present study shows that the beneficial effects of ghrelin were attenuated in obese endotoxemic animals. These data further document the necessity to differentiate between normal weight and obese subjects in the attempt to establish ghrelin as a therapeutic target in endotoxemia.
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PMID:Obesity influences the food consumption and cytokine pattern in ghrelin-treated endotoxemic rats. 1753 46

The melanocortin (MC) system confines unique G-protein coupled receptor pathways, which include the MC(1-5) receptors and their endogenous agonists and antagonists, the MCs and the agouti and agouti-related proteins. The MC4 receptor is an important target for development of drugs for treatment of obesity and cachexia. While natural MC peptides are selective for the MC1 receptor, some cyclic pentapeptides, such as the HS-129 peptide, show high selectivity for the MC4 receptor. Here we gained insight into the mechanisms for its recognition by MC receptors. To this end we correlated the interaction data of four HS peptide analogues with four wild-type and 14 multiple chimeric MC receptors to the binary and physicochemical descriptions of the studied entities by use of partial least squares regression, which resulted in highly valid proteochemometric models. Analysis of the models revealed that the recognition sites of the HS peptides are different from the earlier proteochemometrically mapped linear MSH peptides' recognitions sites, although they overlap partially. The analysis also revealed important amino acids that explain the selectivity of the HS-129 peptide for the MC4 receptor.
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PMID:Proteochemometric analysis of small cyclic peptides' interaction with wild-type and chimeric melanocortin receptors. 1755 35

The melanocortin-4 (MC4) receptor subtype plays a pivotal role in body weight regulation. Knock-out or mutation of MC4 receptors in animals or humans leads to severe obesity and acute or sub-acute antagonism of central MC4 receptors produces an increase in food intake and a decrease in metabolism. Knock-out or antagonism of MC4 receptors in animal models of cachexia leads to a protection from anorexia and the loss of both lean and fat body mass, suggesting that an MC4 antagonist may be beneficial in wasting diseases, which are poorly treated by available therapies. Considerable progress has been made in the discovery of non-peptide antagonists with high affinity and selectivity for MC4 receptors. Optimization of these compounds has produced molecules that are active upon systemic administration and are effective in protecting against cachectic symptoms in animal models of tumor-induced wasting. Further development of such compounds is greatly anticipated as a potential means to combat the cachexia that results from chronic diseases such as cancer, AIDS, renal failure, liver failure, congestive heart failure and lung disease.
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PMID:Melanocortin-4 receptor antagonists as potential therapeutics in the treatment of cachexia. 1758 33

POMC (pro-opiomelanocortin) is a complex polypeptide precursor which is cleaved into smaller biologically active peptides such as the melanocortins, alpha-, beta- and gamma-melanocyte-stimulating hormone. Data from human genetic and murine studies convincingly show that an intact central melanocortin signalling pathway is critical for normal energy homoeostasis. Not only does a loss of normal melanocortin signalling lead to obesity, but there are also data implicating increased melanocortin activity in the pathogenesis of cachexia. The study of POMC biology has lead to some fundamental insights into the mechanisms controlling food intake and body weight. This increased understanding of the physiological roles of the melanocortin system has opened up the potential for the design and development of rational therapies to treat perturbations in energy homoeostasis.
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PMID:Effects of pro-opiomelanocortin (POMC) on food intake and body weight: mechanisms and therapeutic potential? 1762 13

The melanocortin-4 receptor (MC4R) is involved in regulating energy homeostasis and is a potential therapeutic target for obesity and cachexia. Molecular interactions between peptide ligands and MC4R have been studied in detail. Less is known regarding the role of these interactions in the mechanism of MC4R activation. The aim of this study was to investigate the molecular mechanism of human MC4R activation by [Nle4, d-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH), by first defining the role of the His6-d-Phe7-Arg8-Trp9 residues in receptor activation (Emax for stimulation of cAMP accumulation) using modified peptides, then understanding how their interaction with the receptor modulates activation using site-directed mutagenesis and a molecular model of NDP-MSH bound to the active state of the receptor. Alanine substitution indicated that the d-Phe7, Arg8, and Trp9 side chains contribute binding energy but are not essential for the receptor activation event. Conversely, His6 to Ala6 substitution reduced receptor activation but did not affect affinity. Chlorine substitutions on the d-Phe7 side chain also inhibited receptor activation. F261(6.51)A and F284(7.35)A receptor mutations acted as gain-of-function mutations, restoring efficacy to the His6 and d-Phe7 substituted peptides that had lost efficacy at the wild-type receptor. Based on a model of NDP-MSH and MC4R interaction, the antagonist behavior of these peptides is consistent with the prevention of transmembrane 6 (TM6) rotation. This data supports the hypothesis that increasing the size of d-Phe7 directly interferes with TM6 rotation, preventing receptor activation. We further propose that removing the interaction with the His6 side chain reorients the peptide within the binding pocket, indirectly impeding TM6 rotation by strengthening peptide interaction with F261(6.51) and F284(7.35). These findings refine the molecular basis for the mechanism of ligand-stimulated hMC4R activation and will be useful for the development of hMC4R agonists and antagonists.
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PMID:Substituted NDP-MSH peptides paired with mutant melanocortin-4 receptors demonstrate the role of transmembrane 6 in receptor activation. 1771 70

