A pegylated leptin antagonist ameliorates CKD-associated cachexia in mice

Elevated serumleptin levels correlate with inflammation and predict changes in lean bodymass in patients with CKD, and activation of the melanocortin system by leptin signaling mediates the pathophysiology of CKD-associated cachexia.We tested whether treatment with a pegylated leptin receptor antagonist (PLA) attenuates cachexia inmice with CKD. CKD and Shammice received vehicle or PLA (2 or 7 mg/kg per day). At these doses, PLA did not influence serum leptin levels in mice. Treatment with 7 mg/kg per day PLA stimulated appetite and weight gain, improved lean mass and muscle function, reduced energy expenditure, and normalized the levels of hepatic TNF-a and IL-6mRNA inmicewith CKD. Furthermore, treatment with 7 mg/kg per day PLA attenuated the CKD-associated increase in the transcriptional and protein abundance of uncoupling proteins that mediates thermogenesis, and it normalized the molecular signatures of processes associated with muscle wasting in CKD, including proteolysis, myogenesis and muscle regeneration, and expression of proinflammatory muscle cytokines, such as IL-1a, -1b, and -6 and TNF-a. Our results suggest that leptin antagonism may represent a viable therapeutic strategy for cachexia in CKD.