Abstract
Patients with chronic kidney disease (CKD) often have low serum concentrations of 25(OH)D3 and 1,25(OH)2D3. We investigated the differential effects of 25(OH)D3 versus 1,25(OH)2D3 repletion in mice with surgically induced CKD. Intraperitoneal supplementation of 25(OH)D3 (75 μg/kg/day) or 1,25(OH)2D3 (60 ng/kg/day) for 6 weeks normalized serum 25(OH)D3 or 1,25(OH)2D3 concentrations in CKD mice, respectively. Repletion of 25(OH)D3 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)2D3 in CKD mice. Repletion of 25(OH)D3 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)2D3 did not. Significant improvement of muscle fiber size and normalization of fat infiltration of gastrocnemius was apparent with repletion of 25(OH)D3 but not with 1,25(OH)2D3 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)D3 exerts metabolic advantages over repletion of 1,25(OH)2D3 by attenuating adipose tissue browning and muscle wasting in CKD mice.
Highlights
Cachexia in chronic kidney disease (CKD) is a complex metabolic disorder that results in profound loss of adipose tissue and muscle mass [1,2]
We showed that repletion of 25(OH)D3 corrected anorexia and attenuated white adipose tissue (WAT) browning and muscle wasting in CKD mice
Serum parathyroid hormone (PTH) concentrations were still significantly elevated even with successful repletion of 25(OH)D3 or 1,25(OH)2D3 in CKD mice (Table 5). These results show that the effects of vitamin D repletion were independent of PTH concentrations and suggest that vitamin D insufficiency, but not hyperparathyroidism, is a causal factor in CKD-associated WAT browning and muscle wasting
Summary
Cachexia in chronic kidney disease (CKD) is a complex metabolic disorder that results in profound loss of adipose tissue and muscle mass [1,2]. The white adipose tissue (WAT) is a key energy reservoir while brown adipose tissue (BAT) is involved in the regulation of thermogenesis [3,4]. Browning of WAT preceded skeletal muscle atrophy in several disease models [5,6,7,8]. These results reveal the detrimental effects of WAT browning in the setting of disease-associated cachexia. Inhibition of WAT browning may exhibit therapeutic potential for patients with CKD-associated cachexia. We reported that combined supplementation of 25(OH)D3 and 1,25(OH)2D3 attenuated WAT browning and cachexia in CKD mice [12]
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