NDT Advance Access originally published online on December 13, 2005
Nephrology Dialysis Transplantation 2006 21(4):1125-1126; doi:10.1093/ndt/gfi332
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Does leptin contribute to uraemic cachexia?
Email: maubosso{at}tin.itSir,
We read with much interest the article of Andrzej Wiecek entitled ‘How does leptin contribute to uraemic cachexia?’ [1]. Wiecek has critically reviewed the results of a very interesting article by Cheung et al. [2] on the role of leptin and melanocortin signalling in uraemia-associated cachexia published recently in the Journal of Clinical Investigation.
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 uraemia 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 uraemia-associated cachexia via signalling through the central melanocortin system.
Recently, we conducted a study in end-stage renal disease patients receiving chronic haemodialysis to ascertain if hyperleptinaemia is causally implicated in the pathogenesis of anorexia in such patients [3]. Our study has confirmed that haemodialysis patients, both males and females, have higher levels of serum leptin than healthy subjects as well as a higher leptin/body mass index ratio. We also demonstrated that serum leptin levels and the serum leptin/body mass index ratio were not different in anorexic and in non-anorexic haemodialysis 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 haemodialysis 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 intake [4]. Numerous authors have supposed that in obese patients a state of relative leptin resistance may occur [5,6]. This issue has been recently reviewed by Munzberg and Myers [7]. Leptin stimulates the production of anorectic neuropeptides and inhibits the action of orexigenic peptides in the arcuate nucleus through complex mechanisms [7]. When leptin binds to its receptor (LRb) it 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 signalling [7–10].
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 signalling. 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 haemodialysis in which circulating leptin levels are significantly higher than in healthy subjects. If further studies in the next future will confirm these hypotheses, the title of the article by Wiecek could be changed in ‘Does leptin really contribute to uraemic cachexia?’.
Conflict of interest statement. None declared.
Istituto di Clinica Chirurgica Universit Cattolica del Sacro Cuore Largo A.Gemelli, 8 00168 Rome, Italy
References
- Wiecek A. How does leptin contribute to uraemic cachexia? Nephrol Dial Transplant 2005; 20: 2620–2622
[Free Full Text] - Cheung W, Yu PX, Little BM, Cone RD, Marks DL, Mak RH. Role of leptin and melanocortin signalling in uremia-associated cachexia. J Clin Invest 2005; 115: 1659–1665[CrossRef][Web of Science][Medline]
- Bossola M, Muscaritoli M, Valenza V et al. Anorexia and serum leptin levels in hemodialysis patients. Nephron Clin Pract 2004; 97: c76–c82[Medline]
- Frederich RC, Hamann A, Anderson S, Lollmann B, Lowell BB, Flier JS. Leptin levels reflect body lipid content in mice: evidence for diet- induced resistance to leptin action. Nat Med 1995; 1: 1311–1314[CrossRef][Web of Science][Medline]
- Van Heek M, Compton DS, France CF et al. Diet-induced obese mice develop peripheral, but not central, resistance to leptin. J Clin Invest 1997; 99: 385–390[Web of Science][Medline]
- El Haschimi K, Pierroz DD, Hileman SM, Bjorbaek C, Flier JS. Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity. J Clin Invest 2000; 105: 1827–1832[Web of Science][Medline]
- Munzberg H, Myers MG. Molecular and anatomical determinants of central leptin resistance. Nat Neurosc 2005; 8: 566–570[CrossRef][Web of Science][Medline]
- Bjorbaek C. SOCS3 mediates feedback inhibition of the leptin recptor via Tyr985. J Biol Chem 2000; 275: 40649–40657
[Abstract/Free Full Text] - Dunn SL. Feedback inhibition of leptin receptor7Jak2 signalling via Tyr1138 of the leptin recptor and SOCS3. Mol Endocrinol 2005; 19: 925–938
[Abstract/Free Full Text] - Bjorbaek C, Elmquist JK, Shoelson SE, Flier JS. Identification of SOCS3 as potential mediator of central leptin resistance. Mol Cell 1998; 1: 619–625[CrossRef][Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Bossola, S. Giungi, L. Tazza, and G. Luciani Does desacyl ghrelin contribute to uraemic anorexia? Nephrol. Dial. Transplant., December 1, 2007; 22(12): 3673 - 3674. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||