Differential Effects of 25-Hydroxyvitamin D(3) versus 1α 25-Dihydroxyvitamin D(3) on Adipose Tissue Browning in CKD-Associated Cachexia

Patients with chronic kidney disease (CKD) often have low serum concentrations of 25(OH)D(3) and 1,25(OH)(2)D(3). We investigated the differential effects of 25(OH)D(3) versus 1,25(OH)(2)D(3) repletion in mice with surgically induced CKD. Intraperitoneal supplementation of 25(OH)D(3) (75 μg/kg/day) or 1,25(OH)(2)D(3) (60 ng/kg/day) for 6 weeks normalized serum 25(OH)D(3) or 1,25(OH)(2)D(3) concentrations in CKD mice, respectively. Repletion of 25(OH)D(3) normalized appetite, significantly improved weight gain, increased fat and lean mass content and in vivo muscle function, as well as attenuated elevated resting metabolic rate relative to repletion of 1,25(OH)(2)D(3) in CKD mice. Repletion of 25(OH)D(3) in CKD mice attenuated adipose tissue browning as well as ameliorated perturbations of energy homeostasis in adipose tissue and skeletal muscle, whereas repletion of 1,25(OH)(2)D(3) did not. Significant improvement of muscle fiber size and normalization of fat infiltration of gastrocnemius was apparent with repletion of 25(OH)D(3) but not with 1,25(OH)(2)D(3) in CKD mice. This was accompanied by attenuation of the aberrant gene expression of muscle mass regulatory signaling, molecular pathways related to muscle fibrosis as well as muscle expression profile associated with skeletal muscle wasting in CKD mice. Our findings provide evidence that repletion of 25(OH)D(3) exerts metabolic advantages over repletion of 1,25(OH)(2)D(3) by attenuating adipose tissue browning and muscle wasting in CKD mice.