Neuropeptides in cachexia

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A current hypothesis of cachexia in chronic illness is that cytokines released during cancer, CKD, or chronic inflammation act on the central nervous system to alter the release and function of a number of key neurotransmitters, thereby altering both appetite and metabolic rate (54,55). The melanocortin system is critical in mediating the effect of cytokines, such as leptin, on metabolism. There are distinct local counterparts of the pro-opiomelanocortin (POMC) cells: agouti-related protein (AgRP) and neuropeptide Y (NPY) producing cells in the arcuate nucleus. Activation of POMC neurons by leptin triggers the release of a-melanocyte-stimulating hormone (a-MSH) from POMC axon terminals, which in turn activates the type 4 melanocortin receptor-4 (MC-4R), leading to suppressed food intake and increased energy expenditure. Simultaneously, leptin suppresses the activity of arcuate nucleus NPY/AgRP neurons, which otherwise would antagonize the effect of a-MSH on MC-4Rs through the release of AgRP. Not only does the NPY/AgRP system antagonize anorexigenic melanocortin cells at their target sites, where MC-4Rs are located, but it also very robustly and directly inhibits POMC perikarya through both NPY and the inhibitory neurotransmitter GABA, which acts through basketlike synaptic innervation of POMC cells by NPY/AgRP cell terminals. This apparent unidirectional anatomical interaction between the NPY/AgRP and POMC perikarya is of potential significance, as it provides a tonic inhibition of the melanocortin cells whenever the NPY/AgRP neurons are active (56).

Marks et al. studied the role of melanocortin receptors in transducing the prolonged metabolic derangement observed in experimental cancer. These investigators demonstrated that the cachexia (poor appetite and weight loss) induced by cancer can be both reversed and prevented by administration of AgRP. Prevention of tumor-induced hypophagia with early and repeated AgRP injections resulted in maintenance of normal food intake. To further demonstrate that central melanocortin blockade attenuates cancer cachexia, they investigated this metabolic syndrome in MC4R knockout (KO) mice. The MC4-RKO animals had normal feeding and growth even when bearing a carcinoma that produced classic cachexia in wild-type (WT) control animals. These data clearly indicate that hypothalamic MC4-R plays a role in transducing cachexigenic stimuli from the periphery (54).

We recently tested the hypothesis that leptin was an important cause of uremic cachexia via signaling through its receptor. Our results showed that uremic cachexia was attenuated in db/db mice, a model of leptin receptor deficiency. Nephrectomy in db/db mice did not result in any change in weight gain, body composition, resting metabolic rate, and efficiency of food consumption (55). Recent studies suggested that db/db mice resisted LPS-induced anorexia by reducing TNF-a secretion. Thus, leptin may have an important role in the regulation of appetite, body composition, and metabolic rate in uremia. Indeed, elevated serum leptin was associated with lower dietary intake and higher catabolic rate in uremic children (51). In another set of experiments, we demonstrated that uremic cachexia in experimental animals is attenuated by central MC4-R blockade via a genetic approach. Both homozygous and heterozygous MC4-RKO mice had no decrease in appetite after nephrectomy compared with WT animals. The most striking difference was that both the homozygous and heterozygous MC4-RKO animals continued to gain lean body mass and fat mass with no change in food consumption efficiency despite the cachexic effects of uremia, as demonstrated in the WT nephrectomized controls (N). The effects of nephrectomy on increasing resting metabolic rate were also much attenuated in both the homozygous group and the heterozygous group. These results are consistent with previous observations that MC4-RKO animals maintained normal metabolic rate and body composition even when bearing a carcinoma that produced classic cachexia in WT control animals (54). These data strongly suggest that the hypothalamic MC4-R plays a significant role in transducing cachexigenic signals in uremia. We then tested the effect of central melanocortin receptor antagonism in the experimental uremic cachexia models using a pharmacological approach. These data clearly demonstrated that uremic cachexia is ameliorated by central administration of AgRP in WT-N mice. Repeated intracranial infusion of AgRP significantly regulates food intake, weight gain, body composition, resting metabolic rate, efficiency of food consumption, and circulating leptin concentrations in WT-N/AgRP mice as compared with WT-N mice (55). AgRP is an antagonist for MC4-R. Tumor-induced and sepsis-induced cachexia are attenuated by MC4-R blockade with AgRP (54).

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