How does leptin contribute to uraemic cachexia?

Malnutrition (wasting or cachexia) is frequently observed in uraemic patients, both in the predialysis phase and during renal replacement therapy [1,2]. According to the DOPPS, every 4th to 5th dialysis patient suffers from moderate or severe malnutrition [3]. It was also found that dietary energy and protein intakes are inadequate in the majority of haemodialysis patients [4]. For many years, it has been known that wasting or cachexia is an important predictor of morbidity and mortality due to cardiovascular and infectious diseases among uraemic patients [5]. However, the pathophysiology of wasting in these patients is very complex and not entirely known [6]. Several factors contribute to protein–energy malnutrition in patients with end-stage renal disease (ESRD) including: metabolic acidosis, chronic inflammation, low protein diet, resistance to anabolic hormones and anorexia [7]. The discovery of leptin immediately stimulated several additional areas of investigation [8]. These later studies stressed that adipose tissue is an active and important source of several hormones and proinflammatory cytokines [9]. They also increased interest in appetite regulation and the role of anorexia in the common phenomenon of wasting in uraemia [7]. Leptin is a protein hormone, predominantly produced by adipocytes and presumed to be involved in the maintenance of stable body mass [10]. High levels of leptin inhibit food intake and increase energy expenditure through several complicated pathways [10,11]. Low leptin levels stimulate appetite and suppress energy expenditure, thereby increasing fat accumulation, which in consequence raises plasma leptin concentrations again. In recent years, some of the pathways involved in the regulation of appetite have been identified in detail. For non-specialists, it is important to stress that leptin, and to a certain extent insulin, exert their biological actions through increased activity of MC4-Rs (melanocortin receptors 4) located in the hypothalamus (paraventricular region), which suppresses AMPK (AMP-activated protein kinase). MC4-Rs activity is increased directly by suppression of such hormones which improve appetite and decrease energy expenditure like NPY (neuropeptide Y) and AGRP (Agouti Related Peptide) or indirectly through activation of POMC (pro-opiomelanocortin), which induces neurons to release a-MSH (a-melanocyte-stimulating hormone), i.e. a stimulator of MC4-Rs. High levels of leptin and insulin and most probably also certain uraemic metabolites can activate both of the above pathways [11]. For example, chronic treatment with AGRP increases food intake, body fat mass and plasma leptin concentration [12]. The same observations were made in cachexia induced by cancer, which was both reversed and prevented by the administration of AGRP [13]. The above data has been extended by a recent elegant and comprehensive study by Cheung et al. [14], who tested the hypothesis that cachexia associated with uraemia is caused by leptin signalling through the hypothalamic MC4-Rs. They found that uraemiaassociated cachexia is attenuated in leptin receptordeficient (db/db) mice and in MC4-Rs knockout mice. Pharmacological blockade of the MC4-Rs with AGRP obtained the same results. In their study, they also found that gene expression of ubiquitin C and proteasome subunits C2, C3 and C9 was not changed in uraemic mice. The ATP-dependent ubiquitin–proteasome pathway is involved in protein muscle degradation [15]. In acidotic rats with cancer-induced cachexia, an increase in skeletal muscle proteolysis was associated with the increase in gene expression for ubiquitin and proteasome subunits [16]. The authors interpret these results as showing that hypothalamic MC4-Rs, a central signalling system for cytokines such as leptin, play an important role in the pathogenesis of uraemic cachexia. As uraemia is characterized by significant elevations of plasma leptin concentration, the results of Cheung et al. [14] seem to clarify very elegantly the pathogenesis of anorexia and wasting in uraemic Correspondence and offprint requests to: Prof. Andrzej Wiȩcek FRCP (Edin.), Department of Nephrology, Endocrinology and Metabolic Diseases, Medical University of Silesia, Francuska 20/24 Str. 40-027 Katowice/Poland. Email: [email protected]