Abstract
Apart from its function as co-receptor for fibroblast growth factor-23 (FGF23), Klotho is thought to regulate insulin signaling, intracellular oxidative stress, and parathyroid hormone (PTH) secretion in an FGF23 independent fashion. Here, we crossed Klotho deficient (Kl−/−) mice with vitamin D receptor (VDR) mutant mice to examine further vitamin D independent functions of Klotho. All mice were fed a rescue diet enriched with calcium, phosphorus, and lactose to prevent hyperparathyroidism in VDR mutants, and were killed at 4 weeks of age after double fluorochrome labeling. Kl−/− mice displayed hypercalcemia, hyperphosphatemia, dwarfism, organ atrophy, azotemia, pulmonary emphysema, and osteomalacia. In addition, glucose and insulin tolerance tests revealed hypoglycemia and profoundly increased peripheral insulin sensitivity in Kl−/− mice. Compound mutants were normocalcemic and normophosphatemic, did not show premature aging or organ atrophy, and were phenocopies of VDR mutant mice in terms of body weight, bone mineral density, bone metabolism, serum calcium, serum phosphate, serum PTH, gene expression in parathyroid glands, as well as urinary calcium and phosphate excretion. Furthermore, ablation of vitamin D signaling in double mutants completely normalized glucose and insulin tolerance, indicating that Klotho has no vitamin D independent effects on insulin signaling. Histomorphometry of pancreas islets showed similar beta cell volume per body weight in all groups of animals. In conclusion, our findings cast doubt on a physiologically relevant vitamin D and Fgf23 independent function of Klotho in the regulation of glucose metabolism, bone turnover, and steady-state PTH secretion in vivo.
Highlights
The Klotho gene was named after the Greek goddess spinning the thread of life
It has been suggested that the secreted Klotho protein modulates the activity and membrane abundance of the epithelial calcium channel in distal renal tubules [6,7], the function of the sodium-phosphate transporter-2a (NaPi2a) in proximal renal tubules [8], and the activity of the insulin-like growth factor-1 (IGF-1) receptor [9] in an fibroblast growth factor-23 (FGF23) independent fashion
We found that Kl2/2/VDRD/D compound mutant mice were phenocopies of VDRD/D mutants in terms of mineral and bone homeostasis, circulating parathyroid hormone (PTH) levels, parathyroid gene expression, as well as glucose and insulin tolerance, suggesting that Klotho lacks a physiologically relevant vitamin D and Fgf23 independent role in the regulation of glucose metabolism, bone turnover, and steady-state PTH secretion in vivo
Summary
The Klotho gene was named after the Greek goddess spinning the thread of life. Lack of Klotho is known to shorten life span and to cause organ atrophy, vascular calcifications, osteomalacia, hypercalcemia, hyperphosphatemia, elevated circulating vitamin D hormone, and increased peripheral insulin sensitivity in mice [1,2,3]. We found that Kl2/2/VDRD/D compound mutant mice were phenocopies of VDRD/D mutants in terms of mineral and bone homeostasis, circulating PTH levels, parathyroid gene expression, as well as glucose and insulin tolerance, suggesting that Klotho lacks a physiologically relevant vitamin D and Fgf23 independent role in the regulation of glucose metabolism, bone turnover, and steady-state PTH secretion in vivo.
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