Leptin stimulates fibroblast growth factor 23 expression in bone and suppresses renal 1α,25-dihydroxyvitamin D3 synthesis in leptin-deficient ob/ob Mice
✍ Scribed by Kiyomi Tsuji; Toyonobu Maeda; Tetsuya Kawane; Ayako Matsunuma; Noboru Horiuchi
- Publisher
- American Society for Bone and Mineral Research
- Year
- 2010
- Tongue
- English
- Weight
- 383 KB
- Volume
- 25
- Category
- Article
- ISSN
- 0884-0431
- DOI
- 10.1002/jbmr.65
No coin nor oath required. For personal study only.
✦ Synopsis
Abstract
Leptin is the LEP (ob) gene product secreted by adipocytes. We previously reported that leptin decreases renal expression of the 25‐hydroxyvitamin D~3~ 1α‐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 1α‐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 1α,25‐dihydroxyvitamin D~3~ [1,25(OH)~2~D~3~]. Administration of FGF‐23 (5 µg i.p. at 12‐hour intervals for 2 days) to ob/ob mice suppressed renal 1α‐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 1α‐hydroxylase and sodium‐phosphate cotransporters (NaP~i~‐IIa and NaP~i~‐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 1α‐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. © 2010 American Society for Bone and Mineral Research