Leptin Stimulates Fibroblast Growth Factor 23 Expression in Bone and Suppresses Renal 1α,25-Dihydroxyvitamin D3 Synthesis in Leptin-Deficient Mice

Leptin is the LEP (ob) gene product secreted by adipocytes. We previously reported that leptin decreases renal expression of the 25-hydroxyvitamin D-3 1 alpha-hydroxylase (CYP27B1) gene through the leptin receptor (ObRb) by indirectly acting on the proximal tubules. This study focused on bone-derived fibroblast growth factor 23 (FGF-23) as a mediator of the influence of leptin on renal 1 alpha-hydroxylase mRNA expression in leptin-deficient ob/ob mice. Exposure to leptin (200 ng/mL) for 24 hours stimulated FGF-23 expression by primary cultured rat osteoblasts. Administration of leptin (4 mg/kg i.p. at 12-hour intervals for 2 days) to ob/ob mice markedly increased the serum FGF-23 concentration while significantly reducing the serum levels of calcium, phosphate, and 1 alpha,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3]. Administration of FGF-23 (5 mu g i.p. at 12-hour intervals for 2 days) to ob/ob mice suppressed renal 1 a-hydroxylase mRNA expression. The main site of FGF-23 mRNA expression was the bone, and leptin markedly increased the FGF-23 mRNA level in ob/ob mice. In addition, leptin significantly reduced 1 alpha-hydroxylase and sodium-phosphate cotransporters (NaPi-IIa and NaPi-IIc) mRNA levels but did not affect Klotho mRNA expression in the kidneys of ob/ob mice. Furthermore, the serum FGF-23 level and renal expression of 1 alpha-hydroxylase mRNA were not influenced by administration of leptin to leptin receptor deficient (db/db) mice. These results indicate that leptin directly stimulates FGF-23 synthesis by bone cells in ob/ob mice, suggesting that inhibition of renal 1,25(OH)(2)D-3 synthesis in these mice is at least partly due to elevated bone production of FGF-23. (c) 2010 American Society for Bone and Mineral Research.