Leptin and inflammation-associated cachexia in chronic kidney disease

Abstract

Leptin is an adipocyte-derived hormone that acts as a major regulator of food intake and energy homeostasis. It circulates both as a free and as a protein-bound entity. Leptin is released into the blood in proportion to the amount of body fat and exerts sustained inhibitory effects on food intake while increasing energy expenditure. The leptin receptor belongs to the class I cytokine receptor superfamily and possesses strong homology to the signal-transducing subunits of the IL-6 receptor. The hypothalamic melanocortin system, and specifically the melanocortin-4 receptor (MC-4R), is critical in mediating leptin's effect on appetite and metabolism. Serum leptin concentrations are elevated in patients with chronic kidney disease (CKD) and correlate with C-reactive protein levels suggesting that inflammation is an important factor that contributes to hyperleptinemia in CKD. Hyperleptinemia may be important in the pathogenesis of inflammation-associated cachexia in CKD. We showed that experimental uremic cachexia was attenuated in db/db mice, a model of leptin receptor deficiency. Nephrectomy in these animals did not result in any change in weight gain, body composition, resting metabolic rate, and efficiency of food consumption. Furthermore, experimental uremic cachexia could be ameliorated by blocking leptin signaling through the hypothalamic MC-4R. MC-4R knockout mice or mice administered the MC-4R and MC-3R antagonist, agouti-related peptide, resisted uremia-induced loss of lean body mass and maintained normal basal metabolic rates. Thus, melanocortin receptor antagonism may provide a novel therapeutic strategy for inflammation-associated cachexia in CKD.

Body Mass Index And Acute Kidney Injury In The Acute Respiratory Distress Syndrome

“…In humans with obesity, leptin levels may be inappropriately high due to hyporesponsiveness to leptin (35) but the levels decline rapidly during fasting (36). In patients with CKD, leptin is elevated due to decreased plasma clearance and increased production (37). A clinical study found normal plasma leptin levels prior to first dialysis in patients with AKI and no significant differences in leptin levels between survivors and nonsurvivors with AKI (38).…”

Psychosocial Aspects of Chronic Disease

“…75,76 Levels of TNF-␣, a cytokine associated with cachexia, and cortisol, a stress hormone associated with depression and dysregulated carbohydrate metabolism, as well as other such mediators have also been shown to be elevated in ESRD patients treated with HD. 55,77,78 …”

Association between serum leptin levels and peritoneal dialysis: A meta-analysis

“…Serum leptin levels are also known to be higher in patients who are undergoing PD, such as patients with hemolytic uremic syndrome, when compared with individuals with normal renal function. This observation may be caused by the filtering of leptin at the glomerulus without obstruction and the degradation of the protein in the renal tubules, as a result of the impaired clearance by the kidney (17,18). In addition, malnutrition is a dominant characteristic of uremic syndrome, and nutritional indicators, including the body mass index (BMI), the distribution of body fat and the plasma concentration of albumin, are known to be associated with the development of renal failure (19,20).…”