Creatinine promotes adipose tissue wasting in chronic kidney disease via creatine and futile creatine cycle.

OBJECTIVE: Cachexia in chronic kidney disease (CKD) is a wasting syndrome. The futile creatine cycle (FCC) contributes to energy waste in adipocytes. Creatinine is metabolite of creatine. Whether creatinine involves in adipose wasting in CKD remains elusive. METHODS: Cachexia were assessed in unilateral ureteral obstruction induced CKD mice model. Cellular oxygen consumption and FCC-related genes expression were analyzed in adipocytes treated with creatinine in the presence of FCC inhibitor (SBI-425, inhibitor of TNAP) or creatine disruption (β-GPA, a creatine analogue that inhibits creatine transport into cells). The fate of labeled deuterated creatinine (D-3 creatinine) were traced by mass spectrometer. To determine creatinine drives adipose tissue wasting in vivo, two mice models of CKD were established by unilateral ureteral obstruction or renal ischemia and reperfusion injury. 206 patients diagnosed CKD were collected to analyze correlationship between creatinine in serum and adiposity. RESULTS: Adipose tissue wasting presented in CKD mice with serumal creatinine retention. In vitro, creatinine treatment at the concentration relevant of CKD elevated cellular oxygen consumption and FCC-related genes expression by converting into intracellular creatine. In the established CKD mice models, intraperitoneal injection of creatinine enhanced adipose tissue wasting, through increasing creatine accumulation. In contrast, disruption of creatine accumulation by β-GPA ameliorated tissue wasting. In patients with CKD, creatinine in serum negatively correlated with adiposity. CONCLUSIONS: Our results show that elevated serumal creatinine induces creatine accumulation, FCC activation and adipose tissue wasting in CKD, targeting creatinine-induced tissue wasting providing a promising therapeutic to ameliorate cachexia in CKD.