Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0235394 (wasting)
 8,040 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fever is a phylogenetically ancient response that is mounted upon exposure of the host to pathogens or inflammatory agents. Melanocortin agonists act centrally to inhibit fever by acting at receptors, including the melanocortin-4 receptor, which is prominently expressed in key hypothalamic thermoregulatory centers. Furthermore, endogenous melanocortins act centrally as physiological modulators of fever, recruited during the febrile response to restrain its intensity. Functionally, these actions lie at the interface between the anti-inflammatory effects of melanocortins, which involve suppression of the synthesis and actions of proinflammatory cytokines, and the central control of thermoregulation. Considering the extensive neuroanatomic and functional overlaps between central pathways and peripheral effectors involved in thermoregulation and energy balance, it is not surprising that melanocortins have been found to influence the metabolic economy profoundly in pathological as well as normal states. For example, despite suppressing endotoxin-induced fever, endogenous melanocortins appear to mediate the associated anorexia, a classic component of the "illness syndrome" accompanying acute infections, and promote a negative energy balance. The thermoregulatory actions of melanocortins are in several respects functionally opposed, and are remarkably dependent on physiological state, indicating that responsiveness to melanocortins is a physiologically modulated variable. Elucidating the anti-inflammatory and thermoregulatory roles of central melanocortin receptors during inflammatory states may lead to novel pharmacotherapeutic targets based on selective targeting of melanocortin receptor subtypes, for clinical benefit in human disease states involving neuroinflammatory components and metabolic wasting.
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PMID:The central melanocortin system and fever. 1285 23

Reduced appetite combined with increased metabolic rate and decreased lean body mass is a major consequence of disease and other stressors. Studies in rodent species suggest that an understanding of appetite regulation may provide methodologies for intervention to prevent the deterioration of body mass such as observed with cancer or infectious diseases. For example, melanocortin-4 receptor (MC4-R) antagonists have shown a remarkable ability to reverse or prevent cachexia in rodents with sarcoma or treated with endotoxin. Studies in sheep have indicated that a number of peptide neurotransmitters may have a role in regulating appetite in this species. For example, agouti related protein mRNA and protein levels are dramatically altered with fasting in sheep. Moreover, agouti related protein, neuropeptide Y, melanin concentrating hormone and orexin are potent stimuli to increase feed intake in sheep. Recent studies have indicated that one of these neurotransmitters, NPY, can work in principal to improve appetite in endotoxin-treated sheep. Current studies are examining the role that MC4-R antagonists may have in the prevention or correction of body mass wasting diseases as well as practical applications in animal production.
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PMID:Melanocortin-4 receptor in sheep: a potential site for therapeutic intervention in disease models. 1591 73

Loss of function mutations in the receptor tyrosine kinase TrkB pathway resulted in hyperphagia and morbid obesity in human and rodents. Conversely, peripheral or central stimulation of TrkB by its natural ligands BDNF or NT4 reduced body weight and food intake in mice, supporting the idea that TrkB is a key anorexigenic signal downstream of the melanocortin-4 receptor (Mc4r) system. Here we show that in non-human primates TrkB agonists were anorexigenic when applied centrally, but surprisingly orexigenic, leading to gain in appetite, body weight, fat deposits and serum leptin levels, when given peripherally. The orexigenic and pro-obesity effects of peripherally administered TrkB agonists appear to be dose dependent, not associated with fluid retention nor with evidence of receptor down regulation. Our findings revealed that TrkB signaling exerts dual control on energy homeostasis in the primates that could be targeted for the treatment of either wasting disorders or obesity.
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PMID:Appetite enhancement and weight gain by peripheral administration of TrkB agonists in non-human primates. 1838 75

Cachexia is a devastating syndrome of body wasting that is associated with multiple common chronic diseases including cancer, chronic kidney disease, and chronic heart failure. These underlying diseases are associated with increased levels of inflammatory cytokines and result in anorexia, increased resting energy expenditure, and loss of fat and lean body mass. Prior experiments have implicated the central melanocortin system in the hypothalamus with the propagation of these symptoms of cachexia. Pharmacologic blockade of this system using melanocortin antagonists causes attenuation of the signs of cachexia in laboratory models. Recent advances in our knowledge of this disease process have involved further elucidation of the pathophysiology of melanocortin activation and demonstration of the efficacy of melanocortin antagonists in new models of cachexia, including cardiac cachexia. In addition, small molecule antagonists of the melanocortin-4 receptor continue to be introduced, including ones with oral bioavailability. These developments generate optimism that melanocortin antagonism will be used to treat humans with disease-associated cachexia. However, to date, human application has remained elusive and it is unclear when we will know whether humans with cachexia would benefit from treatment with these compounds.
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PMID:Update on melanocortin interventions for cachexia: progress toward clinical application. 2000 82

Appetite control is a major issue in normal growth and in suboptimal growth performance settings. A number of hormones, in particular leptin, activate or inhibit orexigenic or anorexigenic neurotransmitters within the arcuate nucleus of the hypothalamus, where feed intake regulation is integrated. Examples of appetite regulatory neurotransmitters are the stimulatory neurotransmitters neuropeptide Y (NPY), agouti-related protein (AgRP), orexin and melanin-concentrating hormone and the inhibitory neurotransmitter, melanocyte-stimulating hormone (MSH). Examination of messenger RNA (using in situ hybridization and real-time PCR) and proteins (using immunohistochemistry) for these neurotransmitters in ruminants has indicated that physiological regulation occurs in response to fasting for several of these critical genes and proteins, especially AgRP and NPY. Moreover, intracerebroventricular injection of each of the four stimulatory neurotransmitters can increase feed intake in sheep and may also regulate either growth hormone, luteinizing hormone, cortisol or other hormones. In contrast, both leptin and MSH are inhibitory to feed intake in ruminants. Interestingly, the natural melanocortin-4 receptor (MC4R) antagonist, AgRP, as well as NPY can prevent the inhibition of feed intake after injection of endotoxin (to model disease suppression of appetite). Thus, knowledge of the mechanisms regulating feed intake in the hypothalamus may lead to mechanisms to increase feed intake in normal growing animals and prevent the wasting effects of severe disease in animals.
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PMID:Selected hormonal and neurotransmitter mechanisms regulating feed intake in sheep. 2244 39