Comments for:
Abstract
The pathogenesis of cachexia in patients with uremia is unknown. We tested the hypothesis that uremia-associated cachexia is caused by leptin signaling through the hypothalamic melanocortin receptor 4 (MC4-R). We performed either subtotal nephrectomy (N) or sham operations in WT, leptin receptor–deficient (db/db), and MC4-R knockout (MC4-RKO) mice. The animals were on 17% protein diets, and none of the uremic animals were acidotic. WT-N mice produced a classic syndrome of cachexia characterized by decreased food intake, increased metabolic rate, and loss of lean body mass. Corrected leptin levels were elevated. db/db mice and MC4-RKO mice resisted the cachexic effects of uremia on weight gain, body composition, and metabolic rate. Likewise, treatment of WT mice with intracranial agouti-related peptide reversed the cachexic effects of uremia on appetite, weight gain, body composition, and metabolic rate. Gene expression of ubiquitin C and proteasome subunits C2, C3, and C9 was not changed in the uremic animals, suggesting that other pathways are involved in this model of nonacidotic uremic cachexia. The results of this study suggest that elevated circulating levels of cytokines such as leptin may be an important cause of uremia-associated cachexia via signaling through the central melanocortin system.
Authors
Wai Cheung, Pin X. Yu, Brian M. Little, Roger D. Cone, Daniel L. Marks, Robert H. Mak
Letter about Cheung et al.
Submitter: Maurizio Bossola | maubosso@tin.it
(MB) Università Cattolica del Sacro Cuore, (MM) Università La Sapienza, Rome, Italy
Published July 18, 2005
We read with interest the article by Cheung et al on the role of leptin and melanocortin signaling in uremia-associated cachexia .1 The study shows that leptin receptor-deficient (db/db) and MC4-R knockout (MC4 -RKO) mice, undergoing subtotal nephrectomy and consequently showing elevated circulating leptin levels, resisted the cachexic effects of uremia on weight gain, body composition, and metabolic rate. According to the authors, these results suggest that elevated circulating levels of cytokines such as leptin may be an important cause of uremia-associated cachexia via signalling through the central melanocortin system.
Recently, we conducted a study in end-stage renal diseases patients receiving chronic hemodialysis to ascertain if hyperleptinemia is causally implicated in the pathogenesis of anorexia in such patients.2 Our study has confirmed that hemodialysis patients, both males and females, have higher levels of serum leptin than healthy subjects as well as higher leptin/body mass index ratio and has demonstrated that serum leptin levels and the serum leptin/body mass index ratio were not different in anorexic and in non-anorexic hemodialysis patients. Moreover, no statistically significant differences in terms of serum leptin levels and leptin/body mass index ratio were observed between patients with dietary energy intakes of <30 or ≥30 kcal/kg/day and between those with a protein intake of <1.2 or ≥1.2 g/kg/day. The findings of our study would indicate that leptin would not play a major pathogenic role in anorexia of hemodialysis patients.
It is well known that most obese individuals have elevated circulating levels of leptin but they do not respond to these increased leptin levels with reduced food intake3 . Numerous authors have supposed that in obese patients a state of relative leptin resistance may occur 4- 5. This issue has been recently reviewed by Munzberg and Myers 6. Leptin stimulates the production of anorectic neuropeptides and inhibits the action of orexigenic peptides in the arcuate nucleus through complex mechanisms6. When leptin binds to its receptor (LRb) activates the LRb- associated Jak2 tyrosine kinase, leading to the autophosphorylation of tyrosine residues on Jak2 and the phosphorylation of Tyr985 and Tyr1138 on the intracellular tail of LRb. Phosphorylation of Tyr1138 mediates the activation of the transcription factor STAT3. STAT3 also induces the transcription of SOCS3. SOCS3 binding to the LRb-Jak2 complex attenuates LRb-mediated signaling6-9. Munzberg and Myers postulate that when leptin levels are low and thus baseline STAT3 activation is modest, SOCS3 expression is low, and incremental changes in leptin would be almost fully translated into increased LRb signaling. When circulating leptin levels are high (as in obesity), the increased baseline STAT3 activation would lead to an increased expression of SOCS3, mitigating much of the effect of increased leptin binding to LRb6. Taking into account these considerations and the results of our clinical study, it could be suggested that a state of relative leptin resistance may occur also in patients with end-stage renal disease receiving hemodialysis in which circulating leptin levels are significantly higher than in healthy subjects. We believe that further studies are needed to confirm or not this hypotheses.
References
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2. Bossola M, Muscaritoli M, Valenza V, Panocchia N, Tazza L, Cascino A, Laviano A, Liberatori M, Moussier M, Rossi Fanelli F, Lucani G. 2004. Anorexia and serum leptin levels in hemodialysis patients. Nephron Clin Pract 97:c76-c82
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