| Summary: | Mice lacking the functional cystinosin gene (<i>Ctns<sup>−/−</sup></i>), a model of infantile nephropathic cystinosis (INC), exhibit the cachexia phenotype with adipose tissue browning and muscle wasting. Elevated leptin signaling is an important cause of chronic kidney disease-associated cachexia. The pegylated leptin receptor antagonist (PLA) binds to but does not activate the leptin receptor. We tested the efficacy of this PLA in <i>Ctns<sup>−/−</sup></i> mice. We treated 12-month-old <i>Ctns<sup>−/−</sup></i> mice and control mice with PLA (7 mg/kg/day, IP) or saline as a vehicle for 28 days. PLA normalized food intake and weight gain, increased fat and lean mass, decreased metabolic rate and improved muscle function. It also attenuated perturbations of energy homeostasis in adipose tissue and muscle in <i>Ctns<sup>−/−</sup></i> mice. PLA attenuated adipose tissue browning in <i>Ctns<sup>−/−</sup></i> mice. PLA increased gastrocnemius weight and fiber size as well as attenuated muscle fat infiltration in <i>Ctns<sup>−/−</sup></i> mice. This was accompanied by correcting the increased expression of muscle wasting signaling while promoting the decreased expression of myogenesis in gastrocnemius of <i>Ctns<sup>−/−</sup></i> mice. PLA attenuated aberrant expressed muscle genes that have been associated with muscle atrophy, increased energy expenditure and lipolysis in <i>Ctns<sup>−/−</sup></i> mice. Leptin antagonism may represent a viable therapeutic strategy for adipose tissue browning and muscle wasting in INC.
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