From its initial implication in the development of cachexia in the early 1980s, it is now almost 15 years ago that tumour necrosis factor-alpha (TNF-alpha) was first shown to be involved in the development of insulin resistance in obesity. Since the original findings in mice, a wealth of data has been obtained in a variety of settings and species. This intensive research has demonstrated both similarities and differences between rodents and humans regarding the molecular mechanisms and metabolic consequences of TNF-alpha overexpression. This review will focus on the role of TNF-alpha in human white adipose tissue with particular emphasis on its regulation of lipolysis - an important pathway in adipocytes which is linked to insulin-resistant phenotypes in obesity and the metabolic syndrome.
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PMID:Tumour necrosis factor-alpha in human adipose tissue -- from signalling mechanisms to clinical implications. 1787 79

Melanocortin receptors are considered promising candidates for the treatment of behavioral and metabolic disorders ranging from obesity to anorexia and cachexia. These experiments examined the response of mice to peripheral injections of two compounds. PG932 is a derivative of SHU9119 which is non-selective antagonist of melanocortin-3 and melanocortin-4 receptors (Mc3r and Mc4r). PG946 is a derivative of a hybrid of alpha- and beta-MSH, and is a moderately selective Mc3r antagonist. SHU9119 increases food intake when administered intracerebroventricularly but is without effect when injected into the periphery. In contrast, PG932 was found to be highly effective at stimulating food intake when administered peripherally by intraperitoneal injection. The orexigenic effect of PG932 required functional Mc4r, suggesting that inhibition of this receptor is involved in the stimulation of food intake. PG946 did not significantly affect on feeding behavior. PG932 is thus a useful new compound for studies examining the regulation of appetite and energy balance, and may also prove useful for the treatment of cachectic conditions.
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PMID:A derivative of the melanocortin receptor antagonist SHU9119 (PG932) increases food intake when administered peripherally. 1805 19

Since it is widely distributed into the body, beta(3)-adrenoceptor is becoming an attractive target for the treatment of several pathologies such as obesity, type 2 diabetes, metabolic syndrome, cachexia, overactive bladder, ulcero-inflammatory disorder of the gut, preterm labour, anxiety and depressive disorders, and heart failure. New compounds belonging to the class of arylethanolamines bearing one or two stereogenic centres were prepared in good yields as racemates and optically active forms. They were, then, evaluated for their intrinsic activity towards beta(3)-adrenoceptor and their affinity for beta(1)- and beta(2)-adrenergic receptors. Stereochemical features were found to play a crucial role in determining the behaviour of such compounds. In particular, alpha-racemic, (alphaR)- and (alphaS)-2-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxy}-2- methylpropanoic acid, (alpha-rac, beta-rac)-, (alphaR, betaS)- and (alphaR, betaR)- 2-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxy}propanoic acid were found to be endowed with beta(3)-adrenoceptor agonistic activity. Whereas, (alphaS, betaS)- and (alphaS, betaR)-2-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxy}propanoic acid behaved as beta(3)-adrenoceptor inverse agonists. Such compounds showed no affinity for beta(1)- and beta(2)-adrenergic receptor, respectively. Thus, resulting highly selective beta(3)-adrenoceptor ligands.
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PMID:Stereospecific synthesis and bio-activity of novel beta(3)-adrenoceptor agonists and inverse agonists. 1808 78

Rheumatoid cachexia is under-recognized in clinical practice. The loss of lean body tissue, which characterizes cachexia, is often compensated for by gain in body fat-so called 'cachectic obesity'-so that 85% or more RA patients have a normal BMI. Severe cachexia with loss of weight leads to increased morbidity and premature mortality but loss of muscle bulk with a normal BMI also associates with poor clinical outcomes. Increasing BMI, even into the obese range, is associated with less joint damage and reduced mortality. Measurement of body composition using DXA and other techniques is feasible but the results must be interpreted with care. Newer techniques such as whole-body MRI will help define with more confidence the mass and distribution of fat and muscle and help elucidate the relationships between body composition and outcomes. Cachexia shows little response to diet alone but progressive resistance training and anti-TNF therapies show promise in tackling this potentially disabling extra-articular feature of RA.
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PMID:Rheumatoid cachexia: a clinical perspective. 1844 80

Advances in the understanding of appetite are leading to a refined concept of disease cachexia and point to novel therapeutic strategies based on the manipulation of appetite. The complex social and psychological short-term influences on appetite obscure the fact that over the longer term appetite is tightly regulated by physiological considerations; the homeostatic control of energy balance. Like obesity, which is now viewed as a disorder of homeostasis, cachexia can be seen as an adaptive response to the disease state that becomes harmful when prolonged. Several lines of evidence implicate a disorder of appetite regulation in the pathogenesis of cachexia. As the only known circulating mediator of increased appetite the peptide hormone ghrelin has attracted attention as a potential therapy. Trials in patients with various chronic illnesses, including cancer and kidney failure, have demonstrated short-term increases in energy intake. Trials in patients with emphysema and heart failure have also shown benefits in clinical outcomes such as lean body mass and exercise capacity, and longer-term trials using oral analogues are being undertaken. As well as improving nutrition, ghrelin has a number of other actions that may be useful, including an anti-inflammatory effect; of interest since many cachexias are associated with inappropriate immune activation. The manipulation of appetite, in particular by ghrelin agonism, is emerging as an exciting potential therapy for disease cachexia. Future research should focus on the ascertainment of clinically-relevant outcomes, and further characterisation of the non-nutritional effects of this pathway.
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PMID:Gut hormones and the treatment of disease cachexia. 1845 42


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